Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Scope

The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access, devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. It presents structured review articles ("cards") on genes, leukaemias, solid tumours, cancer-prone diseases, more traditional review articles on these and also on surrounding topics ("deep insights"), case reports in hematology, and educational items in the various related topics for students in Medicine and in Sciences.

Editorial correspondance

Jean-Loup Huret Genetics, Department of Medical Information, University Hospital F-86021 Poitiers, France tel +33 5 49 44 45 46 or +33 5 49 45 47 67 [email protected] or [email protected]

Staff Mohammad Ahmad, Mélanie Arsaban, Houa Delabrousse, Marie-Christine Jacquemot-Perbal, Maureen Labarussias, Vanessa Le Berre, Anne Malo, Catherine Morel-Pair, Laurent Rassinoux, Sylvie Yau Chun Wan - Senon, Alain Zasadzinski. Philippe Dessen is the Database Director, and Alain Bernheim the Chairman of the on-line version (Gustave Roussy Institute – Villejuif – France).

The Atlas of Genetics and Cytogenetics in Oncology and Haematology (ISSN 1768-3262) is published 12 times a year by ARMGHM, a non profit organisation, and by the INstitute for Scientific and Technical Information of the French National Center for Scientific Research (INIST-CNRS) since 2008.

The Atlas is hosted by INIST-CNRS (http://www.inist.fr)

http://AtlasGeneticsOncology.org

© ATLAS - ISSN 1768-3262

The PDF version of the Atlas of Genetics and Cytogenetics in Oncology and Haematology is a reissue of the original articles published in collaboration with the Institute for Scientific and Technical Information (INstitut de l’Information Scientifique et Technique - INIST) of the French National Center for Scientific Research (CNRS) on its electronic publishing platform I-Revues. Online and PDF versions of the Atlas of Genetics and Cytogenetics in Oncology and Haematology are hosted by INIST-CNRS. Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Editor

Jean-Loup Huret (Poitiers, France) Editorial Board

Sreeparna Banerjee (Ankara, Turkey) Solid Tumours Section Alessandro Beghini (Milan, Italy) Genes Section Anne von Bergh (Rotterdam, The Netherlands) Genes / Leukaemia Sections Judith Bovée (Leiden, The Netherlands) Solid Tumours Section Vasantha Brito-Babapulle (London, UK) Leukaemia Section Charles Buys (Groningen, The Netherlands) Deep Insights Section Anne Marie Capodano (Marseille, France) Solid Tumours Section Fei Chen (Morgantown, West Virginia) Genes / Deep Insights Sections Antonio Cuneo (Ferrara, Italy) Leukaemia Section Paola Dal Cin (Boston, Massachussetts) Genes / Solid Tumours Section Louis Dallaire (Montreal, Canada) Education Section Brigitte Debuire (Villejuif, France) Deep Insights Section François Desangles (Paris, France) Leukaemia / Solid Tumours Sections Enric Domingo-Villanueva (London, UK) Solid Tumours Section Ayse Erson (Ankara, Turkey) Solid Tumours Section Richard Gatti (Los Angeles, California) Cancer-Prone Diseases / Deep Insights Sections Ad Geurts van Kessel (Nijmegen, The Netherlands) Cancer-Prone Diseases Section Oskar Haas (Vienna, Austria) Genes / Leukaemia Sections Anne Hagemeijer (Leuven, Belgium) Deep Insights Section Nyla Heerema (Colombus, Ohio) Leukaemia Section Jim Heighway (Liverpool, UK) Genes / Deep Insights Sections Sakari Knuutila (Helsinki, Finland) Deep Insights Section Lidia Larizza (Milano, Italy) Solid Tumours Section Lisa Lee-Jones (Newcastle, UK) Solid Tumours Section Edmond Ma (Hong Kong, China) Leukaemia Section Roderick McLeod (Braunschweig, Germany) Deep Insights / Education Sections Cristina Mecucci (Perugia, Italy) Genes / Leukaemia Sections Yasmin Mehraein (Homburg, Germany) Cancer-Prone Diseases Section Fredrik Mertens (Lund, Sweden) Solid Tumours Section Konstantin Miller (Hannover, Germany) Education Section Felix Mitelman (Lund, Sweden) Deep Insights Section Hossain Mossafa (Cergy Pontoise, France) Leukaemia Section Stefan Nagel (Braunschweig, Germany) Deep Insights / Education Sections Florence Pedeutour (Nice, France) Genes / Solid Tumours Sections Elizabeth Petty (Ann Harbor, Michigan) Deep Insights Section Susana Raimondi (Memphis, Tennesse) Genes / Leukaemia Section Mariano Rocchi (Bari, Italy) Genes Section Alain Sarasin (Villejuif, France) Cancer-Prone Diseases Section Albert Schinzel (Schwerzenbach, Switzerland) Education Section Clelia Storlazzi (Bari, Italy) Genes Section Sabine Strehl (Vienna, Austria) Genes / Leukaemia Sections Nancy Uhrhammer (Clermont Ferrand, France) Genes / Cancer-Prone Diseases Sections Dan Van Dyke (Rochester, Minnesota) Education Section Roberta Vanni (Montserrato, Italy) Solid Tumours Section Franck Viguié (Paris, France) Leukaemia Section José Luis Vizmanos (Pamplona, Spain) Leukaemia Section Thomas Wan (Hong Kong, China) Genes / Leukaemia Sections

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Volume 14, Number 11, November 2010

Table of contents

Gene Section

MAPK12 (mitogen-activated protein kinase 12) 1007 Maria Isabel Cerezo-Guisado, Ana Cuenda MAPK3 (mitogen-activated protein kinase 3) 1011 Seda Tuncay, Sreeparna Banerjee MRC1 (mannose receptor, C type 1) 1016 Silvia Rasi, Alessio Bruscaggin, Gianluca Gaidano MUC13 (mucin 13, cell surface associated) 1020 Diane Maher, Brij Gupta, Mara Ebeling, Satoshi Nagata, Meena Jaggi, Subhash C Chauhan OLFM4 (olfactomedin 4) 1024 Wenli Liu, Griffin P Rodgers PDE11A (phosphodiesterase 11A) 1027 Rossella Libé, Jérôme Bertherat PTPN7 (protein tyrosine phosphatase, non-receptor type 7) 1032 Marie Fridberg, Helena Tassidis, Anette Gjörloff Wingren RAP1GAP (RAP1 GTPase activating protein) 1034 Zixing Chen, Xuejun Shao RGS2 (regulator of G-protein signaling 2, 24kDa) 1036 Chau H Nguyen SOX11 (SRY (sex determining region Y)-box 11) 1039 Xiao Wang, Birgitta Sander THY1 (Thy-1 cell surface antigen) 1042 John E Bradley, James S Hagood TYRO3 (TYRO3 protein tyrosine kinase) 1050 Kristen M Jacobsen, Rachel MA Linger, Douglas K Graham YAP1 (Yes-associated protein 1, 65kDa) 1054 Silvia Di Agostino, Sabrina Strano, Giovanni Blandino ALK (anaplastic lymphoma receptor tyrosine kinase) 1059 Michèle Allouche AXL (AXL receptor tyrosine kinase) 1065 Justine Migdall, Douglas K Graham BAK1 (BCL2-antagonist/killer 1) 1070 Grant Dewson, Ruth Kluck

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) Atlast(11;14)(q13;q32) of Genetics in multiple myeloma and Cytogenetics Huret JL, Laï JL in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Leukaemia Section t(3;12)(q27;p13) 1075 Jean-Loup Huret t(3;3)(q25;q27) 1077 Jean-Loup Huret dic(7;9)(p11-12;p12-13) PAX5/LOC392027 1078 Jean-Loup Huret dic(9;12)(p13;p12) PAX5/SLCO1B3 1080 Jean-Loup Huret t(2;14)(p13-16;q32) 1082 Adriana Zamecnikova

Solid Tumour Section t(6;22)(p21;q12) in hidradenoma of the skin 1085 Jean-Loup Huret t(6;22)(p21;q12) in mucoepidermoid carcinoma of the salivary glands 1086 Jean-Loup Huret t(6;22)(p21;q12) in undifferentiated sarcoma 1087 Jean-Loup Huret

Deep Insight Section

Ubiquitin, ubiquitination and the ubiquitin-proteasome system in cancer 1088 Ioannis A Voutsadakis

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

MAPK12 (mitogen -activated protein kinase 12) Maria Isabel Cerezo-Guisado, Ana Cuenda Centro Nacional de Biotecnologia-CSIC, Department of Immunology and Oncology, Madrid, Spain (MICG, AC)

Published in Atlas Database: January 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/MAPK12ID41290ch22q13.html DOI: 10.4267/2042/44881 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Protein Other names: EC 2.7.11.24; ERK3; ERK5; ERK-6; Note ERK6; p38gamma; PRKM12; SAPK-3; SAPK3 p38gamma (MAPK12), also known as Stress-activated HGNC (Hugo): MAPK12 protein kinase 3 (SAPK3) belongs to the p38 subfamily of MAPKs. The p38MAPK subfamily is composed by Location: 22q13.33 four members encoded by different genes, which share DNA/RNA high sequence homologies and are designated as p38alpha (MAPK14, or SAPK2a), p38beta (MAPK11 Description or SAPK2b), p38gamma (MAPK12 or SAPK3) and p38delta (MAPK13 or SAPK4). They are about 60% The MAPK12 entire gene spans 8.46 kb on the long identical in their amino acid sequence but differ in their arm of chromosome 22. It contains 12 exons. expresion patterns, substrate specificities and Transcription sensitivities to chemical inhibitors (Iñesta-Vaquera et The MAPK12 gene encodes a 367 amino-acid protein al., 2008). All p38 MAPKs are strongly activated in of about 42 kDa. MAPK12 mRNA is 1457 bp. No vivo by environmental stresses and inflammatory splice variants have been reported. cytokines, and less by serum and growth factors.

Pseudogene No human or mouse pseudogene known.

MAPK12 genomic context (Chromosome 22, location 22q13.33).

Genomic organization of MAPK12 gene on chromosome 22q13.33. The boxes indicate coding regions (exon 1-12) of the gene.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1007 MAPK12 (mitogen-activated protein kinase 12) Cerezo-Guisado MI, Cuenda A

Schematic representation of the p38gamma (MAPK12) protein structure. Kinase Domain, catalytic kinase domain; TGY, sequence motif containing the regulatory phosphorylation residues. p38gamma (MAPK12) possesses at the C-terminal a sequence that binds to PDZ domain of several proteins.

Description Since p38gamma expression is very high in skeletal muscle in comparison to other tissues, it is not p38gamma (MAPK12) is a Serine/Threonine protein surprising that it may play a fundamental role in kinase of 367 amino acids with a predicted molecular skeletal muscle differentiation. Thus, p38gamma mass of 42 kDa. It possesses the conserved amino acid protein level increases when myoblast differentiate into domains (I-XI) characteristic of protein kinases myotubes endogenous (Tortorella et al., 2003; Cuenda (Mertens et al., 1996). 183 185 and Cohen, 1999). Moreover, it has been shown that The Thr and Tyr residues in subdomain VIII are in over-expression of p38gamma in skeletal muscle cells an equivalent position to the TXY sequence in known leads to differentiation from myoblast to myotubes, and MAPKs. The activation of p38gamma (MAPK12) that a dominant-negative mutant of p38gamma occurs via dual phosphorylation of its TGY motif, in prevented this differentiation process (Lechner et al., the activation loop, by MKK3 and MKK6 (Cuenda et 1996). Recently, Gillespie et al. (2009) reported that al., 1997; Goedert et al., 1997). p38gamma phosphorylates the transciption factor Expression MyoD, which results in a decrease in its transcriptional p38gamma (MAPK12) mRNA is widely expressed activity. p38gamma plays a cardinal role in blocking with high levels of expression in skeletal muscle. the premature differentiation of skeletal muscle stem cells, the satellite cells. Additionally, p38gamma Localisation regulates mitochondrial biogenesis and angiogenesis, p38gamma (MAPK12) localizes to the cytoplasm and and it is required for endurance exercise-induced nucleus of cultured cells. skeletal muscle adaptation (Pogozelski et al., 2009). Function Most of the work published on cellular transformation regulation by p38MAPK pathway has been focused on p38gamma (MAPK12) regulates many cellular studying the role of the isoforms p38alpha and beta, but functions by phosphorylating several proteins. A there are a number of recent publications providing feature that makes p38gamma unique among the p38 evidences for the role of p38gamma (MAPK12) in MAPKs is its short C-terminal sequence -KETXL, an cellular transformation. Overexpression of the active amino acid sequence ideal for binding PDZ domains in form of Rit, a Ras family member, in NIH3T3 cells, proteins. SAPK3/p38gamma binds to a variety of these causes transformation and stimulates p38gamma, but proteins, such as alpha1-syntrophin, SAP90/PSD95 and not other isoforms of p38MAPKs, ERK1, ERK2 or SAP97/hDlg, and under stress conditions is able to ERK5 (Sakabe et al., 2002). phosphorylate them and modulate their activity In rat intestinal epithelial cells, Ras oncogene was (Hasegawa et al., 1999; Sabio et al., 2004; Sabio et al., found to increase p38gamma RNA and protein 2005). These proteins are scaffold proteins usually expression with concurrently stimulated p38alpha targeted to the plasma membrane cytoskeleton at phosphorylation and decreased p38gamma specialised sites such as the neuromuscular junction phosphorylation (Tang et al., 2005; Loesch and Chen, and gap junctions through protein-protein interactions. 2008). These results indicate that increased p38gamma In the case of SAP97/hDlg its phosphorylation by gene expression is required for Ras oncogene activity SAPK3/p38gamma provided a mechanism of but the mechanism by which p38gamma may promote dissociating SAP97/hDlg from the cytoskeleton (Sabio Ras transformation is not clear. Recent studies show et al., 2005). p38gamma can also phosphorylate typical that phospho-p38alpha can down-regulate p38gamma p38 MAPK substrates such as the transcription factors protein expression through c-jun dependent ATF2, Elk-1 or SAP1. However, it cannot ubiquitin/proteasome pathways (Qi et al., 2007; Loesch phosphorylate MAPKAPK2 or MAPKAPK3, which and Chen, 2008). On the other hand other recent study are good substrates for other p38 MAPK isoforms shows that whereas p38gamma mediates Ras-induced (Cuenda et al., 1997; Goedert et al., 1997). Another senescence at least partly by stimulating the p38gamma substrates that do not require PDZ domain transcriptional activity of p53 through direct binding interactions are the mitochondrial protein Sab phosphorylation, p38alpha appears to regulate (Court et al., 2004) and the microtubule-associated senescence in a p53-independent, p16 INK4A dependent protein Tau (Feijoo et al., 2005). manner (Kwong et al., 2009).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1008 MAPK12 (mitogen-activated protein kinase 12) Cerezo-Guisado MI, Cuenda A

Homology cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38). EMBO J. p38gamma (MAPK12) shows 70% identity with 1997 Jan 15;16(2):295-305 p38delta (MAPK13), 60% sequence identity with Goedert M, Cuenda A, Craxton M, Jakes R, Cohen P. p38alpha (MAPK14) and p38beta (MAPK11), 45% Activation of the novel stress-activated protein kinase SAPK4 identity with HOG1 from S. cerevisiae, 47% identity by cytokines and cellular stresses is mediated by SKK3 with human SAP kinase-1 (JNK1) and 42% identity (MKK6); comparison of its substrate specificity with that of other SAP kinases. EMBO J. 1997 Jun 16;16(12):3563-71 with p42 MAP kinase (ERK2). Goedert M, Hasegawa J, Craxton M, Leversha MA, Clegg S. Assignment of the human stress-activated protein kinase-3 Mutations gene (SAPK3) to chromosome 22q13.3 by fluorescence in situ Note hybridization. Genomics. 1997 May 1;41(3):501-2 No mutation reported yet. Cuenda A, Cohen P. Stress-activated protein kinase-2/p38 and a rapamycin-sensitive pathway are required for C2C12 Implicated in myogenesis. J Biol Chem. 1999 Feb 12;274(7):4341-6 Hasegawa M, Cuenda A, Spillantini MG, Thomas GM, Buée- Breast cancer Scherrer V, Cohen P, Goedert M. Stress-activated protein kinase-3 interacts with the PDZ domain of alpha1-syntrophin. A Oncogenesis mechanism for specific substrate recognition. J Biol Chem. In human MCF-7 breast cancer cells, MKK6 1999 Apr 30;274(18):12626-31 expression inhibits DNA synthesis. This inhibitory Pillaire MJ, Nebreda AR, Darbon JM. Cisplatin and UV effect is enhanced by the co-expressed p38gamma radiation induce activation of the stress-activated protein (Pramanik et al., 2003; Loesch and Chen, 2008). Ras kinase p38gamma in human melanoma cells. Biochem Biophys Res Commun. 2000 Nov 30;278(3):724-8 also increases p38gamma protein expression in human breast cancer (Qi et al., 2006). Crnogorac-Jurcevic T, Efthimiou E, Capelli P, Blaveri E, Baron A, Terris B, Jones M, Tyson K, Bassi C, Scarpa A, Lemoine Skin cancer NR. Gene expression profiles of pancreatic cancer and stromal desmoplasia. Oncogene. 2001 Nov 1;20(50):7437-46 Oncogenesis p38gamma isoform is specifically implicated in Sakabe K, Teramoto H, Zohar M, Behbahani B, Miyazaki H, Chikumi H, Gutkind JS. Potent transforming activity of the melanoma death induced by UV radiation, cisplatin small GTP-binding protein Rit in NIH 3T3 cells: evidence for a treatment (Pillaire et al., 2000). Moreover, melanoma role of a p38gamma-dependent signaling pathway. FEBS Lett. cells overexpressing PDGF-Ralpha show a marked 2002 Jan 30;511(1-3):15-20 increase of p38gamma (Faraone et al., 2009). Abdollahi T, Robertson NM, Abdollahi A, Litwack G. Identification of interleukin 8 as an inhibitor of tumor necrosis Hepatoma factor-related apoptosis-inducing ligand-induced apoptosis in Oncogenesis the ovarian carcinoma cell line OVCAR3. Cancer Res. 2003 p38gamma expression is increased in hepatoma cell Aug 1;63(15):4521-6 line HLE (Liu et al., 2003). Liu LX, Liu ZH, Jiang HC, Zhang WH, Qi SY, Hu J, Wang XQ, Wu M. Gene expression profiles of hepatoma cell line HLE. Ovarian cancer World J Gastroenterol. 2003 Apr;9(4):683-7 Oncogenesis Pramanik R, Qi X, Borowicz S, Choubey D, Schultz RM, Han J, p38gamma expression is regulated by the TNF-related Chen G. p38 isoforms have opposite effects on AP-1- apoptosis inducing ligand (TRIAL) and IL-8 in cellular dependent transcription through regulation of c-Jun. The determinant roles of the isoforms in the p38 MAPK signal lines from ovarian cancer (Abdollahi et al., 2003). specificity. J Biol Chem. 2003 Feb 14;278(7):4831-9 Pancreatic cancer Tortorella LL, Lin CB, Pilch PF. ERK6 is expressed in a Oncogenesis developmentally regulated manner in rodent skeletal muscle. Biochem Biophys Res Commun. 2003 Jun 20;306(1):163-8 The levels of p38gamma seem to be decreased in pancreatic cancer cells (Crnogorac-Jurcevic et al., Court NW, Kuo I, Quigley O, Bogoyevitch MA. Phosphorylation of the mitochondrial protein Sab by stress-activated protein 2001). kinase 3. Biochem Biophys Res Commun. 2004 Jun 18;319(1):130-7 References Sabio G, Reuver S, Feijoo C, Hasegawa M, Thomas GM, Lechner C, Zahalka MA, Giot JF, Møller NP, Ullrich A. ERK6, a Centeno F, Kuhlendahl S, Leal-Ortiz S, Goedert M, Garner C, mitogen-activated protein kinase involved in C2C12 myoblast Cuenda A. Stress- and mitogen-induced phosphorylation of the differentiation. Proc Natl Acad Sci U S A. 1996 Apr synapse-associated protein SAP90/PSD-95 by activation of 30;93(9):4355-9 SAPK3/p38gamma and ERK1/ERK2. Biochem J. 2004 May 15;380(Pt 1):19-30 Mertens S, Craxton M, Goedert M. SAP kinase-3, a new member of the family of mammalian stress-activated protein Feijoo C, Campbell DG, Jakes R, Goedert M, Cuenda A. kinases. FEBS Lett. 1996 Apr 1;383(3):273-6 Evidence that phosphorylation of the microtubule-associated protein Tau by SAPK4/p38delta at Thr50 promotes microtubule Cuenda A, Cohen P, Buée-Scherrer V, Goedert M. Activation assembly. J Cell Sci. 2005 Jan 15;118(Pt 2):397-408 of stress-activated protein kinase-3 (SAPK3) by cytokines and

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1009

MAPK12 (mitogen-activated protein kinase 12) Cerezo-Guisado MI, Cuenda A

Sabio G, Arthur JS, Kuma Y, Peggie M, Carr J, Murray-Tait V, Loesch M, Chen G. The p38 MAPK stress pathway as a tumor Centeno F, Goedert M, Morrice NA, Cuenda A. p38gamma suppressor or more? Front Biosci. 2008 May 1;13:3581-93 regulates the localisation of SAP97 in the cytoskeleton by modulating its interaction with GKAP. EMBO J. 2005 Mar Faraone D, Aguzzi MS, Toietta G, Facchiano AM, Facchiano 23;24(6):1134-45 F, Magenta A, Martelli F, Truffa S, Cesareo E, Ribatti D, Capogrossi MC, Facchiano A. Platelet-derived growth factor- Tang J, Qi X, Mercola D, Han J, Chen G. Essential role of receptor alpha strongly inhibits melanoma growth in vitro and p38gamma in K-Ras transformation independent of in vivo. Neoplasia. 2009 Aug;11(8):732-42 phosphorylation. J Biol Chem. 2005 Jun 24;280(25):23910-7 Kwong J, Hong L, Liao R, Deng Q, Han J, Sun P. p38alpha Qi X, Tang J, Loesch M, Pohl N, Alkan S, Chen G. p38gamma and p38gamma mediate oncogenic ras-induced senescence mitogen-activated protein kinase integrates signaling crosstalk through differential mechanisms. J Biol Chem. 2009 Apr between Ras and estrogen receptor to increase breast cancer 24;284(17):11237-46 invasion. Cancer Res. 2006 Aug 1;66(15):7540-7 Pogozelski AR, Geng T, Li P, Yin X, Lira VA, Zhang M, Chi JT, Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, Yan Z. p38gamma mitogen-activated protein kinase is a key function and role in human diseases. Biochim Biophys Acta. regulator in skeletal muscle metabolic adaptation in mice. 2007 Aug;1773(8):1358-75 PLoS One. 2009 Nov 20;4(11):e7934 Qi X, Pohl NM, Loesch M, Hou S, Li R, Qin JZ, Cuenda A, Wagner EF, Nebreda AR. Signal integration by JNK and p38 Chen G. p38alpha antagonizes p38gamma activity through c- MAPK pathways in cancer development. Nat Rev Cancer. Jun-dependent ubiquitin-proteasome pathways in regulating 2009 Aug;9(8):537-49 Ras transformation and stress response. J Biol Chem. 2007 Oct 26;282(43):31398-408 This article should be referenced as such: Inesta-Vaquera FA, Sabio G, Kuma Y, Cuenda A.. Alternative Cerezo-Guisado MI, Cuenda A. MAPK12 (mitogen-activated p38MAPK pathways. Stress activated protein kinases. Topics protein kinase 12). Atlas Genet Cytogenet Oncol Haematol. in Current Genetics. Springer-Verlag Berlin Heidelberg. 2008; 2010; 14(11):1007-1010. 20:17-26.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1010 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

MAPK3 (mitogen -activated protein kinase 3) Seda Tuncay, Sreeparna Banerjee Department of Biological Sciences, Middle East Technical University, Ankara 06531, Turkey (ST, SB)

Published in Atlas Database: January 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/MAPK3ID425ch16p11.html DOI: 10.4267/2042/44882 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity DNA/RNA Other names: EC 2.7.11.24; ERK1; ERK-1; ERT2; Description HS44KDAP; HUMKER1A; MAPK 1; MGC20180; According to Entrez Gene MAPK3 gene maps to PRKM3; P44ERK1; P44MAPK; p44-ERK1; p44- NC_000016.9 and spans a region of 9.21 kb. According MAPK to Spidey mRNA-to-genomic alignment program HGNC (Hugo): MAPK3 ERK1 (MAPK3) variant 1 (the most common variant) Location: 16p11.2 has 8 exons, the sizes being 170, 183, 190, 117, 115, Local order: According to NCBI Map Viewer, genes 132, 110, 123 bps (mRNA coordinates). flanking ERK1 (MAPK3) in centromere to telomere Transcription direction on 16p11.2 are: The promoter analysis of the human MAPK3 has centromere shown that the elements responsible for basal - Hypothetical LOC100271831, Location: 16p11.2 transcriptional activity are located within 200 bp - YPEL3, yippee-like 3 (Drosophila), Location: upstream of the initiation codon in the 5' UTR and rich 16p11.2 in G/C content (80.5%). The sequence has four SP1 sites and an E box as the most relevant motifs. Site- - GDPD3, glycerophosphodiester phosphodiesterase directed mutagenesis, EMSA, and DNase I footprinting domain containing 3, Location: 16p11.2 experiments proved that all these elements are required - MAPK3, 16p11.2 to achieve a significant level of transcription. It has also - CORO1A, coronin, actin binding protein 1A, been reported that the promoter activity is strongly Location: 16p11.2 repressed when the cells are grown under growth arrest conditions, such as confluence or serum withdrawal. - BOLA2B, bolA homolog 2B (E. coli), Location: 16p11.2 Pseudogene - GIYD1, GIY-YIG domain containing 1, Location: No pseudogenes have been reported for MAPK3. 16p11.2 telomere.

Diagram of the ERK1 (MAPK3) gene (isoform 1). Exons are represented by open boxes (in scale). Exons 1 to 8 are from the 5' to 3' direction.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1011 MAPK3 (mitogen-activated protein kinase 3) Tuncay S, Banerjee S

cell cycle control as cyclin D1 gene is essential for G1 Protein to S-phase progression. Note In response to Angiotensin II, ERK1/2 (MAPK3/1) ERK1 (MAPK3) is identified by the specific TEY regulates cell proliferation by either one of two (Thr-Glu-Tyr) sequence in its activation loop. ERK1 signaling pathways which are heterotrimeric G (MAPK3) is activated by dual phosphorylation of protein/PKC zeta-dependent signaling and tyrosine (Tyr204) and threonine (Thr202) residues SRC/YES1/FYN signaling. ERK1/2 (MAPK3/1) which is required for complete activation of the protein. phosphorylates specific transcription factors ELK-1 Activated ERK1 (MAPK3) migrates into the nucleus (leading to c-FOS transcriptional activity) following its and phosphorylates transcription factors. translocation into the nucleus due to heterotrimeric G protein/PKC zeta-dependent signaling. Due to its Description phosphorylation in the cytoplasm by SRC/YES1/FYN ERK1 (MAPK3) is a 43 kDa protein consisting of 379 signaling, ERK1/2 (MAPK3/1) complexes with RSK2 amino acids. ERK1 (MAPK3) protein is 85% identical (RPS6KA), which in turn become activated and to ERK2 (MAPK1) (another MAP kinase family translocates into the nucleus to modulate c-FOS member) and the two proteins have even higher levels transcription and c-FOS protein activity. of similarity in their substrate binding regions. ERK1 The ERK pathway has been found to be responsible for (MAPK3) and ERK2 (MAPK1) both possess 2 DXXD the phosphorylation of BCL2 that contributes to cell docking sites that provide interaction sites with a survival, the suppression of the apoptotic effect of Kinase Interaction Motif (KIM), which can be found on BAD, the up-regulation of the antiapoptotic protein activators (MAPKK), inhibitors (PTP-SL (PTPRR) and MCL-1. Moreover, it has been also shown that ERK1/2 dual specificity phosphatases) and substrates (ELK-1). (MAPK3/1) is one of the regulators of TP53 protein Expression accumulation and activation during the DNA damage response. Ubiquitously expressed with varying levels in different ERK1/2 (MAPK3/1) induces expression of PAI-1 tissues. (plasminogen activator type-1 inhibitor) which is Localisation closely associated with dynamic changes in cellular Subcellular location of ERK1 (MAPK3) protein is the morphology and shape-altering physiologic processes. cytoplasm, and the nucleus. Upon activation by dual ERK1/2 (MAPK3/1) has been shown to regulate phosphorylation on its Tyr and Thr residues by PPARg1 following EGF stimulation. upstream kinases, ERK1 (MAPK3) is translocated into CIITA is a critical transcription factor that initiates the the nucleus from cytoplasm where it phosphorylates its expression of MHC class II genes and the subsequent nuclear targets. induction of the immune response. Studies have indicated that ERK1/2 (MAPK3/1) negatively regulates Function CIITA by blocking expression of the CIITA gene Being one of the most studied cytoplasmic signaling and/or by phosphorylating CIITA at residues including pathways, the ERK pathway is activated via GTP- serine 288, resulting in the loss of CIITA loading of RAS at the plasma membrane and sequential transactivation potential by enabling it to interact with activation of a series of protein kinases. Activated RAS CRM1 (XPO1) which causes export of CIITA protein recruits the RAF family of kinases such as RAF1 to the from the nucleus. plasma membrane which in turn acts as a MAPKKK Homology and activates MAP kinase/ERK kinase 1 and 2 (MEK1 (MAP2K1) and MEK2 (MAP2K2)) by serine - P. troglodytes, MAPK3, mitogen-activated protein phosphorylation. MEK1/2 catalyze the phosphorylation kinase 3 of ERK1 (MAPK3) and ERK2 (MAPK1). Activated - C. lupus familiaris, MAPK3, mitogen-activated ERK1/2 (MAPK3/1) phosphorylates many different protein kinase 3 substrates involved in various cellular responses from - B. taurus, MAPK3, mitogen-activated protein kinase cytoskeletal changes to gene transcription. ERK1 3 (MAPK3) was initially identified as an insulin- - M. musculus, MAPK3, mitogen-activated protein stimulated protein kinase which has an activity towards kinase 3 microtubule-associated protein-2. Today, it is well - R. norvegicus, MAPK3, mitogen activated protein known that ERK1/2 (MAPK3/1) is especially involved kinase 3 in the control of cell proliferation, cell differentiation - D. rerio, MAPK3, mitogen-activated protein kinase 3 and cell survival. - S. pombe, spk1, MAP kinase Spk1 It has been shown that activation of ERK1/2 - S. cerevisiae, FUS3, Fus3p (MAPK3/1) is crucial for cyclin D1 induction, - K. lactis, KLLA0E10527g, hypothetical protein providing a molecular link between ERK signaling and - E. gossypii, AGOS_AFR019W, AFR019Wp - M. grisea, MGG_09565, mitogen-activated protein kinase

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1012 MAPK3 (mitogen-activated protein kinase 3) Tuncay S, Banerjee S

- N. crassa, NCU02393.1, hypothetical protein recent study it was also shown that phosphorylated ((AF348490) MAP kinase [Neurospora crassa ERK1/2 levels were significantly high in breast cancer OR74A]) cell lines with high metastatic potential compared to - A. thaliana, ATMPK13, ATMPK13; MAP kinase/ non metastatic breast cancer cell lines. beta-catenin, kinase cyclin D1, and survivin have been shown to be downstream effectors of pERK1/2, while G1/0 Implicated in proteins, phospholipase C, and protein kinase C serve as upstream activators of pERK1/2 in those cells. Various diseases Colorectal cancer Disease Note Although both ERK1 (MAPK3) and ERK2 (MAPK1) have very similar functions, ERK2 -/- mice are Several lines of evidence indicate that overexpression embryonic lethal while ERK1 -/- mice are viable and and activation of ERK-MAPK pathway play an show normal size and fertility. Thus each isoform may important part in progression of colorectal cancer. The have a unique role, or there may be threshold of total constitutive activation of the RAF/MEK/ERK has been ERK activity for normal viability. shown to be necessary for RAS-induced transformation Although viable, ERK1 -/- mice have reduced ability for of HT1080 human colon carcinoma cell line. thymocyte maturation and proliferation when T cell Non-small-cell lung cancer receptors are activated. These mice also show an Note enhancement of long term memory that was shown to It has been found that nuclear and cytoplasmic ERK1/2 be dependent on the striatum. Additionally, the loss of activation positively correlates with the stage and ERK1 results in a loss of adipocity, with the mice lymph node metastases in lung cancer. Therefore having fewer adipocytes than the wild type ERK1/2 is associated with advanced and aggressive counterparts. NSCLC tumors. Oncogenesis Bladder cancer Elevated and constitutive activation of ERK1/2 has been detected in a large number of human tumors; Note including colon, kidney, gastric, prostate, breast, non- ERK1/2 has been shown to mediate TNF-alpha- small cell lung cancer, bladder, chondrosarcomas and induced MMP-9 expression by regulating the binding glioblastoma multiforme which show especially high activity of the transcription factors, NF-kB, AP-1 and frequencies of kinase activation. The reason for SP-1, in urinary bladder cancer HT1376 cells. constitutive activation of the ERK pathway in the Glioblastoma multiforme majority of tumor cells seems to be due to a disorder in RAF, RAS, EGFR or other upstream signaling Note molecules. In addition, several studies have shown that The activation of ERK1/2 has been implicated in the ERK-MAPK pathway can directly promote cell different pathobiological processes of GBM which is motility and the migration of tumor cells. the most common and malignant brain tumor. The ERK1/2 activation has been linked to EGFR Gastric cancer overexpression and hypermethylation of 9p21 locus. Note Prostate cancer Epidermal growth factor (EGF) and urokinase plasminogen activator receptor (uPAR (PLAUR)) are Note elevated in human gastric cancers and it has been In prostate tumors, the level of activated MAP kinase shown that uPAR expression is induced by EGF via were found to be increased with increasing Gleason ERK1/2 as well as AP-1 (JUN) and NF-kB signaling score and tumor stage while nonneoplastic prostate pathways which in turn, stimulates cell invasiveness in tissue showed little or no staining with activated MAP human gastric cancer AGS cells. kinase antiserum. Breast cancer Kidney cancer Note Note In breast cancer patients, ERK1/2 has been found to be In a high number of human renal cancers ERK1/2 has heavily phosphorylated on tyrosyl residues and have a been found to be constitutively activated. 5-10 fold elevated activity compared to benign Moreover, ERK1/2 activation was observed more conditions (fibroadenoma and fibrocystic disease). frequently with high-grade renal cancer cells (RCC) Localization studies showed that hyperexpressed compared to low-grade RCC. ERK1/2 mRNA localized to malignant epithelial cells. Chondrosarcomas Furthermore, hyperexpression of ERK1/2 mRNA (5-20 Note fold) was also observed in metastatic cells within the Activation of the JNK (MAPK8) and ERK signal lymph nodes of breast cancer patients. In addition, in a

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1013 MAPK3 (mitogen-activated protein kinase 3) Tuncay S, Banerjee S

transduction pathways have been shown to increase the Mazzucchelli C, Vantaggiato C, Ciamei A, Fasano S, Pakhotin activity and expression levels of their downstream P, Krezel W, Welzl H, Wolfer DP, Pagès G, Valverde O, Marowsky A, Porrazzo A, Orban PC, Maldonado R, effectors, transcription factors AP-1 and RUNX2. Ehrengruber MU, Cestari V, Lipp HP, Chapman PF, These transcription factors, in turn, stimulate genes that Pouysségur J, Brambilla R. Knockout of ERK1 MAP kinase are involved in chondroblast cell biology, ultimately enhances synaptic plasticity in the striatum and facilitates inducing chondroblastic tumorigenesis. striatal-mediated learning and memory. Neuron. 2002 May 30;34(5):807-20 Cardiac hypertrophy Samarakoon R, Higgins PJ. MEK/ERK pathway mediates cell- Note shape-dependent plasminogen activator inhibitor type 1 gene expression upon drug-induced disruption of the microfilament It has been implicated that ERK1/2 mediate cardiac and microtubule networks. J Cell Sci. 2002 Aug 1;115(Pt hypertrophy, which is a major risk factor for the 15):3093-103 development of arrhythmias, heart failure and sudden Tárrega C, Blanco-Aparicio C, Muñoz JJ, Pulido R. Two death. clusters of residues at the docking groove of mitogen-activated protein kinases differentially mediate their functional interaction References with the tyrosine phosphatases PTP-SL and STEP. J Biol Chem. 2002 Jan 25;277(4):2629-36 Boulton TG, Gregory JS, Cobb MH. Purification and properties of extracellular signal-regulated kinase 1, an insulin-stimulated Saba-El-Leil MK, Vella FD, Vernay B, Voisin L, Chen L, microtubule-associated protein 2 kinase. Biochemistry. 1991 Labrecque N, Ang SL, Meloche S. An essential function of the Jan 8;30(1):278-86 mitogen-activated protein kinase Erk2 in mouse trophoblast development. EMBO Rep. 2003 Oct;4(10):964-8 Oka H, Chatani Y, Hoshino R, Ogawa O, Kakehi Y, Terachi T, Okada Y, Kawaichi M, Kohno M, Yoshida O. Constitutive Hernández R, García F, Encío I, De Miguel C. Promoter activation of mitogen-activated protein (MAP) kinases in analysis of the human p44 mitogen-activated protein kinase human renal cell carcinoma. Cancer Res. 1995 Sep gene (MAPK3): transcriptional repression under 15;55(18):4182-7 nonproliferating conditions. Genomics. 2004 Jul;84(1):222-6 Seger R, Krebs EG. The MAPK signaling cascade. FASEB J. Vicent S, López-Picazo JM, Toledo G, Lozano MD, Torre W, 1995 Jun;9(9):726-35 Garcia-Corchón C, Quero C, Soria JC, Martín-Algarra S, Manzano RG, Montuenga LM. ERK1/2 is activated in non- Lavoie JN, L'Allemain G, Brunet A, Müller R, Pouysségur J. small-cell lung cancer and associated with advanced tumours. Cyclin D1 expression is regulated positively by the Br J Cancer. 2004 Mar 8;90(5):1047-52 p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J Biol Chem. 1996 Aug 23;271(34):20608-16 Bost F, Aouadi M, Caron L, Even P, Belmonte N, Prot M, Dani C, Hofman P, Pagès G, Pouysségur J, Le Marchand-Brustel Y, Camp HS, Tafuri SR. Regulation of peroxisome proliferator- Binétruy B. The extracellular signal-regulated kinase isoform activated receptor gamma activity by mitogen-activated protein ERK1 is specifically required for in vitro and in vivo kinase. J Biol Chem. 1997 Apr 18;272(16):10811-6 adipogenesis. Diabetes. 2005 Feb;54(2):402-11 Sivaraman VS, Wang H, Nuovo GJ, Malbon CC. Fang JY, Richardson BC. The MAPK signalling pathways and Hyperexpression of mitogen-activated protein kinase in human colorectal cancer. Lancet Oncol. 2005 May;6(5):322-7 breast cancer. J Clin Invest. 1997 Apr 1;99(7):1478-83 Papachristou DJ, Papachristou GI, Papaefthimiou OA, Mandell JW, Hussaini IM, Zecevic M, Weber MJ, VandenBerg Agnantis NJ, Basdra EK, Papavassiliou AG. The MAPK-AP-1/- SR. In situ visualization of intratumor growth factor signaling: Runx2 signalling axes are implicated in chondrosarcoma immunohistochemical localization of activated ERK/MAP pathobiology either independently or via up-regulation of kinase in glial neoplasms. Am J Pathol. 1998 Nov;153(5):1411- VEGF. Histopathology. 2005 Dec;47(6):565-74 23 Godeny MD, Sayeski PP. ERK1/2 regulates ANG II-dependent Gioeli D, Mandell JW, Petroni GR, Frierson HF Jr, Weber MJ. cell proliferation via cytoplasmic activation of RSK2 and Activation of mitogen-activated protein kinase associated with nuclear activation of elk1. Am J Physiol Cell Physiol. 2006 prostate cancer progression. Cancer Res. 1999 Jan Dec;291(6):C1308-17 15;59(2):279-84 Nikodemova M, Watters JJ, Jackson SJ, Yang SK, Duncan ID. Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Minocycline down-regulates MHC II expression in microglia Shimada Y, Ari-i S, Wada H, Fujimoto J, Kohno M. Constitutive and macrophages through inhibition of IRF-1 and protein activation of the 41-/43-kDa mitogen-activated protein kinase kinase C (PKC)alpha/betaII. J Biol Chem. 2007 May signaling pathway in human tumors. Oncogene. 1999 Jan 18;282(20):15208-16 21;18(3):813-22 Baek MK, Kim MH, Jang HJ, Park JS, Chung IJ, Shin BA, Ahn Pagès G, Guérin S, Grall D, Bonino F, Smith A, Anjuere F, BW, Jung YD. EGF stimulates uPAR expression and cell Auberger P, Pouysségur J. Defective thymocyte maturation in invasiveness through ERK, AP-1, and NF-kappaB signaling in p44 MAP kinase (Erk 1) knockout mice. Science. 1999 Nov human gastric carcinoma cells. Oncol Rep. 2008 12;286(5443):1374-7 Dec;20(6):1569-75 Persons DL, Yazlovitskaya EM, Pelling JC. Effect of Kinoshita T, Yoshida I, Nakae S, Okita K, Gouda M, Matsubara extracellular signal-regulated kinase on p53 accumulation in M, Yokota K, Ishiguro H, Tada T. Crystal structure of human response to cisplatin. J Biol Chem. 2000 Nov mono-phosphorylated ERK1 at Tyr204. Biochem Biophys Res 17;275(46):35778-85 Commun. 2008 Dec 26;377(4):1123-7 Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar Lopez-Gines C, Gil-Benso R, Benito R, Mata M, Pereda J, M, Berman K, Cobb MH. Mitogen-activated protein (MAP) Sastre J, Roldan P, Gonzalez-Darder J, Cerdá-Nicolás M. The kinase pathways: regulation and physiological functions. activation of ERK1/2 MAP kinases in glioblastoma Endocr Rev. 2001 Apr;22(2):153-83

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1014 MAPK3 (mitogen-activated protein kinase 3) Tuncay S, Banerjee S

pathobiology and its relationship with EGFR amplification. This article should be referenced as such: Neuropathology. 2008 Oct;28(5):507-15 Tuncay S, Banerjee S. MAPK3 (mitogen-activated protein Voong LN, Slater AR, Kratovac S, Cressman DE. Mitogen- kinase 3). Atlas Genet Cytogenet Oncol Haematol. 2010; activated protein kinase ERK1/2 regulates the class II 14(11):1011-1015. transactivator. J Biol Chem. 2008 Apr 4;283(14):9031-9 Lorenz K, Schmitt JP, Vidal M, Lohse MJ. Cardiac hypertrophy: targeting Raf/MEK/ERK1/2-signaling. Int J Biochem Cell Biol. 2009 Dec;41(12):2351-5

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1015 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Mini Review

MRC1 (mannose receptor, C type 1) Silvia Rasi, Alessio Bruscaggin, Gianluca Gaidano Division of Hematology, Department of Clinical and Experimental Medicine & Center of Biotechnologies for Applied Medical Research, Amedeo Avogadro University of Eastern Piedmont, Via Solaroli 17, 28100 Novara, Italy (SR, AB, GG)

Published in Atlas Database: January 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/MRC1ID44561ch10p12.html DOI: 10.4267/2042/44883 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity LOC340893 consists of two nearly identical genomic regions, that probably are a part of a duplicated region. Other names: CD206; CLEC13D; MMR Note HGNC (Hugo): MRC1 MRC1 belongs to the mannose receptor (MR) family; Location: 10p12.33 all members of the MR family share a common Local order: MRC1 is located on chromosome 10 on extracellular domain structure but distinct ligand- the short arm (forward strand), and lies between the binding properties and cell type expression patterns. FAM23B (family with sequence similarity 23, member The MR family comprises 4 members in mammals: B) and SLC39A12 (solute carrier family 39 - zinc MRC1, MRC2 (mannose receptor C, type 2), LY75 transporter, member 12) genes. (lymphocyte antigen 75) and PLA2R1 (phospholipase A2 receptor 1). The gene loci including MRC1, MRC1L1 (mannose receptor, C type 1-like 1), FAM23B and

A. Chromosomal location of MRC1 gene. B. Mapping of MRC1 gene and local order on genomic context of the chromosome 10.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1016 MRC1 (mannose receptor, C type 1) Rasi S, et al.

Exon-intron structure of MRC1 gene. The blue boxes correspond to protein coding sequences, while the white boxes correspond to non coding regions.

Representation of the MRC1 protein with localization of recognized domains. The ricin b-type lectin domain (RICIN) is shown in green, the fibronectin type-II domain (FN2) in yellow, the C-type lectin-like domains (CTLDs) in blue, while the transmembrane domain (TM) in red (UniProtKB/Swiss-Prot entry P22897).

of recognizing components of the endocytic pathway. DNA/RNA The first 3 exons of MRC1 gene encode the signal Description sequence, the RICIN domain and the FN2 domain, while exon 30 encodes the TM anchor and the MRC1 is a functional gene of 101.74 kb comprising 30 cytoplasmic tail. The other 26 exons encode the 8 exons and 29 introns. The 5' part of exon 1 and the 3' CTLD domains and intervening spacer elements. part of exon 30 are non coding. Probably the MRC1 receptor acts with an alternation Transcription between bent and extended conformations that might Length of the transcript is 5171 bp. serve as a "conformational switch" to regulate ligand Coding sequence: CDS 104-4474. binding and receptor activity. mRNA is mainly expressed in thyroid, spleen and MRC1 interacts with CHEK2 (CHK2 checkpoint blood. homolog - S. pombe) protein. Expression Protein MRC1 is commonly expressed on macrophages and endothelial cells. Description Localisation Protein length of the unprocessed precursor: 1456 amino acids. Plasma membrane. Molecular weight of the unprocessed precursor: 166 Function kDa. - MRC1 mediates the endocytosis of glyproteins by The protein encoded by the MRC1 gene is classified as macrophages binding both sulfated and non-sulfated a type I transmembrane receptor since the protein polysaccharide chains. COOH terminus is located on the cytoplasmic side of - MRC1 acts as a phagocytic receptor binding a range the membrane. of pathogens, such as bacteria, viruses and fungi, MRC1 is a membrane receptor containing: through high-mannose structures that are in their - a ricin b-type lectin domain (RICIN), that is a cystein- surface. rich (CysR) domain located at the extreme N-terminus - MRC1 is required for rapid clearance of a subset of and that can bind specific sulphated glycoproteins, mannose-bearing serum glycoproteins that are normally - a fibronectin type-II domain (FN2), that is the most elevated during inflammation. conserved of the extracellular domains of the MR - MRC1 binds and internalises collagen and gelatin in a family and can bind several forms of collagen, carbohydrate-independent mechanism. - 8 C-type lectin-like domains (CTLDs), that are - MRC1 can function as an antigen-acquisition system Ca(2+)-dependent structural motifs. The fourth of these in a subset of dendritic cells. domains, CTLD4, is the only functional domain. In - MRC1 is implicated in the regulation of macrophage cooperation with CTLD5, CTLD4 is central to ligand migration during different stages of pathogenesis. binding by the receptor, - MRC1 has an important role in binding and - a single transmembrane domain (TM), transmission of HIV-1 by macrophages. - a short cytosolic domain that contains motifs capable

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1017 MRC1 (mannose receptor, C type 1) Rasi S, et al.

Homology Disease Ortholog to murine Mrc1, rat Mrc1, cow LOC787578, Acute monocytic leukemia is a type of acute myeloid chimpanzee MLR1L1, canine LOC487114. leukemias (AML), characterized by a dominance of Paralog to MRC1L1, CD302, PLA2R1, MRC2. monocytes in the bone marrow. Cancer Mutations Note Note MRC1 on lymphatic endothelial cells is involved in No mutations have been reported for MRC1 gene. leukocyte trafficking and contributes to the metastatic behavior of cancer cells. Moreover, expression of the Implicated in MRC1 gene is up-regulated in vascular endothelial cells during early development indicating that this gene Pediatric acute lymphoblastic leukemia is a potential regulator of vasculature formation. (ALL) Blocking of MRC1 may provide a new approach to controlling inflammation and cancer metastasis by Disease targeting the lymphatic vasculature. ALL is a form of leukemia characterized by excess of lymphoblastic cells that is most common in childhood. Kaposi's sarcoma (KS) The rate of cure in children is of nearly 80%, while Note only 30/40% of adults with ALL are cured. KS cells express MRC1, since MRC1 is detected in It is a heterogeneous disease consisting of a number of more than 95% of KS cells in all of the major clinical genetically distinct leukemia subtypes that differ in the forms of the disease. It is likely that KS lesions derive response to chemotherapy. These include B-lineage from tissue accumulation and local proliferation of a leukemias that contain t(9;22)[BCR-ABL], subset of macrophages with endotelial features. t(1;19)[E2A-PBX1], t(12;21)[TEL-AML1], Disease rearrangements in the MLL gene on chromosome KS is a multicentric proliferative disease, involving 11q23, or a hyperdiploid karyotype, and T-lineage cutaneous and visceral tissues. The etiology is leukemias (T-ALL). unknown and the pathogenesis is unclear. KS lesions Prognosis derive from local proliferation of spindleshaped cells ALL is a heterogeneous disease and patients are (KS cells), that represent the histological hallmark of assigned to specific risk groups. In fact, ALL prognosis this disease. differs among individuals and depends on several factors: sex, age and white blood cell count at References diagnosis, leukemia spread to the central nervous system, morphological, immunological, and genetic Taylor ME, Conary JT, Lennartz MR, Stahl PD, Drickamer K. Primary structure of the mannose receptor contains multiple subtypes, patient's response to initial treatment. motifs resembling carbohydrate-recognition domains. J Biol Various genetic alterations are correlated with Chem. 1990 Jul 25;265(21):12156-62 prognosis in ALL. In particular ALLs with the presence Kim SJ, Ruiz N, Bezouska K, Drickamer K. Organization of the of t(12;21)[TEL-AML1] and hyperdiploid karyotype gene encoding the human macrophage mannose receptor have favorable prognosis, while ALLs with (MRC1). Genomics. 1992 Nov;14(3):721-7 t(9;22)[BCR-ABL], t(1;19)[E2A-PBX1] or Eichbaum Q, Clerc P, Bruns G, McKeon F, Ezekowitz RA. rearrangements in MLL (11q23) have a poor prognosis. Assignment of the human macrophage mannose receptor gene (MRC1) to 10p13 by in situ hybridization and PCR-based Oncogenesis somatic cell hybrid mapping. Genomics. 1994 Aug;22(3):656-8 In cases having ALL with MLL rearrangements, expression of MRC1 is lower than in normal cells, Uccini S, Sirianni MC, Vincenzi L, Topino S, Stoppacciaro A, Lesnoni La Parola I, Capuano M, Masini C, Cerimele D, Cella suggesting a putative involvement of MRC1 in MLL- M, Lanzavecchia A, Allavena P, Mantovani A, Baroni CD, Ruco mediated growth of leukemic cells. LP. Kaposi's sarcoma cells express the macrophage- associated antigen mannose receptor and develop in Acute monocytic leukemia (M5-AML) peripheral blood cultures of Kaposi's sarcoma patients. Am J Note Pathol. 1997 Mar;150(3):929-38 In acute monocytic leukemia, a trimannose conjugate Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J (TMC), with a high affinity for mannose-specific Med. 1998 Aug 27;339(9):605-15 lectins, binds to MRC1 and this concatenation may Kanbe E, Emi N, Abe A, Tanaka H, Kobayashi K, Saito H. play an important role in the activation of monocytic Novel synthesized trimannose conjugate induces endocytosis leukemia cells. TMC may be a good candidate to target and expression of immunostimulatory molecules in monocytic leukemia cells. Int J Hematol. 2001 Oct;74(3):309-15 MRC1 in leukemia cells.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1018 MRC1 (mannose receptor, C type 1) Rasi S, et al.

East L, Isacke CM. The mannose receptor family. Biochim McKenzie EJ, Taylor PR, Stillion RJ, Lucas AD, Harris J, Biophys Acta. 2002 Sep 19;1572(2-3):364-86 Gordon S, Martinez-Pomares L. Mannose receptor expression and function define a new population of murine dendritic cells. Lee SJ, Evers S, Roeder D, Parlow AF, Risteli J, Risteli L, Lee J Immunol. 2007 Apr 15;178(8):4975-83 YC, Feizi T, Langen H, Nussenzweig MC. Mannose receptor- mediated regulation of serum glycoprotein homeostasis. Sturge J, Todd SK, Kogianni G, McCarthy A, Isacke CM. Science. 2002 Mar 8;295(5561):1898-901 Mannose receptor regulation of macrophage cell migration. J Leukoc Biol. 2007 Sep;82(3):585-93 Yeoh EJ, Ross ME, Shurtleff SA, Williams WK, Patel D, Mahfouz R, Behm FG, Raimondi SC, Relling MV, Patel A, Llorca O. Extended and bent conformations of the mannose Cheng C, Campana D, Wilkins D, Zhou X, Li J, Liu H, Pui CH, receptor family. Cell Mol Life Sci. 2008 May;65(9):1302-10 Evans WE, Naeve C, Wong L, Downing JR. Classification, subtype discovery, and prediction of outcome in pediatric acute Marttila-Ichihara F, Turja R, Miiluniemi M, Karikoski M, lymphoblastic leukemia by gene expression profiling. Cancer Maksimow M, Niemelä J, Martinez-Pomares L, Salmi M, Cell. 2002 Mar;1(2):133-43 Jalkanen S. Macrophage mannose receptor on lymphatics controls cell trafficking. Blood. 2008 Jul 1;112(1):64-72 Nguyen DG, Hildreth JE. Involvement of macrophage mannose receptor in the binding and transmission of HIV by Wong KS, Proulx K, Rost MS, Sumanas S. Identification of macrophages. Eur J Immunol. 2003 Feb;33(2):483-93 vasculature-specific genes by microarray analysis of Etsrp/Etv2 overexpressing zebrafish embryos. Dev Dyn. 2009 Martinez-Pomares L, Wienke D, Stillion R, McKenzie EJ, Jul;238(7):1836-50 Arnold JN, Harris J, McGreal E, Sim RB, Isacke CM, Gordon S. Carbohydrate-independent recognition of collagens by the This article should be referenced as such: macrophage mannose receptor. Eur J Immunol. 2006 May;36(5):1074-82 Rasi S, Bruscaggin A, Gaidano G. MRC1 (mannose receptor, C type 1). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1016-1019.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1019 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

MUC13 (mucin 13, cell surface associated) Diane Maher, Brij Gupta, Mara Ebeling, Satoshi Nagata, Meena Jaggi, Subhash C Chauhan Cancer Biology Research Center, Sanford Research/University of South Dakota, Sioux Falls, SD 57105, USA (DM, BG, ME, SN, MJ, SCC); Department of OB/GYN, and Basic Biomedical Science Division, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57105, USA (MJ, SCC)

Published in Atlas Database: January 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/MUC13ID41454ch3q21.html DOI: 10.4267/2042/44884 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity DNA/RNA Other names: DRCC1; FLJ20063; MUC-13; RECC Description HGNC (Hugo): MUC13 Human MUC13 was originally identified as a ortholog Location: 3q21.2 of the previously identified murine MUC13 (Williams Note: MUC13 is a membrane bound mucin exhibiting et al., 2001). Based on fluorescence in situ abundant O- and N-glycosylation. The aberrant hybridization, MUC13 was originally identified at expression and localization of MUC13 may be location 3q13.3 (Williams et al., 2001); however, involved in cancer pathobiology and could be a MUC13 is now reported to be located on chromosome potential diagnostic/prognostic biomarker of cancer as 3; location 3q21.2, MUC13 is flanked by ITGB5 (beta well as a target for antibody guided therapy for cancer 5 integrin) and HEG-1 (Heart of Glass), each treatment. transcribed from the reverse strand.

Schematic diagram of the genomic MUC13 DNA (including neighboring genes) and the transcript of MUC13. MUC13 is located on chromosome 3 between ITGB5 and HEG-1. These 3 genes are transcribed from the reverse strand. The MUC13 transcript contains 12 exons and the final mRNA consists of 2,876 base pairs (Figure modified from Ensembl).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1020 MUC13 (mucin 13, cell surface associated) Maher D, et al.

Interestingly, HEG and MUC13 share some molecular invasion of the cancer cells (Hollingsworth and features, suggesting they may be evolutionarily related Swanson, 2004). (Lang et al., 2006). Description Transcription MUC13 is a recently identified membrane bound The predominate MUC13 transcript (exact match mucin (Williams et al., 2001). At the N-terminus, a between Ensembl and Havana) contains 12 exons and signal peptide shuttles the protein into the secretary encodes 511 amino acids. Splice variants have been pathway. The signal peptide is followed by a large detected and may alter the length of the tandem repeat serine-threonine rich tandem repeat domain (TD). domain (Lang et al., 2006); however they have not Composed of 10 degenerate tandem repeats, the tandem been well studied for MUC13. repeat domain provides a scaffold on which cells build oligosaccharide structures. O-glycosylation with Protein complex oligosaccharides is crucial to mucin structure and function. The central region of MUC13 contains Note three epidermal growth factor (EGF)-like domains Members of the mucin family are characterized by a (EGF1, EGF2 and EGF3), suggesting that MUC13 may hallmark feature: the presence of a tandem repeat play an important role in a signaling cascade. A sea domain, consisting of a protein backbone which acts as urchin sperm protein enterokinase arginine (SEA) a scaffold for a large number of complex O-linked module is present between EGF1 and EGF2 like carbohydrate side chains (Williams et al., 2001). In domains, providing a cleavage site which separates general, mucins have important biological roles in the MUC13 into an extracellular a subunit and a lubrication and protection of normal epithelial tissues. transmembrane beta subunit. In normal tissue, mucins are expressed in a tissue type It is expected that the SEA domain is cleaved while in dependent manner; however, for many types of cancer, transport to the cell surface and that after cleavage, the mucin expression becomes altered (down-regulated, alpha and beta subunits are covalently bound together. up-regulated or newly expressed). The mucin's Adjacent to the EGF3-like domain is a short ectodomain may protrude more than 200-2000 nm transmembrane domain (TM), followed by a 69 amino above the cell surface and can effectively block cell- acid long cytoplasmic domain (CD) (Williams et al., cell adhesion. Therefore, the over-expression of mucins 2001; Shimamura et al., 2005). may be implicated in the exfoliation, dissemination and

Schematic diagram and annotated amino acid sequence of MUC13. Left: a schematic diagram shows the structural features of MUC13, highlighting the signal peptide, mucin repeat domain, SEA module, EGF-like domains, transmembrane region and the cytoplasmic domain. Right: The annotated amino acid sequence shows the extensive post-translation modifications that MUC13 undergoes (O-glycosylation, N-glycosylation and predicted disulfide bonds). The signal peptide, SEA module and Transmembrane sequences are indicated by pink, red and green font, respectively.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1021 MUC13 (mucin 13, cell surface associated) Maher D, et al.

Within the cytoplasmic domain of MUC13, there are diagnosed with ovarian cancer and 14600 women will several potential phosphorylation sites (8 serine and 2 die due to this disease (Jemal et al., 2009). A high tyrosine residues) and a protein kinase C consensus percent of women with ovarian cancer are diagnosed at phosphorylation motif, further supporting the an advanced stage (67%) and have a 5 year survival hypothesis that MUC13 may be involved in cell rate of only 46% (Jemal et al., 2009). signaling pathways. Oncogenesis Expression In a recently published report, we analyzed the Among normal tissues, MUC13 mRNA and/or protein expression profile and functions of MUC13 to elucidate has been detected in the large intestine, trachea, kidney, its potential role in ovarian cancer diagnosis and small intestine, gastric epithelium and esophagus pathogenesis. We determined the expression profile of (Williams et al., 2001). MUC13 is normally localized MUC13 by immunohistochemistry, using ovarian to the apical surface of epithelial cells lining the cancer tissue microarrays and 56 additional epithelial mucosal surface. In ovarian, gastric and colon cancers, ovarian cancer (EOC) samples. The expression of MUC13 expression (determined by MUC13 was significantly (p<0.005) higher in cancer immunohistochemical analysis) is increased compared samples compared to the normal ovary/benign tissues. to expression levels of non-neoplastic tissues Among all ovarian cancer types, MUC13 expression (Shimamura et al., 2005; Walsh et al., 2007; Chauhan was highest in EOC. Exogenous expression of full et al., 2009). length MUC13 induced morphological changes, including scattering of cells, marked reduction in cell- Localisation cell adhesion and significant (p<0.05) increases in cell MUC13 is a transmembrane glycoprotein present at the motility and proliferation. Additionally, we observed apical surface in normal cells. In cancer cells, MUC13 increased tumorigenesis in a xenograft mouse model is over-expressed and aberrantly located in the system. These cellular characteristics were correlated cytoplasm and occasionally in the nucleus (Williams et with up-regulation of HER2, p21-activated kinase1 al., 2001; Chauhan et al., unpublished data). (PAK1) and p38 protein expression. These changes Function were abrogated through c-jun NH2-terminal kinase (JNK) chemical inhibitor (SP600125) or JNK2 siRNA. Under normal physiological conditions, mucins, Our findings demonstrate the aberrant expression of including MUC13, protect the epithelial surface of MUC13 in ovarian cancer and show that its expression mucosal surfaces (gastrointestinal tract, respiratory alters the cellular characteristics of SKOV-3 cells. This tract and reproductive tract). Mucins create a physical implies a significant role of MUC13 in ovarian cancer. barrier from the extracellular environment and protect epithelial tissues from noxious and toxic substances. Colon cancer When aberrantly expressed, MUC13 has oncogenic Disease functions which are described below. Colon cancer is the third leading cause of cancer Homology related deaths among men and women worldwide, with an estimated 639000 deaths in 2004 (WHO, 2009). In MUC13 is known to have orthologs in mice, rats, the United States in 2009, approximately 106000 chickens, dogs, cows, chimpanzees and even fish people were diagnosed with colon cancer and 49900 (Williams et al., 2001; Lang et al., 2006; NCBI: people died, making colon cancer the second leading homologene). Additional putative orthologs are likely cause of deaths among all cancers (Jemal et al., 2009). in a variety of different species and can be viewed via Colon cancer has an overall survival rate of 49%, Ensembl. which is drastically dependent on the stage of diagnosis (Jemal, et al., 2009). For example, if colon cancer is Mutations detected in an early stage, prior to metastasis, survival Note is 90%; however, if colon cancer is not treated until an advanced stage (with metastasis to distant organs), While a variety of Single Nucleotide Polymorphisms survival decreases to approximately 10% (Jemal et al., (SNPs) have been identified, the clinical significance 2009). has not yet been determined (NCBI: SNPs). Oncogenesis Implicated in Walsh et al studied the expression of MUC13 in various stages of colon cancer (99 samples) (Walsh et Ovarian cancer al., 2007). Using immunohistochemical analysis, Disease MUC13 was detected predominantly on the apical Ovarian cancer is the most lethal gynecological cancer surface, with some cytoplasmic staining, of glands in and the fifth most common cause of cancer mortality in normal colon. Scoring of the normal tissue was not women in the United States (Jemal et al., 2009). In done for this study, so it is difficult to state a 2009, it is estimated that 21550 women will be comparison of MUC13 staining between normal and

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1022 MUC13 (mucin 13, cell surface associated) Maher D, et al.

cancer cells. However, MUC13 was highly expressed tissues. However, MUC13 staining in gastric cancer in most of the colon tumors, with 81% of well tissue was positive in 64.9% of cases and the cellular differentiated adenocarcinomas exhibiting strong localization of MUC13 was dependent upon the MUC13 staining. Interestingly, although the histological type of gastric cancer. MUC13 was also significance is not yet known, this study also found that detected in 9 out of 10 cases of intestinal metaplasia tumors originating from the left side of the patient's (precancerous lesions of intestinal type gastric cancer). body had a higher proportion of MUC13-positive When correlated with clinicopathological factors, cancer cells. Mucinous tumors expressed MUC13, but MUC13 expression only correlated significantly with at a lower staining intensity (50% indicating strong intestinal types of gastric cancer. MUC13 expression staining) compared to adenocarcinomas. While MUC13 did not correlate with the expression of other mucins was most intense on the apical surface, it was also (MUC2, MUC5AC, MUC6 and CD10), suggesting that detected in the cytoplasm. Basolateral staining was MUC13 may be regulated in a different manner then detected in 24% of the cases, most frequently in poorly other mucins markers for gastric cancer (Shimamura et differentiated tumors (55% of poorly differentiated al., 2005). tumors showed basolateral staining). Although not statistically significant, there was a trend toward poorer References survival in patients with tumors showing basolateral Williams SJ, Wreschner DH, Tran M, Eyre HJ, Sutherland GR, MUC13 expression. Taken together, these observations McGuckin MA. Muc13, a novel human cell surface mucin suggest aberrant expression of MUC13 may affect expressed by epithelial and hemopoietic cells. J Biol Chem. colon cancer pathogenesis. In contrast to these results, 2001 May 25;276(21):18327-36 Packer et al reported that the RNA level of MUC13 Hollingsworth MA, Swanson BJ. Mucins in cancer: protection was decreased in colon cancer; however this was a and control of the cell surface. Nat Rev Cancer. 2004 small study with only 23 samples of colon cancer and 6 Jan;4(1):45-60 normal colon tissues (Packer et al., 2004). In our own Packer LM, Williams SJ, Callaghan S, Gotley DC, McGuckin studies, we have observed the over-expression of MA. Expression of the cell surface mucin gene family in MUC13 in colon and pancreatic cancer compared to adenocarcinomas. Int J Oncol. 2004 Oct;25(4):1119-26 normal colon and pancreas (unpublished data). Taken Shimamura T, Ito H, Shibahara J, Watanabe A, Hippo Y, together, these data suggest that MUC13 may be a Taniguchi H, Chen Y, Kashima T, Ohtomo T, Tanioka F, potential diagnostic/prognostic biomarker for colon, Iwanari H, Kodama T, Kazui T, Sugimura H, Fukayama M, Aburatani H. Overexpression of MUC13 is associated with pancreatic and ovarian cancers. Additionally, due to its intestinal-type gastric cancer. Cancer Sci. 2005 May;96(5):265- cell surface expression, MUC13 may be a suitable 73 target for antibody guided therapy for cancer treatment. Lang T, Hansson GC, Samuelsson T. An inventory of mucin Gastric cancer genes in the chicken genome shows that the mucin domain of Muc13 is encoded by multiple exons and that ovomucin is part Disease of a locus of related gel-forming mucins. BMC Genomics. 2006 Gastric cancer is the second most common cause of Aug 3;7:197 cancer related deaths worldwide, accounting for Walsh MD, Young JP, Leggett BA, Williams SH, Jass JR, approximately 803000 deaths each year (WHO, 2009). McGuckin MA. The MUC13 cell surface mucin is highly In the United States, 21130 people were diagnosed with expressed by human colorectal carcinomas. Hum Pathol. 2007 Jun;38(6):883-92 gastric cancer and 10620 died due to gastric cancer (Jemal et al., 2009). When diagnosed with localized Chauhan SC, Vannatta K, Ebeling MC, Vinayek N, Watanabe gastric cancer, the survival rate is approximately 60%; A, Pandey KK, Bell MC, Koch MD, Aburatani H, Lio Y, Jaggi M. Expression and functions of transmembrane mucin MUC13 in however, if gastric cancer has metastasized to distant ovarian cancer. Cancer Res. 2009 Feb 1;69(3):765-74 sites, the survival rate is very low (4%) (Jemal et al., Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer 2009). statistics, 2009. CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49 Oncogenesis Shimamura et al detected an increased expression of This article should be referenced as such: MUC13 at both mRNA and protein levels (Shimamura Maher D, Gupta B, Ebeling M, Nagata S, Jaggi M, Chauhan et al., 2005). In normal tissue, MUC13 protein was SC. MUC13 (mucin 13, cell surface associated). Atlas Genet detected at the luminal surface of crypts in both the Cytogenet Oncol Haematol. 2010; 14(11):1020-1023. small and large intestines, but not in normal gastric

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1023 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Mini Review

OLFM4 (olfactomedin 4) Wenli Liu, Griffin P Rodgers Molecular and Clinical Hematology Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9N115, 10 Center Drive, Bethesda, MD 20892, USA (WL, GPR)

Published in Atlas Database: January 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/OLFM4ID49730ch13q14.html DOI: 10.4267/2042/44885 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

reading frame of 1530 nucleotides. There is no Identity alternative mRNA splicing. Other names: bA209J19.1; GC1; GW112; hGC-1; mRNA expression: highly in bone marrow and small hOLfD; KIAA4294; OlfD; OLM4; UNQ362 intestine; lowly expressed in stomach, colon, pancreas HGNC (Hugo): OLFM4 and prostate; no expression is detected in other tissues determined by Northern blot. OLFM4 transcription is Location: 13q14.3 regulated by transcription factors, PU1 and NF-kB. Note: OLFM4 is a member of olfactomedin-related protein family. This gene was originally cloned from Protein human myeloblasts and constitutively expressed in normal bone marrow, stomach, small intestine, colon, Description prostate and pancreas. OLFM4 encodes a 510 amino acid protein with a molecular weight of 55 kD. OLFM4 has a signal DNA/RNA peptide and six N-linked glycosylation motifs and forms disulfide-bonded multimers. It has an N-terminal Description coil-coil domain and C-terminal olfactomedin domain. OLFM4 gene locus was mapped to chromosome Expression 13q14.3 with five exons spanning 23220 bp. OLFM4 protein is endogenously expressed in mature Transcription neutrophils and gastric and intestinal epithelial cells. OLFM4 is transcribed to 2861 bp mRNA with an open

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1024 OLFM4 (olfactomedin 4) Liu W, Rodgers GP

Its expression in bone marrow neutrophils is Prostate cancer significantly higher than peripheral blood neutrophils. OLFM4 is more abundantly expressed in intestinal Note crypts than in surface epithelial cells. OLFM4 mRNA expression is upregulated in prostate cancer patients. OLFM4 interacts with GRIM-19, a Localisation mitochondria pro-apoptosis protein and has an anti- OLFM4 is localized in multiple subcellular apoptotic function in prostate cancer cells when it is compartments including cytoplasm, mitochondria and overexpressed. membrane. It is also secreted extracellularly. Pancreatic cancer Function Note OLFM4 binds to cadherins and lectins and mediates OLFM4 mRNA is upregulated in pancreatic cancer cell adhesion. OLFM4 is a robust marker for stem cells patients. OLFM4 promotes S-phase transition in in human intestine. proliferation of pancreatic cancer cells. Homology Breast cancer Human OLFM4 is highly homologous to its mouse Note homologue (pDP4) with 93% amino acid identity. OLFM4 mRNA is upregulated in breast cancer OLFM4 C-terminal olfactomedin domain has patients. significant homology with other olfactomedin-related proteins including olfactomedin, TIGR, Noelin-1, Chronic bowel disease (Crohn's disease Noeline-2 and latrophilin-1, etc. and ulcerative colitis) Note Mutations OLFM4 mRNA expression is upregulated in the Note intestines of chronic bowel disease patients including Crohn's disease and ulcerative colitis. No known genetic mutation in normal or cancer tissues. H. pylori gastritis Implicated in Note Stomach cancer OLFM4 mRNA expression is upregulated in the gastric mucosa of H. pylori infected patients than normal Note individuals. OLFM4 mRNA expression is upregulated in gastric cancer patients. OLFM4 protein staining by References immunohistochemistry was observed more frequently in well-differentiated cancer tissues and more Shinozaki S, Nakamura T, Iimura M, Kato Y, Iizuka B, Kobayashi M, Hayashi N. Upregulation of Reg 1alpha and frequently in stage I/II cases than in stage III/IV cases. GW112 in the epithelium of inflamed colonic mucosa. Gut. Serum OLFM4 is a useful marker for gastric cancer 2001 May;48(5):623-9 patients. Zhang J, Liu WL, Tang DC, Chen L, Wang M, Pack SD, Colon cancer Zhuang Z, Rodgers GP. Identification and characterization of a novel member of olfactomedin-related protein family, hGC-1, Note expressed during myeloid lineage development. Gene. 2002 OLFM4 mRNA is upregulated in colon cancer patients. Jan 23;283(1-2):83-93 OLFM4 protein expression is correlated with prognosis Rosenbauer F, Wagner K, Zhang P, Knobeloch KP, Iwama A, for colon cancer patients. Lower or lost OLFM4 protein Tenen DG. pDP4, a novel glycoprotein secreted by mature expression is correlated with more malignancy and granulocytes, is regulated by transcription factor PU.1. Blood. 2004 Jun 1;103(11):4294-301 poor survival.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1025 OLFM4 (olfactomedin 4) Liu W, Rodgers GP

Zhang X, Huang Q, Yang Z, Li Y, Li CY. GW112, a novel Chin KL, Aerbajinai W, Zhu J, Drew L, Chen L, Liu W, Rodgers antiapoptotic protein that promotes tumor growth. Cancer Res. GP. The regulation of OLFM4 expression in myeloid precursor 2004 Apr 1;64(7):2474-81 cells relies on NF-kappaB transcription factor. Br J Haematol. 2008 Nov;143(3):421-32 Oue N, Aung PP, Mitani Y, Kuniyasu H, Nakayama H, Yasui W. Genes involved in invasion and metastasis of gastric Conrotto P, Roesli C, Rybak J, Kischel P, Waltregny D, Neri D, cancer identified by array-based hybridization and serial Castronovo V. Identification of new accessible tumor antigens analysis of gene expression. Oncology. 2005;69 Suppl 1:17-22 in human colon cancer by ex vivo protein biotinylation and comparative mass spectrometry analysis. Int J Cancer. 2008 Yasui W, Oue N, Aung PP, Matsumura S, Shutoh M, Dec 15;123(12):2856-64 Nakayama H. Molecular-pathological prognostic factors of gastric cancer: a review. Gastric Cancer. 2005;8(2):86-94 Liu W, Liu Y, Zhu J, Wright E, Ding I, Rodgers GP. Reduced hGC-1 protein expression is associated with malignant Aung PP, Oue N, Mitani Y, Nakayama H, Yoshida K, Noguchi progression of colon carcinoma. Clin Cancer Res. 2008 Feb T, Bosserhoff AK, Yasui W. Systematic search for gastric 15;14(4):1041-9 cancer-specific genes based on SAGE data: melanoma inhibitory activity and matrix metalloproteinase-10 are novel Oue N, Sentani K, Noguchi T, Ohara S, Sakamoto N, Hayashi prognostic factors in patients with gastric cancer. Oncogene. T, Anami K, Motoshita J, Ito M, Tanaka S, Yoshida K, Yasui W. 2006 Apr 20;25(17):2546-57 Serum olfactomedin 4 (GW112, hGC-1) in combination with Reg IV is a highly sensitive biomarker for gastric cancer Liu W, Chen L, Zhu J, Rodgers GP. The glycoprotein hGC-1 patients. Int J Cancer. 2009 Nov 15;125(10):2383-92 binds to cadherin and lectins. Exp Cell Res. 2006 Jun 10;312(10):1785-97 van der Flier LG, Haegebarth A, Stange DE, van de Wetering M, Clevers H. OLFM4 is a robust marker for stem cells in Kobayashi D, Koshida S, Moriai R, Tsuji N, Watanabe N. human intestine and marks a subset of colorectal cancer cells. Olfactomedin 4 promotes S-phase transition in proliferation of Gastroenterology. 2009 Jul;137(1):15-7 pancreatic cancer cells. Cancer Sci. 2007 Mar;98(3):334-40 Koshida S, Kobayashi D, Moriai R, Tsuji N, Watanabe N. This article should be referenced as such: Specific overexpression of OLFM4(GW112/HGC-1) mRNA in Liu W, Rodgers GP. OLFM4 (olfactomedin 4). Atlas Genet colon, breast and lung cancer tissues detected using Cytogenet Oncol Haematol. 2010; 14(11):1024-1026. quantitative analysis. Cancer Sci. 2007 Mar;98(3):315-20 Liu W, Zhu J, Cao L, Rodgers GP. Expression of hGC-1 is correlated with differentiation of gastric carcinoma. Histopathology. 2007 Aug;51(2):157-65

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1026 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

PDE11A (phosphodiesterase 11A) Rossella Libé, Jérôme Bertherat INSERM U567, CNRS 8104, Institut Cochin, Service de Maladies Endocriniennes et Metabolique, Hopital Cochin, Paris, France (RL, JB)

Published in Atlas Database: January 2010 Online updated version: http://AtlasGeneticsOncology.org/Genes/PDE11AID44448ch2q31.html DOI: 10.4267/2042/44886 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Protein Other names: FLJ23693; MGC133355; MGC133356; Description PDE11A1; PDE11A2; PDE11A3; PPNAD2 PDE11A4 is a protein of 104 kDa: it contains two N- HGNC (Hugo): PDE11A terminal GAF domains (between exons 3-12) and one Location: 2q31.2 C-terminal catalytic domain (between exons 14-22). DNA/RNA Expression Isoform 1 is present in prostate, pituitary, heart, liver Description and skeletal muscle. Isoform 2 and 3 are expressed in the testis. Isoform 4 is the only isoform of the enzyme PDE11A is the most recently discovered PDE enzyme expressed in the adrenal cortex, where it is expressed family. In this family, only one gene, PDE11A, has substantially less than in the prostate. been identified. It is a dual phosphodiesterase that hydrolyzes both cAMP and cGMP. Localisation Transcription Cytoplasm > cytosol. Four different isoforms of PDE11A (PDE11A1 →A4) Function have been identified. The longest variant, PDE11A4 is PDE11A enzymes catalyze the hydrolysis of both composed of 20 coding exons of varying length, cAMP and cGMP to 5'-AMP and 5'-GMP, respectively. separated by introns, giving the gene a total length of This takes part in the down-regulation of the cAMP and 4441 bps. cGMP signaling.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1027 PDE11A (phosphodiesterase 11A) Libé R, Bertherat J

Inactive mutations of the isoform PDE11A4 gene have Disease been identified in patients with adrenal Cushing ACTH-independant chronic oversecretion of cortisol syndrome due to micronodular adrenocortical due to bilateral adrenal involvement. Pathological hyperplasia. An association of PDE11A4 variants and examination demonstrates diffuse micronodular other neoplasms is suggested since a higher frequency hyperaplasia of the cortex of both adrenal. These of PDE11A4 missense mutations is observed in nodules can be pigmented as observed in primary patients with macronodular adrenal hyperplasia and pigmented nodular adrenocortical disease (PPNAD). testicular tumors than in the controls. Prognosis Homology Morbidity and mortality of non treated Cushing The catalytic domain is conserved among the 4 syndrome is high. However after treatment (bilateral isoforms of PDE11A. adrenalectomy in most cases) there is a clear A high sequence similarity of 42-51% is found within improvement and the overall prognosis is good, the the amino acid sequences of the catalytic regions of main side effect of the treatment being adrenal PDEs containing a Gaf sequence (i.e. PDE2A, PDE5A, deficiency. PDE6B, PDE6C, PDE10A and PDE11A). Oncogenesis Gene conserved among species: Pan troglodytes: In the patients with non-sense mutations a loss of the 98.6%; Canis lupus familiaris: 96.4%; Bos taurus: wild type allele was demonstrated in the adrenal nodes, 95.9%; Mus musculus: 94.6%; Rattus norvegicus: supporting the hypothesis that PDE11A4 is a tumor 94.5%; Gallus gallus: 90%; Danio rerio: 90%. suppressor gene. Mutations ACTH-independent macronodular adrenal hyperplasia (AIMAH) Germinal Disease Non sense. AIMAH is a rare form of benign bilateral Three PDE11A nonsense mutations leading to a adrenocortical tumor. It can be associated to an overt premature stop codon were identified in 3 kindreds Cushing's syndrome (CS). Nowadays, the most with adrenal Cushing syndrome due to micronodular frequent clinical presentation is that of bilateral adrenal adrenocortical hyperplasia. incidentalomas. The initial endocrine evaluation Other missense mutations (genetic variants) are usually demonstrates subtle abnormalities of cortisol described in adrenocortical tumor, as macronodular secretion, suggesting a subclinical CS. adrenal hyperplasia (AIMAH), adrenocortical adenoma Prognosis (ACA), adrenocortical carcinoma (ACC) and testicular Morbidity and mortality of non treated Cushing tumors. syndrome is high. However after treatment (bilateral Somatic adrenalectomy in most cases) there is a clear Loss of heterozygosity with loss of wild type allele has improvement and the overall prognosis is good, the been reported in adrenocortical tumor (benign and main side effect of the treatment being adrenal malignant) with PDE11A4 missense mutations. deficiency. Cytogenetics Implicated in A higher frequency of missense PDE11A mutations (genetic variants) than in healthy subjects is found. Adrenal Cushing syndrome due to Oncogenesis micronodular adrenocortical The higher frequency of PDE11A missense mutations hyperplasia suggests a role of PDE11A in the genetic predisposition to adrenal tumors.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1028 PDE11A (phosphodiesterase 11A) Libé R, Bertherat J

Non-sense mutations (yellow) and missense mutations (green) described in adrenocortical tumor (PPNAD, AIMAH, ACA and ACC).

Testicular germ cells tumors (TGCT) Disease References It is the most common malignancy in Caucasian men Fawcett L, Baxendale R, Stacey P, McGrouther C, Harrow I, aged from 15 to 45 years old. A genetic basis for TGCT Soderling S, Hetman J, Beavo JA, Phillips SC. Molecular cloning and characterization of a distinct human is supported by familial clustering, younger-than-usual phosphodiesterase gene family: PDE11A. Proc Natl Acad Sci age at diagnosis, and an increased risk of bilateral U S A. 2000 Mar 28;97(7):3702-7 disease. Hetman JM, Robas N, Baxendale R, Fidock M, Phillips SC, Prognosis Soderling SH, Beavo JA. Cloning and characterization of two More than 90% of patients with newly diagnosed splice variants of human phosphodiesterase 11A. Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12891-5 TGCT are cured, and delay in diagnosis correlates with a higher stage at presentation for treatment. Yuasa K, Kotera J, Fujishige K, Michibata H, Sasaki T, Omori K. Isolation and characterization of two novel Cytogenetics phosphodiesterase PDE11A variants showing unique structure Recently, PDE11A missense mutations (genetic and tissue-specific expression. J Biol Chem. 2000 Oct variants) have been reported in TGCT. The frequency 6;275(40):31469-79 was significantly higher in patients with TGCT than in Yuasa K, Kanoh Y, Okumura K, Omori K. Genomic healthy subjects. organization of the human phosphodiesterase PDE11A gene. Evolutionary relatedness with other PDEs containing GAF Oncogenesis domains. Eur J Biochem. 2001 Jan;268(1):168-78 PDE11A variants are involved in the testicular Yuasa K, Ohgaru T, Asahina M, Omori K. Identification of rat tumorigenesis and may modify the risk of familial and cyclic nucleotide phosphodiesterase 11A (PDE11A): bilateral TGCT. comparison of rat and human PDE11A splicing variants. Eur J Biochem. 2001 Aug;268(16):4440-8 Adrenocortical carcinoma (ACC) Zoraghi R, Kunz S, Gong K, Seebeck T. Characterization of Disease TbPDE2A, a novel cyclic nucleotide-specific ACC is a rare malignant tumor, with an estimated phosphodiesterase from the protozoan parasite Trypanosoma prevalence between 4 and 12 per million in adults. brucei. J Biol Chem. 2001 Apr 13;276(15):11559-66 Prognosis Ahlström M, Pekkinen M, Huttunen M, Lamberg-Allardt C. Dexamethasone down-regulates cAMP-phosphodiesterase in The overall survival varies according to tumor stage. human osteosarcoma cells. Biochem Pharmacol. 2005 Jan However the overall survival is poor and below 30% at 15;69(2):267-75 5 years in most series. D'Andrea MR, Qiu Y, Haynes-Johnson D, Bhattacharjee S, Cytogenetics Kraft P, Lundeen S. Expression of PDE11A in normal and A higher frequency of a polymorphism in exon 6 malignant human tissues. J Histochem Cytochem. 2005 Jul;53(7):895-903 (E421E) and of three associated polymorphisms located in intron 10-exon 11-intron 11 is found in ACCs than in Francis SH. Phosphodiesterase 11 (PDE11): is it a player in human testicular function? Int J Impot Res. 2005 Sep- healthy subjects. Oct;17(5):467-8 Oncogenesis Loughney K, Taylor J, Florio VA. 3',5'-cyclic nucleotide The synonymous E421E variant and the intron phosphodiesterase 11A: localization in human tissues. Int J 10/intron 11 variants could play a role in the Impot Res. 2005 Jul-Aug;17(4):320-5 predisposition to ACC development.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1029 PDE11A (phosphodiesterase 11A) Libé R, Bertherat J

Pomara G, Morelli G. Inhibition of phosphodiesterase 11 involved in oligomerization. Biochemistry. 2007 Sep (PDE11) impacts on sperm quality. Int J Impot Res. 2005 Jul- 11;46(36):10353-64 Aug;17(4):385-6; author reply 387 Boikos SA, Horvath A, Heyerdahl S, Stein E, Robinson-White Seftel AD. 3',5'-Cyclic nucleotide phosphodiesterase 11A: A, Bossis I, Bertherat J, Carney JA, Stratakis CA. localization in human tissues. J Urol. 2005 Sep;174(3):1044 Phosphodiesterase 11A expression in the adrenal cortex, primary pigmented nodular adrenocortical disease, and other Seftel AD. Phosphodiesterase 11 (PDE11) regulation of corticotropin-independent lesions. Horm Metab Res. 2008 spermatozoa physiology. J Urol. 2005 Sep;174(3):1043-4 May;40(5):347-53 Wayman C, Phillips S, Lunny C, Webb T, Fawcett L, Gross-Langenhoff M, Stenzl A, Altenberend F, Schultz A, Baxendale R, Burgess G. Phosphodiesterase 11 (PDE11) Schultz JE. The properties of phosphodiesterase 11A4 GAF regulation of spermatozoa physiology. Int J Impot Res. 2005 domains are regulated by modifications in its N-terminal May-Jun;17(3):216-23 domain. FEBS J. 2008 Apr;275(8):1643-50 Weeks JL, Zoraghi R, Beasley A, Sekhar KR, Francis SH, Horvath A, Giatzakis C, Tsang K, Greene E, Osorio P, Boikos Corbin JD. High biochemical selectivity of tadalafil, sildenafil S, Libè R, Patronas Y, Robinson-White A, Remmers E, and vardenafil for human phosphodiesterase 5A1 (PDE5) over Bertherat J, Nesterova M, Stratakis CA. A cAMP-specific PDE11A4 suggests the absence of PDE11A4 cross-reaction in phosphodiesterase (PDE8B) that is mutated in adrenal patients. Int J Impot Res. 2005 Jan-Feb;17(1):5-9 hyperplasia is expressed widely in human and mouse tissues: Cazabat L, Ragazzon B, Groussin L, Bertherat J. PRKAR1A a novel PDE8B isoform in human adrenal cortex. Eur J Hum mutations in primary pigmented nodular adrenocortical Genet. 2008 Oct;16(10):1245-53 disease. Pituitary. 2006;9(3):211-9 Horvath A, Stratakis CA. Unraveling the molecular basis of Gross-Langenhoff M, Hofbauer K, Weber J, Schultz A, Schultz micronodular adrenal hyperplasia. Curr Opin Endocrinol JE. cAMP is a ligand for the tandem GAF domain of human Diabetes Obes. 2008 Jun;15(3):227-33 phosphodiesterase 10 and cGMP for the tandem GAF domain Libé R, Fratticci A, Coste J, Tissier F, Horvath A, Ragazzon B, of phosphodiesterase 11. J Biol Chem. 2006 Feb Rene-Corail F, Groussin L, Bertagna X, Raffin-Sanson ML, 3;281(5):2841-6 Stratakis CA, Bertherat J. Phosphodiesterase 11A (PDE11A) Horvath A, Boikos S, Giatzakis C, Robinson-White A, Groussin and genetic predisposition to adrenocortical tumors. Clin L, Griffin KJ, Stein E, Levine E, Delimpasi G, Hsiao HP, Keil M, Cancer Res. 2008 Jun 15;14(12):4016-24 Heyerdahl S, Matyakhina L, Libè R, Fratticci A, Kirschner LS, Tadjine M, Lampron A, Ouadi L, Horvath A, Stratakis CA, Cramer K, Gaillard RC, Bertagna X, Carney JA, Bertherat J, Bourdeau I. Detection of somatic beta-catenin mutations in Bossis I, Stratakis CA. A genome-wide scan identifies primary pigmented nodular adrenocortical disease (PPNAD). mutations in the gene encoding phosphodiesterase 11A4 Clin Endocrinol (Oxf). 2008 Sep;69(3):367-73 (PDE11A) in individuals with adrenocortical hyperplasia. Nat Genet. 2006 Jul;38(7):794-800 Tissier F. [Sporadic adrenocortical tumors: genetics and perspectives for the pathologist]. Ann Pathol. 2008 Horvath A, Giatzakis C, Robinson-White A, Boikos S, Levine E, Oct;28(5):409-16 Griffin K, Stein E, Kamvissi V, Soni P, Bossis I, de Herder W, Carney JA, Bertherat J, Gregersen PK, Remmers EF, Stratakis Waddleton D, Wu W, Feng Y, Thompson C, Wu M, Zhou YP, CA. Adrenal hyperplasia and adenomas are associated with Howard A, Thornberry N, Li J, Mancini JA. Phosphodiesterase inhibition of phosphodiesterase 11A in carriers of PDE11A 3 and 4 comprise the major cAMP metabolizing enzymes sequence variants that are frequent in the population. Cancer responsible for insulin secretion in INS-1 (832/13) cells and rat Res. 2006 Dec 15;66(24):11571-5 islets. Biochem Pharmacol. 2008 Oct 1;76(7):884-93 Wong ML, Whelan F, Deloukas P, Whittaker P, Delgado M, Alevizaki M, Stratakis CA. Multiple endocrine neoplasias: Cantor RM, McCann SM, Licinio J. Phosphodiesterase genes advances and challenges for the future. J Intern Med. 2009 are associated with susceptibility to major depression and Jul;266(1):1-4 antidepressant treatment response. Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15124-9 Bimpaki EI, Nesterova M, Stratakis CA. Abnormalities of cAMP signaling are present in adrenocortical lesions associated with Horvath A, Stratakis C. Primary pigmented nodular ACTH-independent Cushing syndrome despite the absence of adrenocortical disease and Cushing's syndrome. Arq Bras mutations in known genes. Eur J Endocrinol. 2009 Endocrinol Metabol. 2007 Nov;51(8):1238-44 Jul;161(1):153-61 Pomara G, Morelli G, Canale D, Turchi P, Caglieresi C, Cabanero M, Laje G, Detera-Wadleigh S, McMahon FJ. Moschini C, Liguori G, Selli C, Macchia E, Martino E, Association study of phosphodiesterase genes in the Francesca F. Alterations in sperm motility after acute oral Sequenced Treatment Alternatives to Relieve Depression administration of sildenafil or tadalafil in young, infertile men. sample. Pharmacogenet Genomics. 2009 Mar;19(3):235-8 Fertil Steril. 2007 Oct;88(4):860-5 Horvath A, Korde L, Greene MH, Libe R, Osorio P, Faucz FR, Stratakis CA. Adrenocortical tumors, primary pigmented Raffin-Sanson ML, Tsang KM, Drori-Herishanu L, Patronas Y, adrenocortical disease (PPNAD)/Carney complex, and other Remmers EF, Nikita ME, Moran J, Greene J, Nesterova M, bilateral hyperplasias: the NIH studies. Horm Metab Res. 2007 Merino M, Bertherat J, Stratakis CA. Functional Jun;39(6):467-73 phosphodiesterase 11A mutations may modify the risk of familial and bilateral testicular germ cell tumors. Cancer Res. Teranishi KS, Slager SL, Garriock H, Kraft JB, Peters EJ, 2009 Jul 1;69(13):5301-6 Reinalda MS, Jenkins GD, McGrath PJ, Hamilton SP. Variants in PDE11A and PDE1A are not associated with citalopram Hsiao HP, Kirschner LS, Bourdeau I, Keil MF, Boikos SA, response. Mol Psychiatry. 2007 Dec;12(12):1061-3 Verma S, Robinson-White AJ, Nesterova M, Lacroix A, Stratakis CA. Clinical and genetic heterogeneity, overlap with Weeks JL 2nd, Zoraghi R, Francis SH, Corbin JD. N-Terminal other tumor syndromes, and atypical glucocorticoid hormone domain of phosphodiesterase-11A4 (PDE11A4) decreases secretion in adrenocorticotropin-independent macronodular affinity of the catalytic site for substrates and tadalafil, and is adrenal hyperplasia compared with other adrenocortical tumors. J Clin Endocrinol Metab. 2009 Aug;94(8):2930-7

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1030 PDE11A (phosphodiesterase 11A) Libé R, Bertherat J

Kruse LS, Møller M, Tibaek M, Gammeltoft S, Olesen J, Peverelli E, Ermetici F, Filopanti M, Elli FM, Ronchi CL, Kruuse C. PDE9A, PDE10A, and PDE11A expression in rat Mantovani G, Ferrero S, Bosari S, Beck-Peccoz P, Lania A, trigeminovascular pain signalling system. Brain Res. 2009 Jul 24;1281:25-34 Spada A. Analysis of genetic variants of phosphodiesterase 11A in acromegalic patients. Eur J Endocrinol. 2009 Laje G, Perlis RH, Rush AJ, McMahon FJ. Pharmacogenetics Nov;161(5):687-94 studies in STAR*D: strengths, limitations, and results. Psychiatr Serv. 2009 Nov;60(11):1446-57 Stratakis CA. New genes and/or molecular pathways associated with adrenal hyperplasias and related Luo HR, Wu GS, Dong C, Arcos-Burgos M, Ribeiro L, Licinio J, adrenocortical tumors. Mol Cell Endocrinol. 2009 Mar 5;300(1- Wong ML. Association of PDE11A global haplotype with major 2):152-7 depression and antidepressant drug response. Neuropsychiatr Dis Treat. 2009;5:163-70 Weeks JL 2nd, Corbin JD, Francis SH. Interactions between cyclic nucleotide phosphodiesterase 11 catalytic site and Matthiesen K, Nielsen J. Binding of cyclic nucleotides to substrates or tadalafil and role of a critical Gln-869 hydrogen phosphodiesterase 10A and 11A GAF domains does not bond. J Pharmacol Exp Ther. 2009 Oct;331(1):133-41 stimulate catalytic activity. Biochem J. 2009 Oct 12;423(3):401- 9 Louiset E, Gobet F, Libé R, Horvath A, Renouf S, Cariou J, Rothenbuhler A, Bertherat J, Clauser E, Grise P, Stratakis CA, Owen DR, Walker JK, Jon Jacobsen E, Freskos JN, Hughes Kuhn JM, Lefebvre H. ACTH-independent Cushing's syndrome RO, Brown DL, Bell AS, Brown DG, Phillips C, Mischke BV, with bilateral micronodular adrenal hyperplasia and ectopic Molyneaux JM, Fobian YM, Heasley SE, Moon JB, Stallings adrenocortical adenoma. J Clin Endocrinol Metab. 2010 WC, Joseph Rogier D, Fox DN, Palmer MJ, Ringer T, Jan;95(1):18-24 Rodriquez-Lens M, Cubbage JW, Blevis-Bal RM, Benson AG, Acker BA, Maddux TM, Tollefson MB, Bond BR, Macinnes A, This article should be referenced as such: Yu Y. Identification, synthesis and SAR of amino substituted pyrido[3,2b]pyrazinones as potent and selective PDE5 Libé R, Bertherat J. PDE11A (phosphodiesterase 11A). Atlas inhibitors. Bioorg Med Chem Lett. 2009 Aug 1;19(15):4088-91 Genet Cytogenet Oncol Haematol. 2010; 14(11):1027-1031.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1031 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Mini Review

PTPN7 (protein tyrosine phosphatase, non- receptor type 7) Marie Fridberg, Helena Tassidis, Anette Gjörloff Wingren Department of Tumor Biology, Lund University, Malmo University Hospital, Malmo, Sweden (MF, HT); Department of Laboratory Science, Health and Society, Malmo University and Malmo University Hospital, Malmo, Sweden (AGW)

Published in Atlas Database: January 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/PTPN7ID41921ch1q32.html DOI: 10.4267/2042/44887 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Protein Other names: BPTP-4; HEPTP; LC-PTP; LPTP; Description PTPNI The hematopoietic protein tyrosine phosphatase HGNC (Hugo): PTPN7 (HePTP) protein is a 40,5 kDa protein of 360 amino Location: 1q32.1 acids. It is a class I non-receptor PTP that is strongly expressed in T cells. It is composed of a C-terminal DNA/RNA classical PTP domain (residues 44-339) and a short N- terminal extension (residues 1-43) that functions to Description direct HePTP to its physiological substrates. The premessenger has 10 exons and covers 14.59 kb on Expression the genome. Thymus, spleen, leukocytes. Transcription Localisation The complete mRNA is 3784 bp long. 2 alternatively Cytoplasmic. spliced transcript variants encoding different isoforms have been found, but it has also been reported that Function transcription produces 16 different mRNAs, 15 Protein tyrosine phosphatase activity, hydrolase alternatively spliced variants and 1 unspliced form. Of activity, phosphoric monoester hydrolase activity, the 2 described variants, variant 1 (2,805 bp linear receptor activity- participation in MAPK signaling mRNA) contains a different 5' region, which includes a pathways, T cell receptor signaling pathway and part of the coding sequence when compared to variant protein amino acid dephosphorylation. 2. Variant 2 (3,263 bp linear mRNA) contains an The protein can interact with tyrosine-phosphorylated alternate 5' region, which includes an additional in- MAPK1, MAPK3 and several other MAP kinases and frame translation start codon, as compared to variant 1. suppress the MAP kinase activities. Plays a role in the It thus encodes a protein that is 39 aa longer at the N- regulation of T and B-lymphocyte development and terminus. signal transduction. Pseudogene Homology No pseudogenes have been found. HePTP has high homologies with striatal-enriched

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1032 PTPN7 (protein tyrosine phosphatase, non-receptor type 7) Fridberg M, et al.

phosphatase (STEP) and PCPTP (PC12 protein Tyr Zanke B, Squire J, Griesser H, Henry M, Suzuki H, Patterson phosphatase). B, Minden M, Mak TW. A hematopoietic protein tyrosine phosphatase (HePTP) gene that is amplified and overexpressed in myeloid malignancies maps to chromosome Mutations 1q32.1. Leukemia. 1994 Feb;8(2):236-44 Shiozuka K, Watanabe Y, Ikeda T, Hashimoto S, Kawashima Germinal H. Cloning and expression of PCPTP1 encoding protein No germline mutations are described. tyrosine phosphatase. Gene. 1995 Sep 11;162(2):279-84 Somatic Saxena M, Williams S, Gilman J, Mustelin T. Negative regulation of T cell antigen receptor signal transduction by Mutations have not been observed. hematopoietic tyrosine phosphatase (HePTP). J Biol Chem. 1998 Jun 19;273(25):15340-4 Implicated in Mustelin T, Brockdorff J, Rudbeck L, Gjörloff-Wingren A, Han S, Wang X, Tailor P, Saxena M. The next wave: protein Acute leukemia tyrosine phosphatases enter T cell antigen receptor signalling. Cell Signal. 1999 Sep;11(9):637-50 Disease Myelodysplastic syndrome and myelogenous leukemia; Oh-hora M, Ogata M, Mori Y, Adachi M, Imai K, Kosugi A, Hamaoka T. Direct suppression of TCR-mediated activation of HePTP often is dysregulated in the preleukemic extracellular signal-regulated kinase by leukocyte protein disorder myelodysplastic syndrome and myelogenous tyrosine phosphatase, a tyrosine-specific phosphatase. J leukemia (elevated expression of HePTP). The first Immunol. 1999 Aug 1;163(3):1282-8 indication of a role of HePTP in cell proliferation or Saxena M, Williams S, Brockdorff J, Gilman J, Mustelin T. differentiation came from the finding that the HePTP Inhibition of T cell signaling by mitogen-activated protein gene is located on the long arm of chromosome 1, kinase-targeted hematopoietic tyrosine phosphatase (HePTP). which is often found in extra copies (trisomy) in bone J Biol Chem. 1999 Apr 23;274(17):11693-700 marrow cells from patients with myelodysplastic Gjörloff-Wingren A, Saxena M, Han S, Wang X, Alonso A, syndrome, which is characterized by reduced Renedo M, Oh P, Williams S, Schnitzer J, Mustelin T. Subcellular localization of intracellular protein tyrosine hematopoiesis and increased risk of acute leukemia. phosphatases in T cells. Eur J Immunol. 2000 Aug;30(8):2412- Non-Hodgkin Lymphoma 21 Disease Pettiford SM, Herbst R. The MAP-kinase ERK2 is a specific substrate of the protein tyrosine phosphatase HePTP. Pediatric lymphoma; HePTP is down-regulated in Oncogene. 2000 Feb 17;19(7):858-69 pediatric lymphoma compared to control lymphoid cells. Loss of HePTP might indicate increased cell Mustelin T, Tautz L, Page R. Structure of the hematopoietic tyrosine phosphatase (HePTP) catalytic domain: structure of a proliferation and/or survival of lymphoma cells. KIM phosphatase with phosphate bound at the active site. J Mol Biol. 2005 Nov 18;354(1):150-63 References Fridberg M, Kjellström S, Anagnostaki L, Skogvall I, Mustelin T, Wiebe T, Persson JL, Dictor M, Wingren AG. Zanke B, Suzuki H, Kishihara K, Mizzen L, Minden M, Pawson Immunohistochemical analyses of phosphatases in childhood A, Mak TW. Cloning and expression of an inducible lymphoid- B-cell lymphoma: lower expression of PTEN and HePTP and specific, protein tyrosine phosphatase (HePTPase). Eur J higher number of positive cells for nuclear SHP2 in B-cell Immunol. 1992 Jan;22(1):235-9 lymphoma cases compared to controls. Pediatr Hematol Adachi M, Miyachi T, Sekiya M, Hinoda Y, Yachi A, Imai K. Oncol. 2008 Sep;25(6):528-40 Structure of the human LC-PTP (HePTP) gene: similarity in genomic organization within protein-tyrosine phosphatase This article should be referenced as such: genes. Oncogene. 1994 Oct;9(10):3031-5 Fridberg M, Tassidis H, Gjörloff Wingren A. PTPN7 (protein tyrosine phosphatase, non-receptor type 7). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1032-1033.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1033 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Mini Review

RAP1GAP (RAP1 GTPase activating protein) Zixing Chen, Xuejun Shao Jiangsu Institute of Hematology, 1st Affiliated Hospital, Soochow University, Suzhou 215006 JS, China (ZC, XS)

Published in Atlas Database: January 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/RAP1GAPID42043ch1p36.html DOI: 10.4267/2042/44888 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Function GTPase activator for the nuclear Ras-related regulatory Other names: RAPGAP; RAP1GA1; KIAA0474; protein Rap1, converting it to the putatively inactive RAP1GAP1; RAP1GAPII GDP-bound state (according to Swiss-Prot); Regulation HGNC (Hugo): RAP1GAP of small GTPase-mediated signal transduction. Location: 1p36.12 Homology Local order: From centromere to telomere: NBPF3, The RAP1GAP gene is conserved in cow, mouse, rat, ALPL, RAP1GAP, USP48, HSPG2. zebrafish, fruit fly, mosquito, and C. elegans. DNA/RNA Implicated in Description Solid tumors 25 exons encompassing about 73 kb of genomic DNA. Disease Transcription Papillary thyroid cancer, pancreatic cancer, prostate About 3.334 kb mRNA, and has three transcript cancer, melanoma tumors variant, RAP1 GTPase activating protein isoform a, b, Oncogenesis c. Rap1GAP, which acts as a GTPase activator for the nuclear Ras-related regulatory protein Rap1, was a Protein specific negative regulator of Rap1, and the monomeric G protein Rap1 has been implicated in cancer Description tumorigenesis. It signals to pathways involved in cell 663 amino acids; homodimer and heterodimer with adhesion, migration, and survival. Loss of Rap1GAP RAP1B. was discovered in papillary thyroid cancer, pancreatic cancer, prostate cancer, melanoma tumors, and their Expression cell lines, all of them exhibited increased Rap1 activity, Significant expression seen in the brain, kidney and that activation of Rap1 promotes cell proliferation and pancreas. Abundant in the cerebral cortex and migration potentiality through the mitogen-activated expressed at much lower levels in the spinal cord. Not protein kinase pathway and integrin activation. As a detected in the lymphoid tissues. (according to Swiss- putative tumor suppressor gene, Rap1GAP inhibits Prot). tumor growth but induces MMP2- and MMP9- Localisation mediated squamous cell carcinoma invasion and tumor progression, suggesting a role for this protein as a Golgi apparatus membrane; Peripheral membrane biomarker for early N-stage, aggressive squamous cell protein (according to Swiss-Prot). carcinomas.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1034 RAP1GAP (RAP1 GTPase activating protein) Chen Z, Shao X

Myelodysplastic syndrome (MDS) Mitra RS, Goto M, Lee JS, Maldonado D, Taylor JM, Pan Q, Carey TE, Bradford CR, Prince ME, Cordell KG, Kirkwood KL, Disease D'Silva NJ. Rap1GAP promotes invasion via induction of matrix The expression level of Rap1GAP in MDS patients metalloproteinase 9 secretion, which is associated with poor survival in low N-stage squamous cell carcinoma. Cancer Res. significantly increased as compared with patients with 2008 May 15;68(10):3959-69 non-malignant blood diseases or acute myeloid leukemia (AML). Among MDS patients, the expression Qi X, Chen Z, Qian J, Cen J, Gu M. Expression of Rap1GAP in human myeloid disease following microarray selection. Genet level of Rap1GAP in MDS-refractory anemia (RA) was Mol Res. 2008 Apr 29;7(2):379-87 significantly higher than that in MDS-refractory anemia Bailey CL, Kelly P, Casey PJ. Activation of Rap1 promotes with excess of blasts (RAEB). prostate cancer metastasis. Cancer Res. 2009 Jun On the other hand, inhibiting Rap1 activity by 15;69(12):4962-8 expression of Rap1GAP increased leukocyte Ika SA, Qi XF, Chen ZX. Protein RAP1GAP in human transendothelial migration, providing physiological myelodysplastic syndrome detected by flow cytometry and its relevance to the hypothesis that Rap1 augments barrier clinical relevance. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2009 function of inter-endothelial cell junctions, implying Jun;17(3):612-7 the relevance of Rap1GAP in the regulation of Nellore A, Paziana K, Ma C, Tsygankova OM, Wang Y, haematogenesis. Puttaswamy K, Iqbal AU, Franks SR, Lv Y, Troxel AB, Feldman MD, Meinkoth JL, Brose MS. Loss of Rap1GAP in papillary thyroid cancer. J Clin Endocrinol Metab. 2009 References Mar;94(3):1026-32 Wittchen ES, Worthylake RA, Kelly P, Casey PJ, Quilliam LA, Zheng H, Gao L, Feng Y, Yuan L, Zhao H, Cornelius LA. Burridge K. Rap1 GTPase inhibits leukocyte transmigration by Down-regulation of Rap1GAP via promoter hypermethylation promoting endothelial barrier function. J Biol Chem. 2005 Mar promotes melanoma cell proliferation, survival, and migration. 25;280(12):11675-82 Cancer Res. 2009 Jan 15;69(2):449-57 Zhang L, Chenwei L, Mahmood R, van Golen K, Greenson J, Li G, D'Silva NJ, Li X, Burant CF, Logsdon CD, Simeone DM. This article should be referenced as such: Identification of a putative tumor suppressor gene Rap1GAP in Chen Z, Shao X. RAP1GAP (RAP1 GTPase activating pancreatic cancer. Cancer Res. 2006 Jan 15;66(2):898-906 protein). Atlas Genet Cytogenet Oncol Haematol. 2010; Zhang Z, Mitra RS, Henson BS, Datta NS, McCauley LK, 14(11):1034-1035. Kumar P, Lee JS, Carey TE, D'Silva NJ. Rap1GAP inhibits tumor growth in oropharyngeal squamous cell carcinoma. Am J Pathol. 2006 Feb;168(2):585-96

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1035 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

RGS2 (regulator of G -protein signaling 2, 24kDa) Chau H Nguyen Department of Physiology and Pharmacology, University of Western Ontario, London, ON, N6A 5C1, Canada (CHN)

Published in Atlas Database: January 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/RGS2ID42102ch1q31.html DOI: 10.4267/2042/44889 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Expression RGS2 is ubiquitously expressed and its mRNA is found Other names: G0S8 at medium to high levels in brain, heart, lung, kidney, HGNC (Hugo): RGS2 intestine, lymphocytes, placenta, and testis (Larminie et Location: 1q31.2 al., 2004). RGS2 expression (mRNA and protein) can be Note: RGS2 is a member of the RGS protein family of upregulated in response to Gs- and Gq-mediated GTPase accelerating proteins (GAPs) for heterotrimeric signals (Song et al., 1999; Miles et al., 2000; Roy et al., G proteins. It is classified into the B/R4 subfamily. 2006b; Zou et al., 2006), as well as a variety of DNA/RNA stressful stimuli including heat shock (Zmijewski et al., 2001), oxidative stress (Zmijewski et al., 2001), DNA Description damage (Song and Jope, 2006), and infection (McCaffrey et al., 2004). The gene spans 3,233 bases. Localisation Transcription RGS2 is localized to the nucleus and the plasma 6 alternatively spliced mRNA variants have been membrane (Roy et al., 2003; Gu et al., 2007). reported; 1 unspliced form. The best characterized mRNA variant is 1355bp long arising from 5 exons: Function 32bp 5' UTR, 636bp coding sequence, 687 bp 3' UTR. Canonical functions: RGS proteins bind to heterotrimeric G proteins by way of their RGS domain Protein and act as GAPs (GTPase accelerating protein) to turn off G protein coupled receptor (GPCR) signals (Ross and Wilkie, 2000). RGS2 is unique in its selective GAP activity toward Galphaq and its low affinity for Galphai/o subunits (Heximer et al., 1997; Heximer et MTS = Membrane Targeting Sequence (residues 33-53). RGS = Regulator of G protein Signaling Domain (residues 80-205). al., 1999; Cladman and Chidiac, 2002). RGS2 has also been shown to regulate Galphas-mediated signals in a Description GAP-independent manner, which likely reflects its Primary protein product is a 211 amino acid ability to interact with other components of the G hydrophilic, basic protein (pI 9.6) with a calculated protein signaling machinery to interfere with G protein- molecular weight of 24.4 kD (Siderovski et al., 1994). effector interactions. These include adenylyl cyclase Possibly three additional functional proteins arising (Salim et al., 2003; Roy et al., 2006a), select GPCRs from alternative translation initiation of AUG codons (Bernstein et al., 2004; Hague et al., 2005; Roy et al., corresponding to amino acid residues 5, 16, and 33 of 2006a), and the GPCR-scaffolding protein, spinophilin full-length protein (Gu et al., 2008). (Wang et al., 2005). RGS2 has been implicated in the RGS2 can be phosphorylated by PKC and PKGIalpha control of vascular and neurological functions (Ingi et (Cunningham et al., 2001; Tang et al., 2003). al., 1998; Kammermeier and Ikeda, 1999; Oliveira-

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1036 RGS2 (regulator of G-protein signaling 2, 24kDa) Nguyen CH

Dos-Santos et al., 2000; Heximer et al., 2003; Tang et alterations in proliferation and differentiation in these al., 2003). cells. Noncanonical functions: RGS2 has been shown to Hypertension bind and regulate the activity of proteins outside the realm of GPCR signaling networks including tubulin Note (Heo et al., 2006), the TRPV6 calcium channel Studies using RGS2 knockout mice have identified a (Schoeber et al., 2006), and the eukaryotic initation role for RGS2 in vascular function and blood pressure factor, eIF2B (Nguyen et al., 2009). regulation (Heximer et al., 2003; Tang et al., 2003). Homology References All RGS proteins share a homologous (45-80%) 120 Siderovski DP, Heximer SP, Forsdyke DR. A human gene amino acid RGS domain that confers their binding to encoding a putative basic helix-loop-helix phosphoprotein heterotrimeric G protein alpha subunits. RGS2 shares whose mRNA increases rapidly in cycloheximide-treated blood highest homology to other members of the B/R4 mononuclear cells. DNA Cell Biol. 1994 Feb;13(2):125-47 subfamily (Ross and Wilkie, 2000; Sierra et al., 2002). Heximer SP, Watson N, Linder ME, Blumer KJ, Hepler JR. RGS2/G0S8 is a selective inhibitor of Gqalpha function. Proc Implicated in Natl Acad Sci U S A. 1997 Dec 23;94(26):14389-93 Ingi T, Krumins AM, Chidiac P, Brothers GM, Chung S, Snow Colorectal cancer BE, Barnes CA, Lanahan AA, Siderovski DP, Ross EM, Gilman Note AG, Worley PF. Dynamic regulation of RGS2 suggests a novel mechanism in G-protein signaling and neuronal plasticity. J The correlation between RGS2 expression and survival Neurosci. 1998 Sep 15;18(18):7178-88 time of patients with colorectal cancer was studied Heximer SP, Srinivasa SP, Bernstein LS, Bernard JL, Linder (Jiang et al., 2009). The authors determined that RGS2 ME, Hepler JR, Blumer KJ. G protein selectivity is a mRNA levels were lower in tissues from patients with determinant of RGS2 function. J Biol Chem. 1999 Nov recurring colorectal cancer in comparison to those 26;274(48):34253-9 patients without recurrence; however, this study did not Kammermeier PJ, Ikeda SR. Expression of RGS2 alters the identify any causal relationship between RGS2 coupling of metabotropic glutamate receptor 1a to M-type K+ expression and colorectal cancer. and N-type Ca2+ channels. Neuron. 1999 Apr;22(4):819-29 Breast cancer Song L, De Sarno P, Jope RS. Muscarinic receptor stimulation increases regulators of G-protein signaling 2 mRNA levels Note through a protein kinase C-dependent mechanism. J Biol RGS2 mRNA expression was examined in a number of Chem. 1999 Oct 15;274(42):29689-93 breast cancer cell lines and solid breast cancers Miles RR, Sluka JP, Santerre RF, Hale LV, Bloem L, (Smalley et al., 2007). The authors found that RGS2 Boguslawski G, Thirunavukkarasu K, Hock JM, Onyia JE. was expressed at higher levels in the majority of solid Dynamic regulation of RGS2 in bone: potential new insights into parathyroid hormone signaling mechanisms. breast cancers in comparison to control mammary cells. Endocrinology. 2000 Jan;141(1):28-36 No causal relationship between RGS2 expression and breast cancer was identified. Oliveira-Dos-Santos AJ, Matsumoto G, Snow BE, Bai D, Houston FP, Whishaw IQ, Mariathasan S, Sasaki T, Wakeham Prostate cancer A, Ohashi PS, Roder JC, Barnes CA, Siderovski DP, Penninger JM. Regulation of T cell activation, anxiety, and Note male aggression by RGS2. Proc Natl Acad Sci U S A. 2000 RGS2 expression was found to be selectively decreased Oct 24;97(22):12272-7 in androgen-independent prostate cancer cells Ross EM, Wilkie TM. GTPase-activating proteins for compared to androgen-dependent cancer cells, as well heterotrimeric G proteins: regulators of G protein signaling as in human prostate tumor samples (Cao et al., 2006). (RGS) and RGS-like proteins. Annu Rev Biochem. The authors show that exogenous RGS2 is sufficient to 2000;69:795-827 inhibit androgen-independent receptor signaling and Cunningham ML, Waldo GL, Hollinger S, Hepler JR, Harden clonogenic growth of androgen-independent prostate TK. Protein kinase C phosphorylates RGS2 and modulates its capacity for negative regulation of Galpha 11 signaling. J Biol cancer cells. Chem. 2001 Feb 23;276(8):5438-44 Acute myeloid leukemia Zmijewski JW, Song L, Harkins L, Cobbs CS, Jope RS. Note Oxidative stress and heat shock stimulate RGS2 expression in 1321N1 astrocytoma cells. Arch Biochem Biophys. 2001 Aug RGS2 expression was found to be repressed by an 15;392(2):192-6 activating mutation of the fetal liver tyrosine kinase 3 Cladman W, Chidiac P. Characterization and comparison of (Flt3-ITD), which is associated with acute myeloid RGS2 and RGS4 as GTPase-activating proteins for m2 leukemia (Schwable et al., 2005). The authors muscarinic receptor-stimulated G(i). Mol Pharmacol. 2002 demonstrate that exogenous RGS2 is sufficient to Sep;62(3):654-9 modulate Flt3-ITD-mediated signaling in myeloid cells. Sierra DA, Gilbert DJ, Householder D, Grishin NV, Yu K, Further, RGS2 is able to reverse the Flt3-ITD-induced Ukidwe P, Barker SA, He W, Wensel TG, Otero G, Brown G,

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1037 RGS2 (regulator of G-protein signaling 2, 24kDa) Nguyen CH

Copeland NG, Jenkins NA, Wilkie TM. Evolution of the androgen-independent activation of androgen receptor in regulators of G-protein signaling multigene family in mouse prostate cancer cells. Oncogene. 2006 Jun 22;25(26):3719-34 and human. Genomics. 2002 Feb;79(2):177-85 Heo K, Ha SH, Chae YC, Lee S, Oh YS, Kim YH, Kim SH, Kim Heximer SP, Knutsen RH, Sun X, Kaltenbronn KM, Rhee MH, JH, Mizoguchi A, Itoh TJ, Kwon HM, Ryu SH, Suh PG. RGS2 Peng N, Oliveira-dos-Santos A, Penninger JM, Muslin AJ, promotes formation of neurites by stimulating microtubule Steinberg TH, Wyss JM, Mecham RP, Blumer KJ. polymerization. Cell Signal. 2006 Dec;18(12):2182-92 Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice. J Clin Invest. 2003 Feb;111(4):445-52 Roy AA, Baragli A, Bernstein LS, Hepler JR, Hébert TE, Chidiac P. RGS2 interacts with Gs and adenylyl cyclase in Roy AA, Lemberg KE, Chidiac P. Recruitment of RGS2 and living cells. Cell Signal. 2006 Mar;18(3):336-48 RGS4 to the plasma membrane by G proteins and receptors reflects functional interactions. Mol Pharmacol. 2003 Roy AA, Nunn C, Ming H, Zou MX, Penninger J, Kirshenbaum Sep;64(3):587-93 LA, Dixon SJ, Chidiac P. Up-regulation of endogenous RGS2 mediates cross-desensitization between Gs and Gq signaling Salim S, Sinnarajah S, Kehrl JH, Dessauer CW. Identification in osteoblasts. J Biol Chem. 2006 Oct 27;281(43):32684-93 of RGS2 and type V adenylyl cyclase interaction sites. J Biol Chem. 2003 May 2;278(18):15842-9 Schoeber JP, Topala CN, Wang X, Diepens RJ, Lambers TT, Hoenderop JG, Bindels RJ. RGS2 inhibits the epithelial Ca2+ Tang KM, Wang GR, Lu P, Karas RH, Aronovitz M, Heximer channel TRPV6. J Biol Chem. 2006 Oct 6;281(40):29669-74 SP, Kaltenbronn KM, Blumer KJ, Siderovski DP, Zhu Y, Mendelsohn ME. Regulator of G-protein signaling-2 mediates Song L, Jope RS. Cellular stress increases RGS2 mRNA and vascular smooth muscle relaxation and blood pressure. Nat decreases RGS4 mRNA levels in SH-SY5Y cells. Neurosci Med. 2003 Dec;9(12):1506-12 Lett. 2006 Jul 24;402(3):205-9 Bernstein LS, Ramineni S, Hague C, Cladman W, Chidiac P, Zou MX, Roy AA, Zhao Q, Kirshenbaum LA, Karmazyn M, Levey AI, Hepler JR. RGS2 binds directly and selectively to the Chidiac P. RGS2 is upregulated by and attenuates the M1 muscarinic acetylcholine receptor third intracellular loop to hypertrophic effect of alpha1-adrenergic activation in cultured modulate Gq/11alpha signaling. J Biol Chem. 2004 May ventricular myocytes. Cell Signal. 2006 Oct;18(10):1655-63 14;279(20):21248-56 Gu S, He J, Ho WT, Ramineni S, Thal DM, Natesh R, Tesmer Larminie C, Murdock P, Walhin JP, Duckworth M, Blumer KJ, JJ, Hepler JR, Heximer SP. Unique hydrophobic extension of Scheideler MA, Garnier M. Selective expression of regulators the RGS2 amphipathic helix domain imparts increased plasma of G-protein signaling (RGS) in the human central nervous membrane binding and function relative to other RGS R4/B system. Brain Res Mol Brain Res. 2004 Mar 17;122(1):24-34 subfamily members. J Biol Chem. 2007 Nov 9;282(45):33064- 75 McCaffrey RL, Fawcett P, O'Riordan M, Lee KD, Havell EA, Brown PO, Portnoy DA. A specific gene expression program Smalley MJ, Iravani M, Leao M, Grigoriadis A, Kendrick H, triggered by Gram-positive bacteria in the cytosol. Proc Natl Dexter T, Fenwick K, Regan JL, Britt K, McDonald S, Lord CJ, Acad Sci U S A. 2004 Aug 3;101(31):11386-91 Mackay A, Ashworth A. Regulator of G-protein signalling 2 mRNA is differentially expressed in mammary epithelial Hague C, Bernstein LS, Ramineni S, Chen Z, Minneman KP, subpopulations and over-expressed in the majority of breast Hepler JR. Selective inhibition of alpha1A-adrenergic receptor cancers. Breast Cancer Res. 2007;9(6):R85 signaling by RGS2 association with the receptor third intracellular loop. J Biol Chem. 2005 Jul 22;280(29):27289-95 Gu S, Anton A, Salim S, Blumer KJ, Dessauer CW, Heximer SP. Alternative translation initiation of human regulators of G- Schwäble J, Choudhary C, Thiede C, Tickenbrock L, Sargin B, protein signaling-2 yields a set of functionally distinct proteins. Steur C, Rehage M, Rudat A, Brandts C, Berdel WE, Müller- Mol Pharmacol. 2008 Jan;73(1):1-11 Tidow C, Serve H. RGS2 is an important target gene of Flt3- ITD mutations in AML and functions in myeloid differentiation Nguyen CH, Ming H, Zhao P, Hugendubler L, Gros R, Kimball and leukemic transformation. Blood. 2005 Mar 1;105(5):2107- SR, Chidiac P. Translational control by RGS2. J Cell Biol. 2009 14 Sep 7;186(5):755-65 Wang X, Zeng W, Soyombo AA, Tang W, Ross EM, Barnes Jiang Z, Wang Z, Xu Y, Wang B, Huang W, Cai S. Analysis of AP, Milgram SL, Penninger JM, Allen PB, Greengard P, RGS2 expression and prognostic significance in stage II and III Muallem S. Spinophilin regulates Ca2+ signalling by binding colorectal cancer. Biosci Rep. 2010 Dec;30(6):383-90 the N-terminal domain of RGS2 and the third intracellular loop of G-protein-coupled receptors. Nat Cell Biol. 2005 This article should be referenced as such: Apr;7(4):405-11 Nguyen CH. RGS2 (regulator of G-protein signaling 2, 24kDa). Cao X, Qin J, Xie Y, Khan O, Dowd F, Scofield M, Lin MF, Tu Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1036- Y. Regulator of G-protein signaling 2 (RGS2) inhibits 1038.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1038 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Mini Review

SOX11 (SRY (sex determining region Y) -box 11) Xiao Wang, Birgitta Sander Department of Pathology, F46, Karolinska Institutet, SE 141 86 Stockholm, Sweden (XW), Department of Pathology, F46, Karolinska University Hospital and Karolinska Institutet, SE 141 86 Stockholm, Sweden (BS)

Published in Atlas Database: January 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/SOX11ID42357ch2p25.html DOI: 10.4267/2042/44890 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

domains: a Sry-related high-mobility group (HMG) box Identity (Sox) DNA-binding domain, located in the N-terminal HGNC (Hugo): SOX11 third (47-122), and a transactivation domain (TAD), Location: 2p25.2 located at the C-terminus (408-441) (Dy et al., 2008; Penzo-Méndez, 2009). DNA/RNA Expression SOX11 is widely expressed during organogenesis in the embryo and is highly expressed in the central and peripheral nervous system of the human fetus (Jay et al., 1995; Sock et al., 2004). SOX11 expression is more restricted by birth, and low transcript levels of SOX11 The human SOX11 gene. The only exon is indicated by the red were detected in adult colon, small intestine, heart and box. The number above the box shows the size of the exon. brain (Weigle et al., 2005). High level of SOX11 Description mRNA is only present in normal prostate tissue (Brennan et al., 2009). The intronless gene encompasses 8718 base pairs and is located at 2p25.2. Localisation Transcription Nucleus. The mRNA SOX11 transcript contains one exon with Function 8718 base pairs. SOX11 contains domains that may function as transcriptional activators or repressors and is a member Protein of the group C SOX transcription factor family. It appears to have critical roles in embryonic neurogenesis and development of many organ systems including heart, palate and eyelids (Sock et al., 2004). SOX11 can, together with SOX4, regulate the differentiation of neuronal progenitors (Bergsland et The human SOX11 protein and functional domains. Numbers indicate the amino acid positions at the beginning and al., 2006). SOX11 is involved in the transcriptional the end of each domain. The grey bar shows the High-Mobility- regulation of specific gene expression programs in Group (HMG) box DNA-binding domain; and the dark blue bar adult neurogenesis at the stage of the immature neuron shows the TransActivation Domain (TAD). (Haslinger et al., 2009). SOX11 controls morphological Description maturation such as neurite growth (Jankowski et al., The human SOX11 protein has 441 amino acids and 2006) and modulates the regeneration following 46.7 kDa molecular weight. It contains two functional peripheral nerve injury (Jankowski et al., 2009). The class-III beta-tubulin gene TUBB3 is the first and still

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1039 SOX11 (SRY (sex determining region Y)-box 11) Wang X, Sander B

the unique gene to be identified as a direct target of - 2/3 cases of T-cell prolymphocytic leukemia (Dictor SOX11 (Dy et al., 2008). SOX11 has been suggested to et al., 2009; Mozos et al., 2009). bind and regulate LINE retrotransposons (Tchénio, Prognosis 2000). Expression of SOX11 in mantle cell lymphoma is not Homology only a new diagnostic marker but may also carry The two domains are highly conserved regions between information related to the clinical and biological species (from human to fly). In the SOX C group, behaviour (Wang et al., 2008). consisting of SOX4, SOX11 and SOX12, the HMG box Ovarian cancer and C33 domains are more highly conserved among Note Sox4 orthologues and SOX11 orthologues than among SOX11 is overexpressed in many epithelial ovarian SOX12. cancers, and loss of Sox11 is associated with a decreased recurrence-free survival and a more Implicated in aggressive phenotype (Brennan et al., 2009). Malignant glioma Prognosis Note SOX11 is differently expressed in epithelial ovarian SOX11 was identified by screening an expression cancer and is a prognostic marker. database for genes highly expressed in glioblastoma multiforme (Weigle et al., 2005). Overexpression of References SOX11 can prevent tumorigenesis of glioma-initiating Jay P, Gozé C, Marsollier C, Taviaux S, Hardelin JP, Koopman cells by inducing their neuronal differentiation (Hide et P, Berta P. The human SOX11 gene: cloning, chromosomal al., 2009). assignment and tissue expression. Genomics. 1995 Sep 20;29(2):541-5 Disease Tchénio T, Casella JF, Heidmann T. Members of the SRY Malignant glioma comprises of the majority of primary family regulate the human LINE retrotransposons. Nucleic brain tumors with 16800 new cases reported each year Acids Res. 2000 Jan 15;28(2):411-5 in USA. Lee CJ, Appleby VJ, Orme AT, Chan WI, Scotting PJ. Prognosis Differential expression of SOX4 and SOX11 in SOX11 can serve as a target antigen for glioma- medulloblastoma. J Neurooncol. 2002 May;57(3):201-14 directed cytotoxic T lymphocytes (CTLs), and this Sock E, Rettig SD, Enderich J, Bösl MR, Tamm ER, Wegner novel CTL epitope may serve as a suitable candidate M. Gene targeting reveals a widespread role for the high- mobility-group transcription factor Sox11 in tissue remodeling. for a T cell-based immunotherapy of glioma patients Mol Cell Biol. 2004 Aug;24(15):6635-44 (Schmitz et al., 2007). Weigle B, Ebner R, Temme A, Schwind S, Schmitz M, Medulloblastoma Kiessling A, Rieger MA, Schackert G, Schackert HK, Rieber EP. Highly specific overexpression of the transcription factor Note SOX11 in human malignant gliomas. Oncol Rep. 2005 SOX11 has been shown to be overexpressed in most Jan;13(1):139-44 classical medulloblastomas (Lee et al., 2002). Bergsland M, Werme M, Malewicz M, Perlmann T, Muhr J. The Disease establishment of neuronal properties is controlled by Sox4 and Medulloblastomas are brain tumors occurred in the Sox11. Genes Dev. 2006 Dec 15;20(24):3475-86 cerebellum. Jankowski MP, Cornuet PK, McIlwrath S, Koerber HR, Albers KM. SRY-box containing gene 11 (Sox11) transcription factor Haematological malignancies is required for neuron survival and neurite growth. Note Neuroscience. 2006 Dec 1;143(2):501-14 Overexpression of SOX11 was first described as a Schmitz M, Wehner R, Stevanovic S, Kiessling A, Rieger MA, unique marker for a specific malignant B cell Temme A, Bachmann M, Rieber EP, Weigle B. Identification of a naturally processed T cell epitope derived from the glioma- lymphoma, mantle cell lymphoma (Ek et al., 2008; associated protein SOX11. Cancer Lett. 2007 Jan 8;245(1- Wang et al., 2008). 2):331-6 Subsequent studies have demonstrated that Sox11 is Dy P, Penzo-Méndez A, Wang H, Pedraza CE, Macklin WB, also present in: Lefebvre V. The three SoxC proteins--Sox4, Sox11 and Sox12- - 50% of hairy cell leukemia (Chen et al., 2009; Dictor -exhibit overlapping expression patterns and molecular et al., 2009); properties. Nucleic Acids Res. 2008 May;36(9):3101-17 - 25-50% of Burkitt lymphoma cases (Dictor et al., Ek S, Dictor M, Jerkeman M, Jirström K, Borrebaeck CA. 2009; Mozos et al., 2009); Nuclear expression of the non B-cell lineage Sox11 - Almost all of B-cell lymphoblastic transcription factor identifies mantle cell lymphoma. Blood. leukemia/lymphomas and T-cell lymphoblastic 2008 Jan 15;111(2):800-5 leukemia/lymphomas;

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1040 SOX11 (SRY (sex determining region Y)-box 11) Wang X, Sander B

Wang X, Asplund AC, Porwit A, Flygare J, Smith CI, Jankowski MP, McIlwrath SL, Jing X, Cornuet PK, Salerno KM, Christensson B, Sander B. The subcellular Sox11 distribution Koerber HR, Albers KM. Sox11 transcription factor modulates pattern identifies subsets of mantle cell lymphoma: correlation peripheral nerve regeneration in adult mice. Brain Res. 2009 to overall survival. Br J Haematol. 2008 Oct;143(2):248-52 Feb 23;1256:43-54 Brennan DJ, Ek S, Doyle E, Drew T, Foley M, Flannelly G, Mozos A, Royo C, Hartmann E, De Jong D, Baró C, Valera A, O'Connor DP, Gallagher WM, Kilpinen S, Kallioniemi OP, Fu K, Weisenburger DD, Delabie J, Chuang SS, Jaffe ES, Jirstrom K, O'Herlihy C, Borrebaeck CA. The transcription Ruiz-Marcellan C, Dave S, Rimsza L, Braziel R, Gascoyne RD, factor Sox11 is a prognostic factor for improved recurrence- Solé F, López-Guillermo A, Colomer D, Staudt LM, Rosenwald free survival in epithelial ovarian cancer. Eur J Cancer. 2009 A, Ott G, Jares P, Campo E. SOX11 expression is highly May;45(8):1510-7 specific for mantle cell lymphoma and identifies the cyclin D1- negative subtype. Haematologica. 2009 Nov;94(11):1555-62 Dictor M, Ek S, Sundberg M, Warenholt J, György C, Sernbo S, Gustavsson E, Abu-Alsoud W, Wadström T, Borrebaeck C. Chen YH, Gao J, Fan G, Peterson LC. Nuclear expression of Strong lymphoid nuclear expression of SOX11 transcription sox11 is highly associated with mantle cell lymphoma but is factor defines lymphoblastic neoplasms, mantle cell lymphoma independent of t(11;14)(q13;q32) in non-mantle cell B-cell and Burkitt's lymphoma. Haematologica. 2009 neoplasms. Mod Pathol. 2010 Jan;23(1):105-12 Nov;94(11):1563-8 Penzo-Méndez AI. Critical roles for SoxC transcription factors Haslinger A, Schwarz TJ, Covic M, Chichung Lie D. in development and cancer. Int J Biochem Cell Biol. 2010 Expression of Sox11 in adult neurogenic niches suggests a Mar;42(3):425-8 stage-specific role in adult neurogenesis. Eur J Neurosci. 2009 Jun;29(11):2103-14 This article should be referenced as such: Hide T, Takezaki T, Nakatani Y, Nakamura H, Kuratsu J, Wang X, Sander B. SOX11 (SRY (sex determining region Y)- Kondo T. Sox11 prevents tumorigenesis of glioma-initiating box 11). Atlas Genet Cytogenet Oncol Haematol. 2010; cells by inducing neuronal differentiation. Cancer Res. 2009 14(11):1039-1041. Oct 15;69(20):7953-9

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1041 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

THY1 (Thy -1 cell surface antigen) John E Bradley, James S Hagood Departments of Pediatrics, Biochemistry and Molecular Genetics, University of Alabama-Birmingham, AL, USA (JEB), Department of Pediatrics, University of California at San Diego, USA (JSH)

Published in Atlas Database: January 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/THY1ID45672ch11q23.html DOI: 10.4267/2042/44891 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

For example, Thy1 is expressed in mouse thymocytes Identity and splenocytes, but only thymocytes in rat. The Other names: CD90; CDw90; FLJ33325 absence of Thy1 in rat splenocytes is attributed to a HGNC (Hugo): THY1 three nucleotide difference in a conserved 36 bp region within the third intron. In mice, this 36 bp region can Location: 11q23.3 bind an Ets-l-like nuclear factor expressed by both mouse thymocytes and splenocytes. In rats, the three DNA/RNA nucleotide difference renders the 36 bp region no Description longer capable of binding the similar Ets-l-like nuclear factor expressed by rats. However, rat thymocytes but 4 exons; DNA size: 5591. not splenocytes express another nuclear factor which Transcription does recognize the 36 bp region and this is thought to account for the expression of Thy1 in rat thymocytes Transcription of THY1 is initiated at multiple sites but not splenocytes. In humans, THY1 is detected in producing an approximately 5591 bp transcript. After the brain, spleen, kidneys, but not thymus. In mouse, splicing, the transcript is reduced to 2143 bp. Thy1 is detected in the brain, spleen, thymus, but not Transcriptional regulation for tissue-specific expression kidneys. In transgenic mice, deletion of half the 3' end of Thy-1, as well as for controlling expression in cell of intron 1 prevents expression of Thy1 in the brain but sub-populations, and in some cancers, is governed by a allows for its expression in the thymus. The control number of mechanisms. For tissue-specific elements within the first intron of Thy-1 are conserved transcriptional regulation, the regulatory elements are in human and mouse, as replacement of the first intron found exclusively downstream of the transcription in mouse with that from human causes no detectable initiation site within the gene itself. Differential tissue change in Thy1 expression in the brain. expression of Thy1 exists between species as closely related as mouse and rat.

Organization of the human THY1 gene and control elements. There are sequences conferring tissue specificity for the brain in the first intron and kidney in the third intron.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1042 THY1 (Thy-1 cell surface antigen) Bradley JE, Hagood JS

Differences between intron 3 of mouse and human additional intact human chromosome 11 into HONE1 Thy-1 seem to account for expression of Thy-1 in cells decreases colony formation with re-expression of human but not mouse kidney and mouse but not human THY1. Tumor segregants of the HONE1 microcell thymus. In transgenic mice, Thy1 is no longer hybrids were all negative for THY1. Concurrently, the expressed in the thymus but ectopically expressed in region 11q22-23 is shown to be critical for the kidney when the third intron of mouse Thy1 is tumorigenicty in NPC. In both rat and human lung replaced with the third intron of human THY1. The fibroblasts, CpG islands in the Thy-1 gene promoter are aforementioned downstream control elements require at hypermethylated in the Thy-1 negative fibroblast a minimum 300 bp of the endogenous Thy1 promoter subpopulation but not in the positive. Thy1 expression for transcription to occur. Interestingly, the endogenous is induced in Thy1 (-) fibroblasts by treatment with 5- Thy1 promoter in itself does not elicit transcription or aza-2'-deoxycytidine, a DNA methyltransferase tissue specificity absent the downstream elements. inhibitor. Suppression of THY1 transcription via Conversely, the downstream elements are able to direct hypermethylation of its promoter in THY1 (-) lung tissue-specific transcription of Thy1 with a fibroblasts has implications in the disease idiopathic heterologous promoter. Therefore, the downstream pulmonary fibrosis (IPF). Fibroblastic foci are control elements are "promiscuous" with regard to a populated predominantly by THY1 (-) myofibroblasts promoter, while the endogenous promoter is and methylation-specific PCR-in situ hybridization has "monogamous" with the downstream control elements. demonstrated THY1 promoters within these areas to be The validity of these assertions is exemplified in the hypermethylated. design of the murine thy1.2 genomic expression cassette for driving expression in the nervous system. Protein In this cassette, the coding sequences, as well as the third intron of thy1.2 have all been removed, but the Description first intron is retained. Human and mouse Thy-1 are both initially translated as Suppression of Thy-1 transcription within sub- a 161 and 162 amino acid pro-form, respectively. In populations of lung fibroblasts and the tumorigenic mouse, there are two alleles that encode two proteins nasopharyngeal cell carcinoma (NPC) cell line HONE1 distinguished by having either arginine or glutamine at is shown to occur via hypermethylation of CpG position 89. Humans have only one allele of THY1. (cytosine-guanine) islands in the Thy-1 gene promoter. The first 19 aa of the pro-form are a localization signal Moreover, THY1 is thought to function as a tumor that targets it into the ER. Initially, the c-terminal suppressor in NPC as microcell-mediated transfer of an residues 131-161 function as a trans-membrane domain within the ER.

THY1 molecule and proposed soluble forms. THY1 is initially generated as a 161 aa pro form. The initial 19 aa signal peptide is removed, and the terminal 31 aa are replaced with a GPI anchor, generating the mature form, which is anchored to the outer leaflet of the cell membrane by the diacyl group of the GPI anchor. N-linked glycosylation sites depict conserved asparagines within murine Thy1 that are known to be glycosylated. Soluble Thy-1 could be generated either by cleavage of the GPI anchor by GPI-PLD, or by undefined proteases acting at as yet undetermined cleavage sites.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1043 THY1 (Thy-1 cell surface antigen) Bradley JE, Hagood JS

Thy-1 undergoes several post translation modifications, strongly with histological and physiological indicators including proteolytic cleavage, N-linked glycosylation, of brain maturation. Thus, expression of Thy-1 is and addition of a GPI moiety. The localization signal developmentally regulated in the brain. As the brain and trans-membrane domain are proteolytically cleaved develops, expression of Thy1 mRNA precedes away leaving a core protein composed of residues 20- detection of protein by several days, thereby suggesting 131. The N-linked glycosylation sites of murine Thy1 post-transcription regulation of Thy-1 mRNA as a are at asparagine residues 42, 94, and 118. Only two of mechanism for controlling temporal expression of Thy- these residues are conserved in human at positions 42 1 protein in the developing brain. This mode of and 119. The carbohydrate content of THY1 accounts regulation has been shown to be an intrinsic attribute of for nearly 30% of its molecular mass, which ranges immature neurons. Mature Thy1.1-expressing neurons from 25 to 37 kDa. Between species, tissue types, and fused with immature Thy1.2-negative neurons to form cells in different stages of development: these heterokaryons become Thy1 negative within 16 h. As carbohydrate moieties may vary dramatically. After factors that maintained the immature condition of the removal of the trans-membrane domain, a GPI moiety Thy1.2 negative neuron counterpart presumably give is attached to the c-terminal residue of the core protein, way, the heterokaryons express both Thy1.1 and cysteine 130. The GPI moiety contains two fatty-acyl Thy1.2 within 3-4 days after becoming negative. This groups that embed into the membrane thereby suggests that a developmentally regulated diffusible anchoring Thy-1 to the cell surface. Thus, Thy-1 has no suppressor molecule inhibits translation of the Thy1 intra-cellular domain. Thy-1 is a member of the protein in immature neurons. This method of regulation immunoglobulin superfamily and as such possesses is perhaps a means to forgo the time needed to cysteine residues which form disulfide bonds. A transcribe Thy-1 mRNA and thereby prime the soluble variety of Thy-1 exists and is presumably immature neuron for immediate expression of Thy-1 produced by a proteolytic and/or lipolytic cleavage at protein to coincide with maturation. In response to the cell surface. If the latter is the case, it is presumed injury, Thy1 expression in mature neurons mimics that to occur in close proximity to the c-terminus. of a developing neuron. In young adult rats, Thy1 Completely deglycosylated membranous and soluble expression dramatically decreases in dorsal root THY1 have indistinguishable migration speeds through ganglion neurons two days post a crush injury of the a polyacrylamide gel. sciatic nerve reaching a low around day four. Thy1 Expression expression gradually returns to pre-injury levels 1 week after the sciatic nerve crush and coincides with In mouse and human, Thy-1 is expressed at the cell recovery of sensory function. Central nervous system surface of mature neurons, a subset of fibroblasts, and neurons do not have the same potential to recover from activated natural killer cells. With the exception of traumatic injury as peripheral nervous system neurons these cell types, mouse and human each have unique do. Response to traumatic injury by central nervous Thy-1 expression profiles. Thy1 covers up to 10-20% system ganglion cells also differs with respect to Thy1 of mouse thymocyte cell surface but levels diminish in expression. Specifically, optic nerve crush results in locations of greater thymocyte maturation. Specifically, cell loss due to apoptosis after 2 weeks. Prior to any cortical thymocytes express higher levels of Thy1 than cell loss, levels of Thy1 mRNA decrease over the medullary thymocytes and Lymph node cells have course of 7 days with no change in the number of Thy1 levels less than both. The only human thymocytes to expressing cells. This suggests the decrease in Thy1 express THY1 are a small population of cortical mRNA is an injury response rather than a consequence thymocytes, whereas expression of Thy1 in the mouse of apoptosis. The optic ganglion cells of Bax knockout is broader and also includes peripheral T cells. In mice are resistant to cell death following optic nerve humans, THY1 is also expressed by endothelial cells crush. Despite this, the same decrease in Thy1 mRNA (conditionally), smooth muscle cells, some glial cells, a is observed following optic nerve crush in Bax subset of CD34 (+) bone marrow cells, and umbilical knockout mice. Additional means of optic nerve injury cord blood- and fetal liver-derived hematopoietic stem also cause a decrease in Thy1 mRNA levels including cells. intravitreal injections of N-methyl-D-aspartate and A soluble variety of THY1 is detectable in serum, induced elevated intraocular pressure. cerebral spinal fluid, wound fluid from venous leg ulcers, and the synovial fluid from joints in rheumatoid Localisation arthritis. Cultured lung fibroblasts shed THY1 into the At the cell surface, Thy-1, like many GPI anchored media when treated with pro-inflammatory cyokines, proteins, localizes to cholesterol-rich lipid rafts. such as IL-1beta and TNF-alpha. The opposite effect is Release of Thy-1 into the extracellular space and into elicited in endothelial cells, in which pro-inflammatory body fluids, such as serum and cerebral spinal fluid, cytokines stimulate increased THY1 expression. occurs via unknown mechanisms. In-vitro, both Relative to the neonatal and developing brain, the adult mammalian GPI-PLD and bacterial PLC are capable of brain expresses far greater levels of THY1. Moreover, separating the diacyl glycerol from the remainder of the postnatal increase in Thy-1 expression coincides GPI-moiety. When Thy-1 is released from the cell

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1044 THY1 (Thy-1 cell surface antigen) Bradley JE, Hagood JS

surface by GPI-PLD the phosphate is not retained, but CD4+CD8+ double-positive to the CD4+ or CD8+ is when released by PLC. In order for Thy-1 to be single-positive mature T cell. Thy1 supports adhesion susceptible to release by GPI-PLD, lipid rafts must be of thymocytes to thymic epithelial cells. Accordingly, disrupted by detergents or saponins. PLC has no such the contacts between thymus cells of the Thy1 null requirement. However, Thy1 in certain cell types is mice are atypical as evaluated by electron microscopy. more resistant to PLC. Thus, Thy-1 is thought to be The role of Thy-1 in thymocyte adhesion and afforded some protection from GPI-PLD catalyzed maturation may not be mutually exclusive. Thy1 seems release by its localization within lipid rafts. to have a continued role in T cell activity beyond For Thy-1 to signal, it must be localized to its native maturation from thymocytes. Cross-linking Thy1 using lipid raft microdomain. Thy1 (-) neurons grown on a bivalent antibodies against Thy1 results in T cell monolayer of astrocytes and expressing exogenous activation as indicated by proliferation and IL-2 human THY1 or mouse Thy1.2 experienced inhibited synthesis. It is important to note there is no known neurite outgrowth. Yet under the same conditions, ligand for Thy-1 that the cross-linking antibody Thy1 (-) neurons expressing a construct of Thy1 in presumably mimics. Traditionally, activation of a T cell which the GPI anchor is replaced by the is thought to require two simultaneous signals. One is a transmembrane domain of CD8 have normal neurite B7 family member engaging T cell CD28 receptor and outgrowth. The transmembrane domain of CD8 does the other is the T cell receptor being presented its not localize Thy1 to lipid raft microdomains. This same specific antigen by an MHC. Cross-linking Thy1 with construct was later used in experiments to assess the antibodies partially supplies the latter signal to activate role of the Thy1 GPI anchor in modulating fibroblast T cells when the CD28 receptor is engaged by anti- phenotypes. Not unlike the results in the neuron CD28 antibodies. The activation is only partial experiments, Thy1 (-) fibroblasts made to express the because, although the T cells adhere to target cells and Thy1-CD8 construct maintained their "negative" express perforin, granzyme B, and Fas ligand, they are phenotype in that they remained insensitive to unable to kill target cells. The specific role Thy1 has in thrombospondin-mediated transient phosphorylation of T cell activation and thymocyte maturation in vivo, and FAK and SFK, focal adhesion disassembly, and whether they are related is unknown. migration. Thy-1 expression modulates fibroblast phenotype. Function Pulmonary fibroblasts sorted into Thy-1 (+) and (-) populations have dissimilar potential for differentiating The Thy1 antigen was initially discovered in an attempt into myofibroblasts, response to pro-inflammatory to raise antiserum against leukemia-specific antigens cytokines, and localization into areas of active fibrosis. from the CH3 mouse strain in the AKR mouse strain Rat Thy1 (-) pulmonary fibroblasts have greater and vice versa. The antibodies were found to strongly myofibroblastic differentiation relative to Thy1 (+) as label thymocytes as well as peripheral T cells, hence assessed by contractility and myogenic gene expression the name Thy1. Thy-1 has several immunological of MyoD, myocardin, myf5, and myogenin, both at functions, most mediated through interactions with baseline and in response to fibrogenic mediators. In integrins. In particular, Thy1 binds integrins addition, Thy1 (-) fibroblasts resist apoptosis in a alpha Mbeta 2 and alpha Xbeta 2 which are both expressed contracting collagen matrix. Thy1 (+) and (-) by leukocytes. In cell adhesion assays, monocytes and pulmonary fibroblasts have dissimilar production of polymorphonuclear cells adhere to exogenous Thy1- and/or responses to various cytokines. In response to expressing CHO cells and activated THY1-expressing PDGF-BB, both populations undergo concentration- Human Dermal Microvascular Endothelial Cells dependent proliferation. However, only the Thy1 (-) (HDMECs). This adherence was found to be mediated population proliferates in response to PDGF-AA. by the interaction between THY1 and alpha Mbeta 2. Consistent with the proliferation assays, both Antibodies against alpha Mbeta 2 blocked adherence, populations express PDGFR-beta. Only Thy1 (-) while exogenously expressing alpha Mbeta 2 but not pulmonary fibroblast express PDGFR-alpha. control CHO cells are able to retain biotynilated Thrombospondin-1 or its N-terminal heparin-binding purified THY1 at their cell surface. Moreover, the domain alone is a potent inducer of cell migration. interaction of THY1 with alpha Mbeta 2 was found to be Coordinated focal adhesion disassembly is critical for vital in transendothelial migration of the cell migration to occur. Thy1 (+) but not Thy1 (-) aforementioned leukocytes across a monolayer of pulmonary fibroblasts respond to Thrombospondin- HDMECs. Thereby, THY1 is implicated in the 1/HEP-I with transient phosphorylation of FAK and regulation of leukocyte recruitment to sites of SFK, focal adhesion disassembly, and migration. inflammation. Exogenous expression of WT Thy1 by Thy1 (-) Early evidence showed surface Thy1 expression pulmonary fibroblasts creates sensitivity to diminishes as thymocytes mature into T cells, Thrombospondin-1/HEP-I. It is important to note that suggesting a role for Thy-1 in regulating thymocyte as for other described functions of Thy-1, localization lineage. Thymocytes from Thy1 null mice have a of Thy-1 within lipid rafts is required (see Localisation, reduced maturation rate from the immature above). Thy1 (-) pulmonary fibroblasts, in contrast to

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1045 THY1 (Thy-1 cell surface antigen) Bradley JE, Hagood JS

Thy1 (+), are capable of activating latent TGF-beta. microcell-mediated chromosome 11 transfer or THY1 Only Thy1 (-) murine pulmonary fibroblasts produce expression inducible system suppresses tumorigenicity. IL-1 in response to TNF-alpha. Moreover, proliferation Idiopathic pulmonary fibrosis (IPF) and IL-6 expression induced by IL-1beta treatment is greater in Thy1 (-) cells relative to Thy1 (+). Note Phenotypes attributed to the Thy1 (-) and Thy1 (+) Evidence from both in vivo and in vitro experiments fibroblast population of one tissue may be different or implicates loss of fibroblast THY1 is important in the reversed in those from another tissue. Unlike in the disease Idiopathic Pulmonary Fibrosis (IPF). The most lung, only THY1 (+) orbital fibroblasts appear capable characteristic histopathologic feature of IPF is of differentiating into myofibroblasts, whereas THY1 (- aggregates of proliferating fibroblasts and ) are incapable of doing so but are unique in their myofibroblasts called fibrotic foci. The number of FF ability to differentiate into mature adipocytes. Thus, the directly correlates with severity of the disease. Though effects of THY1 on cell signaling are likely to be the vast majority of quiescent lung fibroblasts are context-dependent. THY1 positive, FF are exclusively occupied by THY1 Purified Thy1 immobilized on microbeads has been (-) myofibroblasts. Thy1 (-) lung fibroblasts have a shown to bind 3 on astrocytes causing them to form more fibrotic phenotype including response to focal adhesion sites. However, inhibition of neurite profibrotic cytokines and propensity to differentiate outgrowth in Thy1 expressing neurons is not believed into myofibroblasts. Moreover, the chemically induced to require induced focal adhesion formation or factors model for lung fibrosis, intra-tracheal administered emanating from the astrocytes. Thy1 (-) neurons bleomycin, is more severe in Thy1 knockout mice with expressing a construct of Thy1 at the cell surface that respect to accumulation of myofibroblasts, collagen, does not localize to lipid rafts and grown on a and increased activation of TGF-beta. THY1 monolayer of astrocytes are capable of normal neurite expression has been shown to be epigenetically outgrowth. Despite Thy1 being able to engage integrin silenced by DNA hypermethylation in fibroblasts from beta 3 on the astrocyte, neurite outgrowth is not IPF lesions in vivo and in vitro. inhibited. Thy1 requires correct localization to its Prognosis native membrane micro domain to exert an inhibitory The prognosis for a patient with IPF is almost effect which suggests that Thy1 functions as a receptor universally poor, with a mean survival of only 2 to 4 of the neuron rather than a ligand for the astrocyte. years after diagnosis. Onset of the disease and Remarkably, Thy1 deficient mice have only subtle subsequent diagnosis usually occur after the age of 50. nervous system irregularities, including inhibition of Over the course of the disease, patients suffer severe hippocampal long-term potentiation in the dentate dyspnea. For the estimated 40000 to 130000 IPF gyrus and failure to transmit social cues regarding food patients in the United States, there is no medical selection. intervention that affords a survival benefit save for a lung transplant. Implicated in Experimental glomerulonephritis Nasopharyngeal carcinoma Note Note Intravenous administration of crosslinking anti-Thy1 In nasopharyngeal carcinoma, THY1 is believed to antibodies to rats induces glumerulonephritis and function as a tumor suppressor. The tumorigenic NPC serves as a model for study of the disease. The use of cell line, HONE1, decrease colony formation with Thy1 antibodies for this purpose is supported by in addition of an intact chromosome 11 via microcell- vitro experiments. Cross linking Thy1 expressed on mediated transfer and coincides with reexpression of glomerular mesangial cells with anti-Thy1 antibodies THY-1. The THY1 gene is located within region induces apoptosis as confirmed by TdT-mediated dUTP 11q22-23 which is critical for tumorigenicity in NPC. nick-end labeling (TUNEL) and annexin V assays. Additionally, tumor segregants of the HONE1 Glumerulonephritis induced with anti-Thy1 antibodies microcell hybrids were all negative for THY1. THY1 in vivo has recently been shown to result from the expression is decreased in more invasive/metastatic combination of complement-mediated necrosis as well NPC and this is thought to occur via epigenetic as apoptosis. silencing. Graves'ophthalmopathy (GO) Ovarian cancer Note Note GO is characterized by an increase in volume of the The loss of heterozygosity at 11q23.3-q24.3 for extraocular muscles and/or the intraorbital adipose patients with ovarian cancer is associated with poor tissues which causes the eyeball to bulge from the orbit. prognosis. This region of chromosome 11 contains the Intraorbital fibroblasts, including those that reside THY1 gene. THY1 expression in the tumorigenic around and within the extraocular muscles, have a ovarian cancer cell line, SKOV-3, induced by either pathogenic role in this disease. The THY1 (+), but not

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1046 THY1 (Thy-1 cell surface antigen) Bradley JE, Hagood JS

the THY1 (-), orbital fibroblast subpopulation Almqvist P, Carlsson SR. Characterization of a hydrophilic differentiates into myofibroblasts as indicated by alpha- form of Thy-1 purified from human cerebrospinal fluid. J Biol Chem. 1988 Sep 5;263(25):12709-15 smooth muscle actin expression. The opposite is true for differentiation into lipofibroblasts assessed by Spanopoulou E, Giguere V, Grosveld F. Transcriptional unit of the murine Thy-1 gene: different distribution of transcription accumulation of cytoplasmic lipid droplets. The orbital initiation sites in brain. Mol Cell Biol. 1988 Sep;8(9):3847-56 adipose/connective tissue taken from GO patients was shown to have greater THY1 mRNA and protein Saleh M, Bartlett PF. Evidence from neuronal heterokaryons for a trans-acting factor suppressing Thy-1 expression during expression relative to the same tissue retrieved from neuronal development. J Neurosci Res. 1989 Aug;23(4):406- individuals with no history of Graves'disease whose 15 corneas were being procured for transplantation. Phipps RP, Baecher C, Frelinger JG, Penney DP, Keng P, Fibroblasts cultured from these two tissue sources were Brown D. Differential expression of interleukin 1 alpha by Thy- examined for THY1 expression. As with total tissue 1+ and Thy-1- lung fibroblast subpopulations: enhancement of levels, there was greater expression of THY1 by interleukin 1 alpha production by tumor necrosis factor-alpha. fibroblasts cultured from tissue obtained from GO Eur J Immunol. 1990 Aug;20(8):1723-7 patients. Vidal M, Morris R, Grosveld F, Spanopoulou E. Tissue-specific control elements of the Thy-1 gene. EMBO J. 1990 References Mar;9(3):833-40 He HT, Naquet P, Caillol D, Pierres M. Thy-1 supports REIF AE, ALLEN JM. THE AKR THYMIC ANTIGEN AND ITS adhesion of mouse thymocytes to thymic epithelial cells DISTRIBUTION IN LEUKEMIAS AND NERVOUS TISSUES. J through a Ca2(+)-independent mechanism. J Exp Med. 1991 Exp Med. 1964 Sep 1;120:413-33 Feb 1;173(2):515-8 Schlesinger M, Yron I. Antigenic changes in lymph-node cells Xue GP, Rivero BP, Morris RJ. The surface glycoprotein Thy-1 after administration of antiserum to thymus cells. Science. is excluded from growing axons during development: a study of 1969 Jun 20;164(886):1412-3 the expression of Thy-1 during axogenesis in hippocampus and hindbrain. Development. 1991 May;112(1):161-76 Barclay AN, Letarte-Muirhead M, Williams AF, Faulkes RA. Chemical characterisation of the Thy-1 glycoproteins from the Tiveron MC, Barboni E, Pliego Rivero FB, Gormley AM, Seeley membranes of rat thymocytes and brain. Nature. 1976 Oct PJ, Grosveld F, Morris R. Selective inhibition of neurite 14;263(5578):563-7 outgrowth on mature astrocytes by Thy-1 glycoprotein. Nature. 1992 Feb 20;355(6362):745-8 Barclay AN. Localization of the Thy-1 antigen in the cerebellar cortex of rat brain by immunofluorescence during postnatal Xue GP, Morris R. Expression of the neuronal surface development. J Neurochem. 1979 Apr;32(4):1249-57 glycoprotein Thy-1 does not follow appearance of its mRNA in developing mouse Purkinje cells. J Neurochem. 1992 Hoessli D, Bron C, Pink JR. T-lymphocyte differentiation is Feb;58(2):430-40 accompanied by increase in sialic acid content of Thy-1 antigen. Nature. 1980 Feb 7;283(5747):576-8 Williams AF, Parekh RB, Wing DR, Willis AC, Barclay AN, Dalchau R, Fabre JW, Dwek RA, Rademacher TW. Abbott J, Doyle PJ, Ngiam K, Olson CL. Ontogeny of murine T Comparative analysis of the N-glycans of rat, mouse and lymphocytes. I. Maturation of thymocytes induced in vitro by human Thy-1. Site-specific oligosaccharide patterns of neural tumor necrosis factor-positive serum (TNF+)1,2. Cell Immunol. Thy-1, a member of the immunoglobulin superfamily. 1981 Jan 1;57(1):237-50 Glycobiology. 1993 Aug;3(4):339-48 McKenzie JL, Fabre JW. Human thy-1: unusual localization Bergman AS, Carlsson SR. Saponin-induced release of cell- and possible functional significance in lymphoid tissues. J surface-anchored Thy-1 by serum glycosylphosphatidylinositol- Immunol. 1981 Mar;126(3):843-50 specific phospholipase D. Biochem J. 1994 Mar 15;298 Pt Seeger RC, Danon YL, Rayner SA, Hoover F. Definition of a 3:661-8 Thy-1 determinant on human neuroblastoma, glioma, sarcoma, Tiveron MC, Nosten-Bertrand M, Jani H, Garnett D, Hirst EM, and teratoma cells with a monoclonal antibody. J Immunol. Grosveld F, Morris RJ. The mode of anchorage to the cell 1982 Feb;128(2):983-9 surface determines both the function and the membrane Williams AF, Gagnon J. Neuronal cell Thy-1 glycoprotein: location of Thy-1 glycoprotein. J Cell Sci. 1994 Jul;107 ( Pt homology with immunoglobulin. Science. 1982 May 7):1783-96 14;216(4547):696-703 Morita H, Isobe K, Cai Z, Miyazaki T, Matsumoto Y, Shinzato Gunter KC, Malek TR, Shevach EM. T cell-activating T, Yoshikai Y, Kimata K, Maeda K. Thy-1 antigen mediates properties of an anti-Thy-1 monoclonal antibody. Possible apoptosis of rat glomerular cells in vitro and in vivo. Nephron. analogy to OKT3/Leu-4. J Exp Med. 1984 Mar 1;159(3):716-30 1996;73(2):293-8 Giguére V, Isobe K, Grosveld F. Structure of the murine Thy-1 Nosten-Bertrand M, Errington ML, Murphy KP, Tokugawa Y, gene. EMBO J. 1985 Aug;4(8):2017-24 Barboni E, Kozlova E, Michalovich D, Morris RG, Silver J, Stewart CL, Bliss TV, Morris RJ. Normal spatial learning Low MG, Kincade PW. Phosphatidylinositol is the membrane- despite regional inhibition of LTP in mice lacking Thy-1. anchoring domain of the Thy-1 glycoprotein. Nature. 1985 Nov Nature. 1996 Feb 29;379(6568):826-9 7-13;318(6041):62-4 Hueber AO, Bernard AM, Battari CL, Marguet D, Massol P, Seki T, Spurr N, Obata F, Goyert S, Goodfellow P, Silver J. Foa C, Brun N, Garcia S, Stewart C, Pierres M, He HT. The human Thy-1 gene: structure and chromosomal location. Thymocytes in Thy-1-/- mice show augmented TCR signaling Proc Natl Acad Sci U S A. 1985 Oct;82(19):6657-61 and impaired differentiation. Curr Biol. 1997 Sep 1;7(9):705-8

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1047 THY1 (Thy-1 cell surface antigen) Bradley JE, Hagood JS

Ishizu A, Ishikura H, Nakamaru Y, Kikuchi K, Koike T, Yoshiki Koumas L, Smith TJ, Feldon S, Blumberg N, Phipps RP. Thy-1 T. Interleukin-1alpha regulates Thy-1 expression on rat expression in human fibroblast subsets defines myofibroblastic vascular endothelial cells. Microvasc Res. 1997 Jan;53(1):73-8 or lipofibroblastic phenotypes. Am J Pathol. 2003 Oct;163(4):1291-300 Killeen N. T-cell regulation: Thy-1 - hiding in full view. Curr Biol. 1997 Dec 1;7(12):R774-7 Zhao Y, Ohdan H, Manilay JO, Sykes M. NK cell tolerance in mixed allogeneic chimeras. J Immunol. 2003 Jun Tokugawa Y, Koyama M, Silver J. A molecular basis for 1;170(11):5398-405 species differences in Thy-1 expression patterns. Mol Immunol. 1997 Dec;34(18):1263-72 Abeysinghe HR, Pollock SJ, Guckert NL, Veyberman Y, Keng P, Halterman M, Federoff HJ, Rosenblatt JP, Wang N. The role Devasahayam M, Catalino PD, Rudd PM, Dwek RA, Barclay of the THY1 gene in human ovarian cancer suppression based AN. The glycan processing and site occupancy of recombinant on transfection studies. Cancer Genet Cytogenet. 2004 Thy-1 is markedly affected by the presence of a Feb;149(1):1-10 glycosylphosphatidylinositol anchor. Glycobiology. 1999 Dec;9(12):1381-7 Barker TH, Pallero MA, MacEwen MW, Tilden SG, Woods A, Murphy-Ullrich JE, Hagood JS. Thrombospondin-1-induced Hagood JS, Miller PJ, Lasky JA, Tousson A, Guo B, Fuller GM, focal adhesion disassembly in fibroblasts requires Thy-1 McIntosh JC. Differential expression of platelet-derived growth surface expression, lipid raft integrity, and Src activation. J Biol factor-alpha receptor by Thy-1(-) and Thy-1(+) lung fibroblasts. Chem. 2004 May 28;279(22):23510-6 Am J Physiol. 1999 Jul;277(1 Pt 1):L218-24 Haeryfar SM, Hoskin DW. Thy-1: more than a mouse pan-T Saalbach A, Wetzig T, Haustein UF, Anderegg U. Detection of cell marker. J Immunol. 2004 Sep 15;173(6):3581-8 human soluble Thy-1 in serum by ELISA. Fibroblasts and activated endothelial cells are a possible source of soluble Wetzel A, Chavakis T, Preissner KT, Sticherling M, Haustein Thy-1 in serum. Cell Tissue Res. 1999 Nov;298(2):307-15 UF, Anderegg U, Saalbach A. Human Thy-1 (CD90) on activated endothelial cells is a counterreceptor for the Schäfer H, Bartels T, Hahn G, Otto A, Burger R. T-cell- leukocyte integrin Mac-1 (CD11b/CD18). J Immunol. 2004 Mar activating monoclonal antibodies, reacting with both leukocytes 15;172(6):3850-9 and erythrocytes, recognize the guinea pig Thy-1 differentiation antigen: characterization and cloning of guinea pig CD90. Cell Zhou Y, Hagood JS, Murphy-Ullrich JE. Thy-1 expression Immunol. 1999 Nov 1;197(2):116-28 regulates the ability of rat lung fibroblasts to activate transforming growth factor-beta in response to fibrogenic Mayeux-Portas V, File SE, Stewart CL, Morris RJ. Mice lacking stimuli. Am J Pathol. 2004 Aug;165(2):659-69 the cell adhesion molecule Thy-1 fail to use socially transmitted cues to direct their choice of food. Curr Biol. 2000 Jan Chen CH, Wang SM, Yang SH, Jeng CJ. Role of Thy-1 in in 27;10(2):68-75 vivo and in vitro neural development and regeneration of dorsal root ganglionic neurons. J Cell Biochem. 2005 Mar Saalbach A, Haustein UF, Anderegg U. A ligand of human thy- 1;94(4):684-94 1 is localized on polymorphonuclear leukocytes and monocytes and mediates the binding to activated thy-1-positive Choi J, Leyton L, Nham SU. Characterization of alphaX I- microvascular endothelial cells and fibroblasts. J Invest domain binding to Thy-1. Biochem Biophys Res Commun. Dermatol. 2000 Nov;115(5):882-8 2005 Jun 3;331(2):557-61 Shimizu A, Masuda Y, Kitamura H, Ishizaki M, Ohashi R, Hagood JS, Prabhakaran P, Kumbla P, Salazar L, MacEwen Sugisaki Y, Yamanaka N. Complement-mediated killing of MW, Barker TH, Ortiz LA, Schoeb T, Siegal GP, Alexander CB, mesangial cells in experimental glomerulonephritis: cell death Pardo A, Selman M. Loss of fibroblast Thy-1 expression by a combination of apoptosis and necrosis. Nephron. 2000 correlates with lung fibrogenesis. Am J Pathol. 2005 Oct;86(2):152-60 Aug;167(2):365-79 Leyton L, Schneider P, Labra CV, Rüegg C, Hetz CA, Quest Lung HL, Bangarusamy DK, Xie D, Cheung AK, Cheng Y, AF, Bron C. Thy-1 binds to integrin beta(3) on astrocytes and Kumaran MK, Miller L, Liu ET, Guan XY, Sham JS, Fang Y, Li triggers formation of focal contact sites. Curr Biol. 2001 Jul L, Wang N, Protopopov AI, Zabarovsky ER, Tsao SW, 10;11(13):1028-38 Stanbridge EJ, Lung ML. THY1 is a candidate tumour suppressor gene with decreased expression in metastatic Schlamp CL, Johnson EC, Li Y, Morrison JC, Nickells RW. nasopharyngeal carcinoma. Oncogene. 2005 Sep Changes in Thy1 gene expression associated with damaged 29;24(43):6525-32 retinal ganglion cells. Mol Vis. 2001 Aug 15;7:192-201 Rege TA, Hagood JS. Thy-1 as a regulator of cell-cell and cell- Campsall KD, Mazerolle CJ, De Repentingy Y, Kothary R, matrix interactions in axon regeneration, apoptosis, adhesion, Wallace VA. Characterization of transgene expression and Cre migration, cancer, and fibrosis. FASEB J. 2006 recombinase activity in a panel of Thy-1 promoter-Cre Jun;20(8):1045-54 transgenic mice. Dev Dyn. 2002 Jun;224(2):135-43 Rege TA, Hagood JS. Thy-1, a versatile modulator of signaling Abeysinghe HR, Cao Q, Xu J, Pollock S, Veyberman Y, affecting cellular adhesion, proliferation, survival, and Guckert NL, Keng P, Wang N. THY1 expression is associated cytokine/growth factor responses. Biochim Biophys Acta. 2006 with tumor suppression of human ovarian cancer. Cancer Oct;1763(10):991-9 Genet Cytogenet. 2003 Jun;143(2):125-32 Rege TA, Pallero MA, Gomez C, Grenett HE, Murphy-Ullrich Haeryfar SM, Al-Alwan MM, Mader JS, Rowden G, West KA, JE, Hagood JS. Thy-1, via its GPI anchor, modulates Src Hoskin DW. Thy-1 signaling in the context of costimulation family kinase and focal adhesion kinase phosphorylation and provided by dendritic cells provides signal 1 for T cell subcellular localization, and fibroblast migration, in response to proliferation and cytotoxic effector molecule expression, but thrombospondin-1/hep I. Exp Cell Res. 2006 Nov fails to trigger delivery of the lethal hit. J Immunol. 2003 Jul 15;312(19):3752-67 1;171(1):69-77

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1048 THY1 (Thy-1 cell surface antigen) Bradley JE, Hagood JS

Sanders YY, Kumbla P, Hagood JS. Enhanced myofibroblastic Sanders YY, Pardo A, Selman M, Nuovo GJ, Tollefsbol TO, differentiation and survival in Thy-1(-) lung fibroblasts. Am J Siegal GP, Hagood JS. Thy-1 promoter hypermethylation: a Respir Cell Mol Biol. 2007 Feb;36(2):226-35 novel epigenetic pathogenic mechanism in pulmonary fibrosis. Am J Respir Cell Mol Biol. 2008 Nov;39(5):610-8 Scotton CJ, Chambers RC. Molecular targets in pulmonary fibrosis: the myofibroblast in focus. Chest. 2007 Bradley JE, Ramirez G, Hagood JS. Roles and regulation of Oct;132(4):1311-21 Thy-1, a context-dependent modulator of cell phenotype. Biofactors. 2009 May-Jun;35(3):258-65 Surviladze Z, Harrison KA, Murphy RC, Wilson BS. FcepsilonRI and Thy-1 domains have unique protein and lipid Kusner LL, Young A, Tjoe S, Leahy P, Kaminski HJ. Perimysial compositions. J Lipid Res. 2007 Jun;48(6):1325-35 fibroblasts of extraocular muscle, as unique as the muscle fibers. Invest Ophthalmol Vis Sci. 2010 Jan;51(1):192-200 Khoo TK, Coenen MJ, Schiefer AR, Kumar S, Bahn RS. Evidence for enhanced Thy-1 (CD90) expression in orbital This article should be referenced as such: fibroblasts of patients with Graves' ophthalmopathy. Thyroid. 2008 Dec;18(12):1291-6 Bradley JE, Hagood JS. THY1 (Thy-1 cell surface antigen). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1042- 1049.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1049 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

TYRO3 (TYRO3 protein tyrosine kinase) Kristen M Jacobsen, Rachel MA Linger, Douglas K Graham Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA (KMJ, RMAL, DKG)

Published in Atlas Database: January 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/TYRO3ID42739ch15q15.html DOI: 10.4267/2042/44892 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

encoded by exons 2-5) and two fibronectin (FN) type Identity III domains (predicted to be encoded by exons 6-9). Other names: Brt; BYK; DTK; FLJ16467; RSE; SKY; Exons 12-19 are predicted to encode the tyrosine kinase Tif domain, within the intracellular region (Hubbard et al., HGNC (Hugo): TYRO3 2009). Location: 15q15.1 Transcription A 4.2 kilobase mRNA transcript of TYRO3 has been DNA/RNA identified in several tissues, including brain, placenta, lung, heart, kidney, pancreas, ovary and testis (Polvi et Description al., 1993; Dai et al., 1994). Alternative splicing results The human TYRO3 gene is located on chromosome in three different splice variants. Isoform I contains 15q15.1 and contains 19 exons. By sequence analysis, exon 2A, Isoform II contains exon 2B, while exon 2C exons 1-9 are predicted to encode the extracellular is found in Isoform III. All three splice variants encode domain, exon 10 may encode the transmembrane a transmembrane TYRO3 protein, but differ in the domain and exons 11-19 are predicted to encode the signal peptide sequence at the amino terminus intracellular domain. Within the extracellular domain, (Biesecker et al., 1995; Lewis et al., 1996; Lu et al., there are two immunoglobulin (Ig) domains (predicted 1999). to be

The cartoon depicts the structure of the TYRO3 gene (bottom) roughly aligned with the corresponding functional protein domains (top). The genomic DNA is represented by boxes (exons) and connecting lines (introns). The exons are drawn approximately 10-fold larger than the introns to facilitate alignment with the protein domains. The open ended boxes for exons 1 and 19 indicate untranslated regions which are not shown here. Exon 2 can be alternatively spliced resulting in transcripts containing either exon 2A, 2B, or 2C.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1050 TYRO3 (TYRO3 protein tyrosine kinase) Jacobsen KM, et al.

The cartoon on the top depicts the domain structure of the TYRO3 receptor tyrosine kinase. The conserved sequence within the kinase domain is shown. The amino acids at positions three and five within the conserved sequence are leucine (L) residues in TYRO3 and isoleucine (I) residues in the related receptor tyrosine kinases, AXL and MERTK. The cartoon on the bottom depicts the domain structure of the ligands, Gas6 and Protein S, which share 43% homology. Thrombin cleavage sites are present in the loop region of Protein S, but not Gas6. Gas6 and Protein S are rendered active by vitamin K-dependent carboxylation of the gamma-carboxyglutamic acid (Gla) domain.

that is only found in the TAM receptor family members Protein (Graham et al., 1994). Following ligand binding to the Description extracellular domain, the TYRO3 receptors dimerize and autophosphorylation of the tyrosine kinase domain TYRO3 is synthesized as an 890 amino acid protein. occurs. In addition to ligand-dependent signaling, The predicted molecular weight of TYRO3 is 97 kD, studies suggest that TYRO3 signaling can be initated however, the extracellular domain contains sites for through a ligand-independent mechanism (Taylor et al., NH2-linked glycosylation. Due to the potential for 1995; Heiring et al., 2004). post-translational modifications, TYRO3 proteins can range in size from 100 to 140 kD (Linger et al., 2008). Three tyrosine residues (Y681, Y685, Y686) located The extracellular domain of the TYRO3 receptor within the activation loop of the kinase domain of the contains two Ig domains (aa 60-117 for domain 1 and TYRO3 receptor correspond to three tyrosine residues aa 156-203 for domain 2) and two FNIII domains (aa in the MERTK receptor kinase domain, which have 224-313 for domain 1 and aa 322-409 for domain 2) been identified as sites of autophosphorylation, (Ohashi et al., 1994). The two Ig domains and two however, there is no direct evidence that Y681, Y685, FNIII domains define TYRO3 as a member of a family and Y686 are autophosphorylated in the TYRO3 of receptor tyrosine kinases (RTKs), which also receptor (Linger et al., 2008). TYRO3 phosphorylation includes AXL and MERTK. TYRO3, AXL, and has been linked to the activation of ERK1/ERK2 and MERTK constitute the TAM family of receptor AKT (Chen et al., 1997; Lan et al., 2000; Prieto et al., tyrosine kinases (Linger et al., 2008). The extracellular 2007), but the downstream signaling events following domain of TYRO3 is the ligand-binding region for the ligand binding of the TYRO3 receptor are poorly ligands GAS6 and Protein S. GAS6 has been shown to understood. Studies have shown potential interactions bind the TYRO3 receptor specifically in the Ig domains between TYRO3 and RanBMP, protein phosphatase 1 (Heiring et al., 2004). (PP1) and the p85 subunit of PI3K (via one of its SH2 The tyrosine kinase domain (aa 525-776) is within the domains), as well as members of the Src family kinases intracellular region of the TYRO3 receptor. This kinase (Toshima et al., 1995; Lan et al., 2000; Hafizi et al., domain contains a signature motif, KW(I/L)A(I/L)ES, 2005).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1051 TYRO3 (TYRO3 protein tyrosine kinase) Jacobsen KM, et al.

Expression Implicated in High levels of TYRO3 expression are detected in the nervous system, including the neocortex, hippocampus Malignancy and cerebellum. TYRO3 is also expressed in Disease monocytes, macrophages, platelets, dendritic cells and TYRO3, as well as the other TAM receptor family NK cells. TYRO3 has also been found in the breast, members have been implicated in several malignant ovary, testis, lung, kidney, retinal pigment epithelium diseases. Studies have shown that TYRO3 expression is and osteoclasts (Linger et al., 2008). Upregulation of upregulated in AML, CML, multiple myeloma, the TYRO3 receptor has been found in AML, CML, endometrial cancer and melanoma (Liu et al., 1988; multiple myeloma, and melanoma, as well as uterine Crosier et al., 1995; De Vos et al., 2001; Sun et al., endometrial cancers (Sun et al., 2003; Linger et al., 2003; Zhu et al., 2009). In addition to TYRO3 2008; Zhu et al., 2009). overexpression in many cancers, it has also been shown Localisation to have transforming abilities (Lan et al., 2000). TYRO3, like its family members, may function as a TYRO3 is a transmembrane receptor tyrosine kinase. prosurvival factor in tumorigenesis. In melanoma cells,

TYRO3 knockdown inhibits proliferation and leads to Function increased sensitivity to chemotherapeutic agents in TYRO3 activation and downstream signaling through vitro (Zhu et al., 2009). MAPK/ERK and PI3K/AKT may facilitate the cellular Autoimmune disease functions of TYRO3, including actin reorganization/cell migration and cell survival. Within Disease the brain, activation of MAPK and PI3K pathways via Triple mutant mice that lack all three TAM receptors TYRO3 may lead to expression of genes involved in (TYRO3, AXL and MERTK) have a alterations in the consolidation of memories, addictive lymphoproliferative disorder of broad-spectrum behaviors, and circadian rhythms, as well as autoimmunity. Specifically, triple mutant mice have modulating synaptic plasticity (Prieto et al., 2007). high titers of auto-antibodies to nucleoproteins, dsDNA TYRO3 has also been shown to mediate the survival and collagen, leading to the development of diseases and migration of Gonadotropin-releasing hormone resembling rheumatoid arthritis, pemphigus vulgaris (GnRH) neurons within the forebrain (Pierce et al., and systemic lupus erythematosus (Lu et al., 2001). 2008). There is evidence suggesting that TYRO3 plays These finding suggest a role for TYRO3 in regulation a role in the clearance of apoptotic cells by dendritic of the immune system however, no human cases have cells, and to a lesser extent, macrophages and is been reported. essential for NK cell maturation and differentiation (Caraux et al., 2006; Seitz et al., 2007). TYRO3 is References necessary for normal platelet aggregation and clot Liu E, Hjelle B, Bishop JM. Transforming genes in chronic stabilization (Angelillo-Scherrer et al., 2005). TYRO3 myelogenous leukemia. Proc Natl Acad Sci U S A. 1988 may also mediate cell entry by filoviruses (Shimojima Mar;85(6):1952-6 et al., 2006). In addition to its functions within the Polvi A, Armstrong E, Lai C, Lemke G, Huebner K, Spritz RA, brain and immune cells, TYRO3 is also involved in the Guida LC, Nicholls RD, Alitalo K. The human TYRO3 gene and reabsorption of bone by osteoclasts (Nakamura et al., pseudogene are located in chromosome 15q14-q25. Gene. 1998). 1993 Dec 8;134(2):289-93 Dai W, Pan H, Hassanain H, Gupta SL, Murphy MJ Jr. Homology Molecular cloning of a novel receptor tyrosine kinase, tif, highly The two Ig domains and two FNIII domains within the expressed in human ovary and testis. Oncogene. 1994 extracelluar domain of TYRO3 are shared with the Mar;9(3):975-9 other members of the TAM family, AXL and MERTK. Graham DK, Dawson TL, Mullaney DL, Snodgrass HR, Earp Within the extracellular regions, the TAM receptors HS. Cloning and mRNA expression analysis of a novel human protooncogene, c-mer. Cell Growth Differ. 1994 Jun;5(6):647- share 31-36% sequence identity (52-57% similarity). 57 The protein sequences in the intracellular domains are 54-59% identical (72-75% similar), with higher Ohashi K, Mizuno K, Kuma K, Miyata T, Nakamura T. Cloning of the cDNA for a novel receptor tyrosine kinase, Sky, homology in the tyrosine kinase domains (Graham et predominantly expressed in brain. Oncogene. 1994 al., 1995). Mar;9(3):699-705 Biesecker LG, Giannola DM, Emerson SG. Identification of Mutations alternative exons, including a novel exon, in the tyrosine kinase receptor gene Etk2/tyro3 that explain differences in 5' cDNA Note sequences. Oncogene. 1995 Jun 1;10(11):2239-42 No mutations in TYRO3 have been documented.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1052 TYRO3 (TYRO3 protein tyrosine kinase) Jacobsen KM, et al.

Crosier PS, Hall LR, Vitas MR, Lewis PM, Crosier KE. Conway EM, Wehrle-Haller B, Carmeliet P. Role of Gas6 Identification of a novel receptor tyrosine kinase expressed in receptors in platelet signaling during thrombus stabilization and acute myeloid leukemic blasts. Leuk Lymphoma. 1995 implications for antithrombotic therapy. J Clin Invest. 2005 Aug;18(5-6):443-9 Feb;115(2):237-46 Graham DK, Bowman GW, Dawson TL, Stanford WL, Earp Hafizi S, Gustafsson A, Stenhoff J, Dahlbäck B. The Ran HS, Snodgrass HR. Cloning and developmental expression binding protein RanBPM interacts with Axl and Sky receptor analysis of the murine c-mer tyrosine kinase. Oncogene. 1995 tyrosine kinases. Int J Biochem Cell Biol. 2005 Jun 15;10(12):2349-59 Nov;37(11):2344-56 Taylor IC, Roy S, Varmus HE. Overexpression of the Sky Caraux A, Lu Q, Fernandez N, Riou S, Di Santo JP, Raulet receptor tyrosine kinase at the cell surface or in the cytoplasm DH, Lemke G, Roth C. Natural killer cell differentiation driven results in ligand-independent activation. Oncogene. 1995 Dec by Tyro3 receptor tyrosine kinases. Nat Immunol. 2006 21;11(12):2619-26 Jul;7(7):747-54 Toshima J, Ohashi K, Iwashita S, Mizuno K. Shimojima M, Takada A, Ebihara H, Neumann G, Fujioka K, Autophosphorylation activity and association with Src family Irimura T, Jones S, Feldmann H, Kawaoka Y. Tyro3 family- kinase of Sky receptor tyrosine kinase. Biochem Biophys Res mediated cell entry of Ebola and Marburg viruses. J Virol. 2006 Commun. 1995 Apr 17;209(2):656-63 Oct;80(20):10109-16 Lewis PM, Crosier KE, Wood CR, Crosier PS. Analysis of the Prieto AL, O'Dell S, Varnum B, Lai C. Localization and murine Dtk gene identifies conservation of genomic structure signaling of the receptor protein tyrosine kinase Tyro3 in within a new receptor tyrosine kinase subfamily. Genomics. cortical and hippocampal neurons. Neuroscience. 2007 Dec 1996 Jan 1;31(1):13-9 5;150(2):319-34 Chen J, Carey K, Godowski PJ. Identification of Gas6 as a Seitz HM, Camenisch TD, Lemke G, Earp HS, Matsushima ligand for Mer, a neural cell adhesion molecule related receptor GK. Macrophages and dendritic cells use different tyrosine kinase implicated in cellular transformation. Axl/Mertk/Tyro3 receptors in clearance of apoptotic cells. J Oncogene. 1997 May 1;14(17):2033-9 Immunol. 2007 May 1;178(9):5635-42 Nakamura YS, Hakeda Y, Takakura N, Kameda T, Hamaguchi Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor I, Miyamoto T, Kakudo S, Nakano T, Kumegawa M, Suda T. tyrosine kinases: biologic functions, signaling, and potential Tyro 3 receptor tyrosine kinase and its ligand, Gas6, stimulate therapeutic targeting in human cancer. Adv Cancer Res. the function of osteoclasts. Stem Cells. 1998;16(3):229-38 2008;100:35-83 Lu Q, Gore M, Zhang Q, Camenisch T, Boast S, Casagranda Pierce A, Bliesner B, Xu M, Nielsen-Preiss S, Lemke G, Tobet F, Lai C, Skinner MK, Klein R, Matsushima GK, Earp HS, Goff S, Wierman ME. Axl and Tyro3 modulate female reproduction SP, Lemke G. Tyro-3 family receptors are essential regulators by influencing gonadotropin-releasing hormone neuron survival of mammalian spermatogenesis. Nature. 1999 Apr and migration. Mol Endocrinol. 2008 Nov;22(11):2481-95 22;398(6729):723-8 Hubbard TJ, Aken BL, Ayling S, Ballester B, Beal K, Bragin E, Lan Z, Wu H, Li W, Wu S, Lu L, Xu M, Dai W. Transforming Brent S, Chen Y, Clapham P, Clarke L, Coates G, Fairley S, activity of receptor tyrosine kinase tyro3 is mediated, at least in Fitzgerald S, Fernandez-Banet J, Gordon L, Graf S, Haider S, part, by the PI3 kinase-signaling pathway. Blood. 2000 Jan Hammond M, Holland R, Howe K, Jenkinson A, Johnson N, 15;95(2):633-8 Kahari A, Keefe D, Keenan S, Kinsella R, Kokocinski F, Kulesha E, Lawson D, Longden I, Megy K, Meidl P, Overduin De Vos J, Couderc G, Tarte K, Jourdan M, Requirand G, B, Parker A, Pritchard B, Rios D, Schuster M, Slater G, Delteil MC, Rossi JF, Mechti N, Klein B. Identifying intercellular Smedley D, Spooner W, Spudich G, Trevanion S, Vilella A, signaling genes expressed in malignant plasma cells by using Vogel J, White S, Wilder S, Zadissa A, Birney E, Cunningham complementary DNA arrays. Blood. 2001 Aug 1;98(3):771-80 F, Curwen V, Durbin R, Fernandez-Suarez XM, Herrero J, Lu Q, Lemke G. Homeostatic regulation of the immune system Kasprzyk A, Proctor G, Smith J, Searle S, Flicek P. Ensembl by receptor tyrosine kinases of the Tyro 3 family. Science. 2009. Nucleic Acids Res. 2009 Jan;37(Database issue):D690- 2001 Jul 13;293(5528):306-11 7 Sun WS, Fujimoto J, Tamaya T. Coexpression of growth Zhu S, Wurdak H, Wang Y, Galkin A, Tao H, Li J, Lyssiotis CA, arrest-specific gene 6 and receptor tyrosine kinases Axl and Yan F, Tu BP, Miraglia L, Walker J, Sun F, Orth A, Schultz PG, Sky in human uterine endometrial cancers. Ann Oncol. 2003 Wu X. A genomic screen identifies TYRO3 as a MITF regulator Jun;14(6):898-906 in melanoma. Proc Natl Acad Sci U S A. 2009 Oct 6;106(40):17025-30 Heiring C, Dahlbäck B, Muller YA. Ligand recognition and homophilic interactions in Tyro3: structural insights into the This article should be referenced as such: Axl/Tyro3 receptor tyrosine kinase family. J Biol Chem. 2004 Feb 20;279(8):6952-8 Jacobsen KM, Linger RMA, Graham DK. TYRO3 (TYRO3 protein tyrosine kinase). Atlas Genet Cytogenet Oncol Angelillo-Scherrer A, Burnier L, Flores N, Savi P, DeMol M, Haematol. 2010; 14(11):1050-1053. Schaeffer P, Herbert JM, Lemke G, Goff SP, Matsushima GK, Earp HS, Vesin C, Hoylaerts MF, Plaisance S, Collen D,

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1053 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

YAP1 (Yes -associated protein 1, 65kDa) Silvia Di Agostino, Sabrina Strano, Giovanni Blandino Molecular Medicine Department, Regina Elena Cancer Institute, Rome 00144, Italy (SD, SS, GB)

Published in Atlas Database: January 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/YAP1ID42855ch11q22.html DOI: 10.4267/2042/44893 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity - MMP20, matrix metalloproteinase 20, 11q22.2 Note: YAP interacts with the SH3 domain of c-Yes Other names: YAP; YAP2; YAP65; YKI (and also c-Src), through a stretch of proline residues. HGNC (Hugo): YAP1 YAP protein contains a WW domain that is found in Location: 11q22.1 various structural, regulatory and signaling molecules Local order: Genes flanking YAP1 on 11q22.1 are: in yeast, nematode, and mammals, and it is involved in protein-protein interaction. - CNTN5, contactin-5, 11q22.1 - FLJ42335, Hypothetical protein LOC100128386, DNA/RNA 11q22.1 - FLJ32810, Rho-type GTPase-activating protein Description FLJ32810, 11q22.1 The genomic size is 122863 bases and the gene is - TMEM133, transmembrane protein 133, 11q22.1 located on plus strand. YAP1 gene is composed of 7 exons. The open reading frame of the coding region is - PGR, progesterone receptor, 11q22-q23 1364 bp. No polymorphism of YAP1 is known. - TRPC6, transient receptor potential cation channel, SNP: 1590 single nucleotide polymorphisms are subfamily C, member 6, 11q22.1 present in the human gene according to NCBI database. - ANGPTL5, angiopoietin-like 5, 11q22.1 Transcription - YAP1, Yes-associated protein 1, 11q22.1 The human YAP1 coding sequence consists of 1364 bp - RPS6P17, ribosomal protein S6 pseudogene 17, from the start codon to the stop codon. A differentially 11q22.2 spliced isoform of YAP1 (9 exons), with two WW - BIRC3, baculoviral IAP repeat-containing protein 3, domains known as YAP2 also exists (Sudol et al., 11q22.2 1995). - BIRC2, baculoviral IAP repeat-containing protein 2, Pseudogene 11q22.2 No pseudogene of YAP1 is known.

YAP1 mRNA spans approximately 5218 bases and has 7 exons.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1054 YAP1 (Yes-associated protein 1, 65kDa) Di Agostino S, et al.

Structure of human YAP isoforms. The protein domains and their length (indicated by number of limiting residues) are reported. YAP1 contains a proline-rich domain, a WW domain, a glutamine rich domain and portion of protein that regulates the transcription activation.

Protein Interactors of YAP Reference Note YES Sudol et al., 1995 The Yes-associated protein (YAP), a critical mediator WBP1 and WBP2 Chen and Sudol, 1995 of p73 function, binds p73 to regulate its transcriptional NFE2 Gavva et al., 1997 activity (Strano et al., 2001) and subsequent cell-death induction (Basu et al., 2003). This binding is negatively RUNX1 and RUNX2 Yagi et al., 1999 regulated by AKT-mediated YAP phosphorylation EBP50 Mohler et al., 1999 (Basu et al., 2003) and enhanced by DNA damage TP53BP2 Espanel and Sudol, 2001 (Strano et al., 2005). In addition to increase p73 transcriptional activity via the p300 acetyltansferase TP73 Strano et al., 2001 (Strano et al., 2005), YAP can stabilize p73 protein in a TEAD1, 2, 3, 4 Vassilev et al., 2001 posttranslational manner by competing with the ITCH E3-ligase for binding to p73 (Levy et al., 2007). SMAD7 Ferrigno et al., 2002 Description AKT Basu et al., 2003 Structure: YAP protein consists of 454 amino acids, ERBB4 Komuro et al., 2003 with a molecular weight of 65 kDa. It was identified as HNRNPU Howell et al., 2004 a protein that interacted with the non receptor tyrosine LATS1 Hao et al., 2008 kinase c-Yes, which is a member of the Src family (Sudol, 1994). In fact, Yap is able to interact with the ABL1 Levy et al., 2008 SH3 domain of c-Yes (and also c-Src), through a PML Lapi et al., 2008 stretch of proline residues; this proline-rich region is able to interact with SH3 domains of many other EGR1 Zagurovskaya et al., 2009 proteins. In addition Yap contains another binding Table 1: Modified by Bertini et al., 2009. domain of a different nature. Due to the presence of Expression two tryptophan residues, which appear to be conserved along evolution and that play an important role in the By Northern blot analysis YAP1 expression shows a domain structure and function, it was named WW major transcript of approximately 5 kb in several domain (Sudol et al., 1995; Sudol and Hunter, 2000). human tissues. High expression was found in placenta, The WW domain binds to short stretches of prolines prostate, testis, ovary, and small intestine, and lower (PY motif), and therefore mediating the interaction expression was found in brain, liver, and spleen. No between proteins. The WW domain of Yap belongs to expression was found in peripheral blood leukocytes the first of four different classes that differ in terms of (Sudol et al., 1995). the sequence of the interacting motif, a PPxY in the YAP1 is the predominant isoform and is ubiquitously case of WW type I. Yap has been found to interact with expressed in the major part of tissues for twelve normal many proteins, whose function often is quite human tissues (out of 28 tissues shown) hybridized substantially different, and the majority of these against Affymetrix GeneChips HG-U95A-E (GeneNote interactions are mostly mediated by the WW domain data) and for 22 normal human tissues hybridized (Bertini et al., 2009). against HG-U133A (GNF Symatlas data) (Su et al., The interaction with PEBP2 (a RunX transcription 2004). factor) was the first example of Yap1 as a co-activator Localisation of transcription. The WW domain of Yap1 interacts Posttranslational modification of YAP determines its with the PY motif present in the transcription activation binding and localisation. Lapi et al. (2008) have shown domain of PEBP2 and in this occasion Yap1 was Akt-mediated phosphorylation promotes YAP reported for the first time to have a strong intrinsic cytoplasmic retention, demonstrating that active Akt transactivation activity (Yagi et al., 1999). The counters cisplatin-induced increases in PML transcriptional coactivator Yes-associated protein transcription via the YAP-p73 complex. Recently, Levy (YAP) was shown to interact with and to enhance p73- et al. (2008) have also shown that cisplatin induces dependent apoptosis in response to DNA damage ABL1-mediated YAP phosphorylation, resulting in (Strano et al., 2001; Strano et al., 2005).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1055 YAP1 (Yes-associated protein 1, 65kDa) Di Agostino S, et al.

YAP nuclear localization and increased p73 binding differentially regulate either pro-growth or pro- and activation of pro-apoptotic genes. apoptotic genes. YAP binding of p73 and its coordination of other Organ size and cell differentiation: Yap plays an binding proteins probably depend on an integration of important role in controlling organ growth. The works phosphorylation by AKT, ABL1, and other kinases. done on Drosophila show how a disrupted Hippo However, the shuttling of Yap between nucleus and signalling pathway has a negative impact on the growth cytoplasm has emerged as an important means for of imaginal discs (Pan et al., 2007) and how the regulating the activity of this protein. presence of mutated forms of Yap in particular has an Function effect on size and shape of fly wings (Zhao et al., 2007). Yap is a small protein that binds to many transcription In addition Dong et al. (2007) reported that factors and modulates their activity. Yap increases the overexpression of Yap in mice increases liver size, and ability of p73 to induce apoptosis as a consequence of in the long term it induces nodules which present damage to the DNA, and therefore its activity was characteristics of HCC (Dong et al., 2007). This is in thought to favor tumor suppression. However, other accordance with another important study where studies have recently shown a role for Yap in cell increased levels of Yap are shown to enlarge liver size differentiation, cell transformation and in the regulation in a reversible manner (Camargo et al., 2007). of organ size. It has been demonstrated that the However, many questions are unsolved. For instance, it Drosophila Hippo pathway has a mammalian would be interesting to check whether the Hippo equivalent, and that Yap is part of this pathway, where pathway plays a role in choices taken by Yap during it could stimulate proliferation (Pan, 2007; Harvey et cell differentiation; to verify whether activity of Yap al., 2007). could be extended to a cellular context beside intestine Apoptosis: The transcriptional coactivator Yes- epithelium; to find the molecular mechanism used by associated protein (YAP) has demonstrated to interact Yap to control transcription of those genes that are in with and to enhance p73-dependent apoptosis in charge of cell differentiation; and obviously, a screen response to DNA damage (Strano et al., 2001; Strano et for these genes. al., 2005). It has been reported that YAP is phosphorylated by AKT, and such modification impairs Homology YAP-nuclear translocation and attenuates p73-mediated Orthologs: YAP1 is evolutionarily principally apoptosis (Basu et al., 2003). Recently, it was conserved in 8 eukaryotes: Canis familiaris, Pan demonstrated that p73 is required for the nuclear troglodytes, Bos taurus, Mus musculus, Galus gallus, translocation of endogenous YAP in cells exposed to Danio rerio, Xenopus laevis, Silurana tropicalis. cisplatin and that YAP is recruited by PML into nuclear Orthologies between human and Drosophyla bodies to promote p73 transcriptional activity (Strano melanogaster, Caenorabditis elegans and Saccaromyces et al., 2005). It was found that YAP contributes to p73 cerevisiae are quite low. For details see: HomoloGene. stabilization in response to DNA damage and promotes p73-dependent apoptosis through the specific and Mutations selective coactivation of apoptotic p73 target genes and potentiation of p300-mediated acetylation of p73 Note (Strano et al., 2005). Then, it was described the No mutations of YAP1 are known. existence of a proapoptotic autoregulatory feedback loop between p73, YAP, and the promyelocytic Implicated in leukemia (PML) tumor suppressor gene (Lapi et al., 2008). PML is a direct transcriptional target of Various cancers p73/YAP. PML contributes to the p73-dependent Note apoptotic response by regulating YAP stability. Overholtzer and collaborators identified a mouse Importantly, PML and YAP physically interact through mammary tumor with a small amplicon involving the their PVPVY and WW domains, respectively, causing Yap1 gene. They noted that amplification of the YAP stabilization upon cisplatin treatment, which syntenic locus on human chromosome 11q22 is present occurs through PML mediated sumoylation (Lapi et al., in different cancers (breast, colon, prostate). 2008). Overexpression of human YAP1 in nontransformed Together with this proapoptotic role, YAP recently was mammary epithelial cells induced epithelial-to- identified as a tumor suppressor in breast cancer (Yuan mesenchymal transition, suppression of apoptosis, et al., 2008). The findings that YAP plays opposing growth factor-independent proliferation, and roles in tissue growth/development and DNA anchorage-independent growth in soft agar damage/apoptosis appear at first contradictory, but this (Overholtzer et al., 2006). They concluded that YAP1 can be explained if YAP binds and activates or contributes to malignant transformation in cancers inactivates different transcription factors to harboring the 11q22 amplicon.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1056 YAP1 (Yes-associated protein 1, 65kDa) Di Agostino S, et al.

Tumor suppression cytoplasm. Genes Dev. 2001 May 15;15(10):1229-41 Note Ferrigno O, Lallemand F, Verrecchia F, L'Hoste S, Camonis J, Atfi A, Mauviel A. Yes-associated protein (YAP65) interacts As previously described, the regulation of p73 activity with Smad7 and potentiates its inhibitory activity against TGF- by YAP has been investigated in the context of DNA- beta/Smad signaling. Oncogene. 2002 Jul 25;21(32):4879-84 damage signaling. As an activating cofactor for a Basu S, Totty NF, Irwin MS, Sudol M, Downward J. Akt proapoptotic transcription factor, it was assumed that phosphorylates the Yes-associated protein, YAP, to induce YAP plays a tumor suppressor role in cancer. YAP has interaction with 14-3-3 and attenuation of p73-mediated also been identified as an oncogenic progrowth, cell apoptosis. Mol Cell. 2003 Jan;11(1):11-23 size regulator in both Drosophila melanogaster and Komuro A, Nagai M, Navin NE, Sudol M. WW domain- mammalian cells (Dong et al., 2007; Zhao et al., 2007). containing protein YAP associates with ErbB-4 and acts as a The mechanism for the growth control role of YAP or co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus. J Biol Chem. 2003 its fly homolog, Yki, is the result of its inactivation by Aug 29;278(35):33334-41 the MST2 (HIPPO in fly) pathway, where the tumor suppressor LATS1 kinase (WTS in fly) directly Howell M, Borchers C, Milgram SL. Heterogeneous nuclear ribonuclear protein U associates with YAP and regulates its co- phosphorylates YAP (Yki), inhibiting its coactivation activation of Bax transcription. J Biol Chem. 2004 Jun of the TEAD (Scalloped in fly) transcription factor to 18;279(25):26300-6 upregulate pro-growth genes (Zhao et al., 2008). Su AI, Wiltshire T, Batalov S, Lapp H, Ching KA, Block D, The MST2/LATS1 pathway can also enhance YAP-p73 Zhang J, Soden R, Hayakawa M, Kreiman G, Cooke MP, binding and activation of proapoptotic genes Walker JR, Hogenesch JB. A gene atlas of the mouse and downstream of Fas signaling in breast cancer cells human protein-encoding transcriptomes. Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6062-7 (Matallanas et al., 2007). Strano S, Monti O, Pediconi N, Baccarini A, Fontemaggi G, Lapi E, Mantovani F, Damalas A, Citro G, Sacchi A, Del Sal G, References Levrero M, Blandino G. The transcriptional coactivator Yes- Sudol M. Yes-associated protein (YAP65) is a proline-rich associated protein drives p73 gene-target specificity in phosphoprotein that binds to the SH3 domain of the Yes proto- response to DNA Damage. Mol Cell. 2005 May 13;18(4):447- oncogene product. Oncogene. 1994 Aug;9(8):2145-52 59 Chen HI, Sudol M. The WW domain of Yes-associated protein Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, binds a proline-rich ligand that differs from the consensus Deng CX, Brugge JS, Haber DA. Transforming properties of established for Src homology 3-binding modules. Proc Natl YAP, a candidate oncogene on the chromosome 11q22 Acad Sci U S A. 1995 Aug 15;92(17):7819-23 amplicon. Proc Natl Acad Sci U S A. 2006 Aug 15;103(33):12405-10 Sudol M, Bork P, Einbond A, Kastury K, Druck T, Negrini M, Huebner K, Lehman D. Characterization of the mammalian Camargo FD, Gokhale S, Johnnidis JB, Fu D, Bell GW, YAP (Yes-associated protein) gene and its role in defining a Jaenisch R, Brummelkamp TR. YAP1 increases organ size novel protein module, the WW domain. J Biol Chem. 1995 Jun and expands undifferentiated progenitor cells. Curr Biol. 2007 16;270(24):14733-41 Dec 4;17(23):2054-60 Gavva NR, Gavva R, Ermekova K, Sudol M, Shen CJ. Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford Interaction of WW domains with hematopoietic transcription SA, Gayyed MF, Anders RA, Maitra A, Pan D. Elucidation of a factor p45/NF-E2 and RNA polymerase II. J Biol Chem. 1997 universal size-control mechanism in Drosophila and mammals. Sep 26;272(39):24105-8 Cell. 2007 Sep 21;130(6):1120-33 Espanel X, Sudol M. A single point mutation in a group I WW Harvey K, Tapon N. The Salvador-Warts-Hippo pathway - an domain shifts its specificity to that of group II WW domains. J emerging tumour-suppressor network. Nat Rev Cancer. 2007 Biol Chem. 1999 Jun 11;274(24):17284-9 Mar;7(3):182-91 Mohler PJ, Kreda SM, Boucher RC, Sudol M, Stutts MJ, Levy D, Adamovich Y, Reuven N, Shaul Y. The Yes- Milgram SL. Yes-associated protein 65 localizes p62(c-Yes) to associated protein 1 stabilizes p73 by preventing Itch-mediated the apical compartment of airway epithelia by association with ubiquitination of p73. Cell Death Differ. 2007 Apr;14(4):743-51 EBP50. J Cell Biol. 1999 Nov 15;147(4):879-90 Matallanas D, Romano D, Yee K, Meissl K, Kucerova L, Yagi R, Chen LF, Shigesada K, Murakami Y, Ito Y. A WW Piazzolla D, Baccarini M, Vass JK, Kolch W, O'neill E. domain-containing yes-associated protein (YAP) is a novel RASSF1A elicits apoptosis through an MST2 pathway directing transcriptional co-activator. EMBO J. 1999 May 4;18(9):2551- proapoptotic transcription by the p73 tumor suppressor protein. 62 Mol Cell. 2007 Sep 21;27(6):962-75 Sudol M, Hunter T. NeW wrinkles for an old domain. Cell. 2000 Pan D. Hippo signaling in organ size control. Genes Dev. 2007 Dec 22;103(7):1001-4 Apr 15;21(8):886-97 Strano S, Munarriz E, Rossi M, Castagnoli L, Shaul Y, Sacchi Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, Xie J, Ikenoue A, Oren M, Sudol M, Cesareni G, Blandino G. Physical T, Yu J, Li L, Zheng P, Ye K, Chinnaiyan A, Halder G, Lai ZC, interaction with Yes-associated protein enhances p73 Guan KL. Inactivation of YAP oncoprotein by the Hippo transcriptional activity. J Biol Chem. 2001 May pathway is involved in cell contact inhibition and tissue growth 4;276(18):15164-73 control. Genes Dev. 2007 Nov 1;21(21):2747-61 Vassilev A, Kaneko KJ, Shu H, Zhao Y, DePamphilis ML. Hao Y, Chun A, Cheung K, Rashidi B, Yang X. Tumor TEAD/TEF transcription factors utilize the activation domain of suppressor LATS1 is a negative regulator of oncogene YAP. J YAP65, a Src/Yes-associated protein localized in the Biol Chem. 2008 Feb 29;283(9):5496-509

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1057 YAP1 (Yes-associated protein 1, 65kDa) Di Agostino S, et al.

Lapi E, Di Agostino S, Donzelli S, Gal H, Domany E, Rechavi dependent gene induction and growth control. Genes Dev. G, Pandolfi PP, Givol D, Strano S, Lu X, Blandino G. PML, 2008 Jul 15;22(14):1962-71 YAP, and p73 are components of a proapoptotic autoregulatory feedback loop. Mol Cell. 2008 Dec Bertini E, Oka T, Sudol M, Strano S, Blandino G. YAP: at the 26;32(6):803-14 crossroad between transformation and tumor suppression. Cell Cycle. 2009 Jan 1;8(1):49-57 Levy D, Adamovich Y, Reuven N, Shaul Y. Yap1 phosphorylation by c-Abl is a critical step in selective activation Zagurovskaya M, Shareef MM, Das A, Reeves A, Gupta S, of proapoptotic genes in response to DNA damage. Mol Cell. Sudol M, Bedford MT, Prichard J, Mohiuddin M, Ahmed MM. 2008 Feb 15;29(3):350-61 EGR-1 forms a complex with YAP-1 and upregulates Bax expression in irradiated prostate carcinoma cells. Oncogene. Yuan M, Tomlinson V, Lara R, Holliday D, Chelala C, Harada 2009 Feb 26;28(8):1121-31 T, Gangeswaran R, Manson-Bishop C, Smith P, Danovi SA, Pardo O, Crook T, Mein CA, Lemoine NR, Jones LJ, Basu S. This article should be referenced as such: Yes-associated protein (YAP) functions as a tumor suppressor in breast. Cell Death Differ. 2008 Nov;15(11):1752-9 Di Agostino S, Strano S, Blandino G. YAP1 (Yes-associated protein 1, 65kDa). Atlas Genet Cytogenet Oncol Haematol. Zhao B, Ye X, Yu J, Li L, Li W, Li S, Yu J, Lin JD, Wang CY, 2010; 14(11):1054-1058. Chinnaiyan AM, Lai ZC, Guan KL. TEAD mediates YAP-

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1058 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

ALK (anaplastic lymphoma receptor tyrosine kinase) Michèle Allouche INSERM U.563 CPTP, Bat. B, Pavillon Lefevre, CHU Purpan, BP 3028, 31024 Toulouse Cedex 3, France (MA)

Published in Atlas Database: February 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/ALK.html DOI: 10.4267/2042/44894 This article is an update of : Huret JL, Senon S. ALK (anaplastic lymphoma kinase). Atlas Genet Cytogenet Oncol Haematol 2003;7(4):217-220. Huret JL. ALK (anaplastic lymphoma kinase). Atlas Genet Cytogenet Oncol Haematol 2001;5(4):249-251. Huret JL. ALK (anaplastic lymphoma kinase). Atlas Genet Cytogenet Oncol Haematol 1997;1(1):4.

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity DNA/RNA Other names: anaplastic lymphoma kinase (Ki-1); Description CD246 The gene is composed of 29 exons spanning in a region HGNC (Hugo): ALK of 728793 bp. Location: 2p23 Transcription 6226 bp cDNA; coding sequence: 4.9 kb. Protein Description 1620 amino acids; 177 kDa; after glycosylation, produces a 200 kDa mature glycoprotein; type I transmembrane receptor; composed of an extracellular region (containing two MAM and one LDLa domains, and one glycin-rich region), a transmembrane, and an intracellular region (composed of a juxta-membrane domain, a tyrosine kinase domain (1122-1376), and a C-terminal domain; dimerization. Expression Is tissue specific; mainly in: central and peripheral nervous system during development (less in adult), and testis; not in the lymphocytes. Localisation Cell membrane.

ALK (2p23) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1059 ALK (anaplastic lymphoma receptor tyrosine kinase) Allouche M

Function (i.e. composed of the oligomerization domain and the metal binding site of NPM1, and the entire cytoplasmic ALK is a membrane associated tyrosine kinase receptor portion of ALK); no apparent expression of the of the insulin receptor superfamily. The function of the ALK/NPM1 counterpart. Characteristic localisation in full-length ALK receptor is poorly understood. It has a the cytoplasm, nucleus and nucleolus, due to probable role in the central and peripheral nervous heterooligomerization of NPM1-ALK and normal system development and maintenance. ALK is a NPM1 whereas the normal NPM1 protein is confined dependence receptor, which may exert antagonist to the nucleus and nucleolus; constitutive activation of functions, proapoptotic or antiapoptotic, depending on the catalytic domain of ALK. the absence or presence of a ligand (Mourali et al., 2006). Dependence receptors have a potential role in Oncogenesis cancer and development (Allouche, 2007). Ligands Via the kinase function activated by oligomerization of available for this demonstration were agonist anti-ALK NPM1-ALK mediated by the NPM1 part. antibodies (Motegi et al., 2004; Moog-Lutz et al., Cytoplasmic ALK+ anaplasic large cell 2005). If a specific ALK ligand (jelly belly) has been lymphoma (ALCL) clearly identified in Drosophila, it has no homologue in vertebrates (Palmer et al., 2009). ALK is still an orphan Prognosis receptor, given the high level of controversy about Present a favourable prognosis comparable to the one pleiotrophin and midkine, which have been proposed as found in t(2;5) ALK+ ALCL. ligands by Stoica et al. (2001, 2002) (see review by Cytogenetics Chiarle et al., 2008). Either t(X;2)(q11;p23), t(1;2)(q25;p23), Homology inv(2)(p23q35), t(2;3)(p23;q21), t(2;17)(p23;q23), t(2;17)(p23;q25), t(2;19)(p23;p13.1) or Homologies with the insulin receptor super family: t(2;22)(p23;q11.2). LTK (leucocyte tyrosine kinase), IGF1-R, IRb, TRKA, ROS (homolog of the drosophila Sevenless). Hybrid/Mutated gene 5' MSN, TPM3, ATIC, TFG, CLTC, ALO17, TPM4 or Implicated in MYH9 - 3' ALK. Abnormal protein ALK+ anaplastic large cell lymphoma N-term amino acids from the partner gene fused to the (ALCL) 563 C-term amino acids (in the great majority of cases) Disease from ALK (i.e. the entire cytoplasmic portion of ALK ALCL are high grade non Hodgkin lymphomas. ALK+ with the tyrosine kinase domain); ALCL are ALCL where ALK is involved in a fusion cytoplasmic/membraneous localisation only. gene; systemic ALK+ ALCL (as opposed to cutaneous Oncogenesis ALCL, which are usually ALK negative) represent 60 The partner gene seems to provoke the dimerization of to 80 % of ALCL cases (they are CD30+, ALK+); 70 the fused X-ALK, which should lead to constitutive to 80% of ALK+ ALCL cases bear a t(2;5); the autophosphorylation and activation of the ALK remaining ALK+ ALCL cases bear variant tyrosine kinase, as for NPM1-ALK (see translocations "X-ALK", where X designates a partner t(2;5)(p23;q35)). gene. Inflammatory myofibroblastic tumours Prognosis with 2p23 rearrangements Although presenting as a high grade tumour, an 80% five year survival is associated with this anomaly, but Disease recurrence is a concern. Rare soft tissue tumour found in children and young adults about one third to half of inflammatory Cytogenetics myofibroblastic tumour cases present with a 2p23 The prototype anomaly is the t(2;5)(p23;q35) rearrangement involving ALK. generating the NPM1-ALK fusion. Alternative anomalies involving the ALK gene in Prognosis ALCL are described below as "cytoplasmic ALK+ Good prognosis. ALCL" cases, among which the t(1;2) TPM3-ALK is Cytogenetics found in 20% of ALK+ ALCL. t(1;2)(q25;p23), t(2;2)(p23;q13) or inv(2)(p23;q11-13), Complex karyotypes may also be found. inv(2)(p23;q35), t(2;4)(p23;q21), Hybrid/Mutated gene t(2;11)(p23;p15), t(2;17)(p23;q23), 5' NPM1 - 3' ALK on the der(5). or t(2;19)(p23;p13.1) so far. Abnormal protein Hybrid/Mutated gene 680 amino acids, 80 kDa; N-term 117 amino acids from 5' TPM3 in the t(1;2), RANBP2 in the t(2;2) or NPM1 fused to the 563 C-term amino acids of ALK inv(2)(p23;q11-13), 5' ATIC in inv(2)(p23;q35), 5'

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1060 ALK (anaplastic lymphoma receptor tyrosine kinase) Allouche M

SEC31L1 in t(2;4), 5' CARS in the t(2;11), 5' CLTC in ALK fusion starts at a portion encoded by exon 20. the t(2;17), or 5' TPM4 in the t(2;19) - 3' ALK. Abnormal protein Abnormal protein N-term amino acids from the partner gene fused to the N-term amino acids from the partner gene fused to the 563 C-term amino acids from ALK (i.e. the entire 563 C-term amino acids from ALK (i.e. the entire cytoplasmic portion of ALK with the tyrosine kinase cytoplasmic portion of ALK with the tyrosine kinase domain); homodimerization of the fusion protein is domain); homodimerization of the fusion protein is known or suspected; protein is difficult to detect by known or suspected. classical immunohistochemistry methods (low Oncogenesis expression). Fused-ALK is constitutively activated. Oncogenesis ALK+ diffuse large B-cell lymphoma Fused-ALK is constitutively activated. Note: in a European study, EML4-ALK fusion (DLBCL) transcript has also been found in up to 9% non-tumour Disease lung tissue from lung tumour patients. Interestingly, the Very rare form of DLBCL (40 cases described) EML4-ALK transcript was not detected in matching expressing either ALK in fusion with CLTC tumour samples from the same patients (Martelli et al., (cytoplasmic granular localisation) associated to 2009). t(2;17)(p23;q23) (most frequently), or (rarely) NPM1- Familial neuroblastoma and sporadic ALK in t(2;5)(p23;q35); tumours are EMA+, CD30- and CD20-negative. neuroblastoma Prognosis Disease Poor prognosis: aggressive lymphoma with 25% five Neuroblastoma is a cancer of early childhood that year survival. arises from the developing autonomic nervous system, giving rise to peripheral tumours. It is the most Cytogenetics common malignancy diagnosed in the first year of life t(2;5)(p23;q35) or t(2;17)(p23;q23). and shows a wide range of clinical phenotypes, with a Hybrid/Mutated gene few patients having tumours that regress 5' NPM1 or CLTC - 3' ALK. spontaneously, whereas most patients have aggressive Abnormal protein metastatic disease. It can be transmitted in an N-term amino acids from the partner gene fused to the autosomal dominant mode as a familial predisposition, 563 C-term amino acids from ALK (i.e. the entire or occur as a sporadic disease. cytoplasmic portion of ALK with the tyrosine kinase Prognosis domain); homodimerization of the fusion protein is Aggressive neuroblastoma cases have survival known or suspected. probabilities of less then 40% despite intensive Oncogenesis chemoradiotherapy, and the disease continues to Fused-ALK is constitutively activated. account for 15% of childhood cancer mortality. ALK+ non-small cell lung cancer Cytogenetics Gene amplifications or mutations of ALK; (NSCLC) Associated alterations: tumours from patients with an Disease aggressive phenotype often show amplification of the 1-6 % of all NSCLC present a rearrangement involving MYCN oncogene, and/or deletions of chromosome ALK fused to EML4 in an inv(2)(p21p23); studies on arms 1p and 11q. East Asian and American/European patients (Soda et Hybrid/Mutated gene al., 2007; Perner et al., 2008). Several point mutations located in the coding region of Prognosis the receptor intracellular portion, mostly in the tyrosine 50% survival at 24 months, so far (first identification in kinase domain. 2007). Abnormal protein Cytogenetics 54 ALK mutations reported, affecting 12 different inv(2)(p21;p23). residues (Caren et al., 2008; Chen et al., 2008; George Hybrid/Mutated gene et al., 2008; Janoueix-Lerosey et al., 2008; Mosse et al., 5' EML4 - 3' ALK; multiple variants of EML4-ALK 2008); two hotspots: F1174 and R1275. noted depending on the breakpoint on the EML gene; Most frequent germline mutations (familial cases): G1128A, R1192P, R1275Q.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1061 ALK (anaplastic lymphoma receptor tyrosine kinase) Allouche M

Most frequent somatic mutations (sporadic cases): chimeric protein p80NPM/ALK: a distinct clinicopathologic F1174L/I, F1245C/V. entity. Blood. 1995 Sep 1;86(5):1954-60 Oncogenesis Lamant L, Meggetto F, al Saati T, Brugières L, de Paillerets BB, Dastugue N, Bernheim A, Rubie H, Terrier-Lacombe MJ, Gene amplifications or point mutations both confer Robert A, Rigal F, Schlaifer D, Shiuta M, Mori S, Delsol G. constitutive kinase activation. High incidence of the t(2;5)(p23;q35) translocation in anaplastic large cell lymphoma and its lack of detection in Hodgkin's disease. Comparison of cytogenetic analysis, Breakpoints reverse transcriptase-polymerase chain reaction, and P-80 Note immunostaining. Blood. 1996 Jan 1;87(1):284-91 Most of the breakpoints occur in the same intron of Bischof D, Pulford K, Mason DY, Morris SW. Role of the ALK, whichever partner is involved in the fusion nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma- associated NPM-anaplastic lymphoma kinase fusion protein in protein. oncogenesis. Mol Cell Biol. 1997 Apr;17(4):2312-25 Iwahara T, Fujimoto J, Wen D, Cupples R, Bucay N, Arakawa To be noted T, Mori S, Ratzkin B, Yamamoto T. Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the Note nervous system. Oncogene. 1997 Jan 30;14(4):439-49 ALK in fusion to several gene partners, is found Morris SW, Naeve C, Mathew P, James PL, Kirstein MN, Cui implicated both in hematopoietic and non- X, Witte DP. ALK, the chromosome 2 gene locus altered by the hematopoietic solid tumours; this was a new concept in t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural 2003, that several different types of tumour may result receptor tyrosine kinase that is highly related to leukocyte from the same chromosomal/genes rearrangement(s). tyrosine kinase (LTK) Oncogene. 1997 May 8;14(18):2175-88 Pulford K, Lamant L, Morris SW, Butler LH, Wood KM, Stroud References D, Delsol G, Mason DY. Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK Morris SW, Kirstein MN, Valentine MB, Dittmer KG, Shapiro proteins in normal and neoplastic cells with the monoclonal DN, Saltman DL, Look AT. Fusion of a kinase gene, ALK, to a antibody ALK1. Blood. 1997 Feb 15;89(4):1394-404 nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science. 1994 Mar 4;263(5151):1281-4 Griffin CA, Hawkins AL, Dvorak C, Henkle C, Ellingham T, Perlman EJ. Recurrent involvement of 2p23 in inflammatory Shiota M, Nakamura S, Ichinohasama R, Abe M, Akagi T, myofibroblastic tumors. Cancer Res. 1999 Jun 15;59(12):2776- Takeshita M, Mori N, Fujimoto J, Miyauchi J, Mikata A, Nanba 80 K, Takami T, Yamabe H, Takano Y, Izumo T, Nagatani T, Mohri N, Nasu K, Satoh H, Katano H, Fujimoto J, Yamamoto T, Hernández L, Pinyol M, Hernández S, Beà S, Pulford K, Mori S. Anaplastic large cell lymphomas expressing the novel Rosenwald A, Lamant L, Falini B, Ott G, Mason DY, Delsol G,

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1062 ALK (anaplastic lymphoma receptor tyrosine kinase) Allouche M

Campo E. TRK-fused gene (TFG) is a new partner of ALK in Cools J, Wlodarska I, Somers R, Mentens N, Pedeutour F, anaplastic large cell lymphoma producing two structurally Maes B, De Wolf-Peeters C, Pauwels P, Hagemeijer A, different TFG-ALK translocations. Blood. 1999 Nov Marynen P. Identification of novel fusion partners of ALK, the 1;94(9):3265-8 anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor. Genes Chromosomes Lamant L, Dastugue N, Pulford K, Delsol G, Mariamé B. A new Cancer. 2002 Aug;34(4):354-62 fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation. Blood. 1999 May Dirks WG, Fähnrich S, Lis Y, Becker E, MacLeod RA, Drexler 1;93(9):3088-95 HG. Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines. Int J Cancer. Colleoni GW, Bridge JA, Garicochea B, Liu J, Filippa DA, 2002 Jul 1;100(1):49-56 Ladanyi M. ATIC-ALK: A novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent Hernández L, Beà S, Bellosillo B, Pinyol M, Falini B, Carbone cryptic chromosomal inversion, inv(2)(p23q35). Am J Pathol. A, Ott G, Rosenwald A, Fernández A, Pulford K, Mason D, 2000 Mar;156(3):781-9 Morris SW, Santos E, Campo E. Diversity of genomic breakpoints in TFG-ALK translocations in anaplastic large cell Drexler HG, Gignac SM, von Wasielewski R, Werner M, Dirks lymphomas: identification of a new TFG-ALK(XL) chimeric WG. Pathobiology of NPM-ALK and variant fusion genes in gene with transforming activity. Am J Pathol. 2002 anaplastic large cell lymphoma and other lymphomas. Apr;160(4):1487-94 Leukemia. 2000 Sep;14(9):1533-59 Stoica GE, Kuo A, Powers C, Bowden ET, Sale EB, Riegel AT, Lamant L, Pulford K, Bischof D, Morris SW, Mason DY, Delsol Wellstein A. Midkine binds to anaplastic lymphoma kinase G, Mariamé B. Expression of the ALK tyrosine kinase gene in (ALK) and acts as a growth factor for different cell types. J Biol neuroblastoma. Am J Pathol. 2000 May;156(5):1711-21 Chem. 2002 Sep 27;277(39):35990-8 Lawrence B, Perez-Atayde A, Hibbard MK, Rubin BP, Dal Cin Debelenko LV, Arthur DC, Pack SD, Helman LJ, Schrump DS, P, Pinkus JL, Pinkus GS, Xiao S, Yi ES, Fletcher CD, Fletcher Tsokos M. Identification of CARS-ALK fusion in primary and JA. TPM3-ALK and TPM4-ALK oncogenes in inflammatory metastatic lesions of an inflammatory myofibroblastic tumor. myofibroblastic tumors. Am J Pathol. 2000 Aug;157(2):377-84 Lab Invest. 2003 Sep;83(9):1255-65 Ma Z, Cools J, Marynen P, Cui X, Siebert R, Gesk S, Gascoyne RD, Lamant L, Martin-Subero JI, Lestou VS, Harris Schlegelberger B, Peeters B, De Wolf-Peeters C, Wlodarska I, NL, Müller-Hermelink HK, Seymour JF, Campbell LJ, Horsman Morris SW. Inv(2)(p23q35) in anaplastic large-cell lymphoma DE, Auvigne I, Espinos E, Siebert R, Delsol G. ALK-positive induces constitutive anaplastic lymphoma kinase (ALK) diffuse large B-cell lymphoma is associated with Clathrin-ALK tyrosine kinase activation by fusion to ATIC, an enzyme rearrangements: report of 6 cases. Blood. 2003 Oct involved in purine nucleotide biosynthesis. Blood. 2000 Mar 1;102(7):2568-73 15;95(6):2144-9 Lamant L, Gascoyne RD, Duplantier MM, Armstrong F, Stein H, Foss HD, Dürkop H, Marafioti T, Delsol G, Pulford K, Raghab A, Chhanabhai M, Rajcan-Separovic E, Raghab J, Pileri S, Falini B. CD30(+) anaplastic large cell lymphoma: a Delsol G, Espinos E. Non-muscle myosin heavy chain (MYH9): review of its histopathologic, genetic, and clinical features. a new partner fused to ALK in anaplastic large cell lymphoma. Blood. 2000 Dec 1;96(12):3681-95 Genes Chromosomes Cancer. 2003 Aug;37(4):427-32 Touriol C, Greenland C, Lamant L, Pulford K, Bernard F, Onciu M, Behm FG, Downing JR, Shurtleff SA, Raimondi SC, Rousset T, Mason DY, Delsol G. Further demonstration of the Ma Z, Morris SW, Kennedy W, Jones SC, Sandlund JT. ALK- diversity of chromosomal changes involving 2p23 in ALK- positive plasmablastic B-cell lymphoma with expression of the positive lymphoma: 2 cases expressing ALK kinase fused to NPM-ALK fusion transcript: report of 2 cases. Blood. 2003 Oct CLTCL (clathrin chain polypeptide-like). Blood. 2000 May 1;102(7):2642-4 15;95(10):3204-7 Motegi A, Fujimoto J, Kotani M, Sakuraba H, Yamamoto T. Trinei M, Lanfrancone L, Campo E, Pulford K, Mason DY, ALK receptor tyrosine kinase promotes cell growth and neurite Pelicci PG, Falini B. A new variant anaplastic lymphoma kinase outgrowth. J Cell Sci. 2004 Jul 1;117(Pt 15):3319-29 (ALK)-fusion protein (ATIC-ALK) in a case of ALK-positive anaplastic large cell lymphoma. Cancer Res. 2000 Feb Pulford K, Lamant L, Espinos E, Jiang Q, Xue L, Turturro F, 15;60(4):793-8 Delsol G, Morris SW. The emerging normal and disease- related roles of anaplastic lymphoma kinase. Cell Mol Life Sci. Bridge JA, Kanamori M, Ma Z, Pickering D, Hill DA, Lydiatt W, 2004 Dec;61(23):2939-53 Lui MY, Colleoni GW, Antonescu CR, Ladanyi M, Morris SW. Fusion of the ALK gene to the clathrin heavy chain gene, Moog-Lutz C, Degoutin J, Gouzi JY, Frobert Y, Brunet-de CLTC, in inflammatory myofibroblastic tumor. Am J Pathol. Carvalho N, Bureau J, Créminon C, Vigny M. Activation and 2001 Aug;159(2):411-5 inhibition of anaplastic lymphoma kinase receptor tyrosine kinase by monoclonal antibodies and absence of agonist Duyster J, Bai RY, Morris SW. Translocations involving activity of pleiotrophin. J Biol Chem. 2005 Jul anaplastic lymphoma kinase (ALK). Oncogene. 2001 Sep 15;280(28):26039-48 10;20(40):5623-37 Turner SD, Alexander DR. What have we learnt from mouse Stoica GE, Kuo A, Aigner A, Sunitha I, Souttou B, Malerczyk C, models of NPM-ALK-induced lymphomagenesis? Leukemia. Caughey DJ, Wen D, Karavanov A, Riegel AT, Wellstein A. 2005 Jul;19(7):1128-34 Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin. J Biol Chem. 2001 May Mourali J, Bénard A, Lourenço FC, Monnet C, Greenland C, 18;276(20):16772-9 Moog-Lutz C, Racaud-Sultan C, Gonzalez-Dunia D, Vigny M, Mehlen P, Delsol G, Allouche M. Anaplastic lymphoma kinase Tort F, Pinyol M, Pulford K, Roncador G, Hernandez L, Nayach is a dependence receptor whose proapoptotic functions are I, Kluin-Nelemans HC, Kluin P, Touriol C, Delsol G, Mason D, activated by caspase cleavage. Mol Cell Biol. 2006 Campo E. Molecular characterization of a new ALK Aug;26(16):6209-22 translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma. Lab Invest. 2001 Mar;81(3):419-26 Panagopoulos I, Nilsson T, Domanski HA, Isaksson M, Lindblom P, Mertens F, Mandahl N. Fusion of the SEC31L1

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1063 ALK (anaplastic lymphoma receptor tyrosine kinase) Allouche M

and ALK genes in an inflammatory myofibroblastic tumor. Int J E, Devoto M, Maris JM. Identification of ALK as a major familial Cancer. 2006 Mar 1;118(5):1181-6 neuroblastoma predisposition gene. Nature. 2008 Oct 16;455(7215):930-5 Allouche M. ALK is a novel dependence receptor: potential implications in development and cancer. Cell Cycle. 2007 Jul Perner S, Wagner PL, Demichelis F, Mehra R, Lafargue CJ, 1;6(13):1533-8 Moss BJ, Arbogast S, Soltermann A, Weder W, Giordano TJ, Beer DG, Rickman DS, Chinnaiyan AM, Moch H, Rubin MA. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, EML4-ALK fusion lung cancer: a rare acquired event. Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka Neoplasia. 2008 Mar;10(3):298-302 H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H. Identification of the transforming Martelli MP, Sozzi G, Hernandez L, Pettirossi V, Navarro A, EML4-ALK fusion gene in non-small-cell lung cancer. Nature. Conte D, Gasparini P, Perrone F, Modena P, Pastorino U, 2007 Aug 2;448(7153):561-6 Carbone A, Fabbri A, Sidoni A, Nakamura S, Gambacorta M, Fernández PL, Ramirez J, Chan JK, Grigioni WF, Campo E, Chen Y, Takita J, Choi YL, Kato M, Ohira M, Sanada M, Wang Pileri SA, Falini B. EML4-ALK rearrangement in non-small cell L, Soda M, Kikuchi A, Igarashi T, Nakagawara A, Hayashi Y, lung cancer and non-tumor lung tissues. Am J Pathol. 2009 Mano H, Ogawa S. Oncogenic mutations of ALK kinase in Feb;174(2):661-70 neuroblastoma. Nature. 2008 Oct 16;455(7215):971-4 Palmer RH, Vernersson E, Grabbe C, Hallberg B. Anaplastic Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G. The lymphoma kinase: signalling in development and disease. anaplastic lymphoma kinase in the pathogenesis of cancer. Biochem J. 2009 May 27;420(3):345-61 Nat Rev Cancer. 2008 Jan;8(1):11-23 Takeuchi K, Choi YL, Togashi Y, Soda M, Hatano S, Inamura George RE, Sanda T, Hanna M, Fröhling S, Luther W 2nd, K, Takada S, Ueno T, Yamashita Y, Satoh Y, Okumura S, Zhang J, Ahn Y, Zhou W, London WB, McGrady P, Xue L, Nakagawa K, Ishikawa Y, Mano H. KIF5B-ALK, a novel fusion Zozulya S, Gregor VE, Webb TR, Gray NS, Gilliland DG, Diller oncokinase identified by an immunohistochemistry-based L, Greulich H, Morris SW, Meyerson M, Look AT. Activating diagnostic system for ALK-positive lung cancer. Clin Cancer mutations in ALK provide a therapeutic target in Res. 2009 May 1;15(9):3143-9 neuroblastoma. Nature. 2008 Oct 16;455(7215):975-8 Webb TR, Slavish J, George RE, Look AT, Xue L, Jiang Q, Cui Janoueix-Lerosey I, Lequin D, Brugières L, Ribeiro A, de X, Rentrop WB, Morris SW. Anaplastic lymphoma kinase: role Pontual L, Combaret V, Raynal V, Puisieux A, Schleiermacher in cancer pathogenesis and small-molecule inhibitor G, Pierron G, Valteau-Couanet D, Frebourg T, Michon J, development for therapy. Expert Rev Anticancer Ther. 2009 Lyonnet S, Amiel J, Delattre O. Somatic and germline Mar;9(3):331-56 activating mutations of the ALK kinase receptor in neuroblastoma. Nature. 2008 Oct 16;455(7215):967-70 Janoueix-Lerosey I, Schleiermacher G, Delattre O. Molecular pathogenesis of peripheral neuroblastic tumors. Oncogene. Mano H. Non-solid oncogenes in solid tumors: EML4-ALK 2010 Mar 18;29(11):1566-79 fusion genes in lung cancer. Cancer Sci. 2008 Dec;99(12):2349-55 This article should be referenced as such: Mossé YP, Laudenslager M, Longo L, Cole KA, Wood A, Allouche M. ALK (anaplastic lymphoma receptor tyrosine Attiyeh EF, Laquaglia MJ, Sennett R, Lynch JE, Perri P, kinase). Atlas Genet Cytogenet Oncol Haematol. 2010; Laureys G, Speleman F, Kim C, Hou C, Hakonarson H, 14(11):1059-1064. Torkamani A, Schork NJ, Brodeur GM, Tonini GP, Rappaport

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1064 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

AXL (AXL receptor tyrosine kinase) Justine Migdall, Douglas K Graham Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO 80045, USA (JM, DKG)

Published in Atlas Database: February 2010 Online updated version: http://AtlasGeneticsOncology.org/Genes/AXLID733ch19q13.html DOI: 10.4267/2042/44895 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

proteolytic cleavage (see protein description), as well Identity as the entire transmembrane domain. Exons 12-20 Other names: JTK11; UFO encode the intracellular domain, which includes the HGNC (Hugo): AXL tyrosine kinase domain (exons 13-20) (O'Bryan et al., 1991; Hubbard et al., 2009). Location: 19q13.2 Transcription DNA/RNA There are two 4.7 kb mRNA variants of AXL distinguished by the presence or absence of exon 10, a Description 27 bp region in the C-terminal end of the extracellular The human AXL gene is located on chromosome domain, via alternative splicing. Both variants exist 19q13.2 and encodes 20 exons. Exons 1-10 encode the ubiquitously and at much higher levels in many extracellular domain, which includes a signal peptide cancers. Although the longer transcript is more highly (exon 1), two immunoglobulin (Ig) domains (exons 2-3 expressed in tumor tissue relative to its shorter and 4-5), and two fibronectin type III (FNIII) domains counterpart, both forms of the protein have the same (exons 6-7 and 8-9). Exon 11 encodes a short transforming potential (O'Bryan et al., 1991). extracellular region subject to

The diagram depicts the structure of the AXL gene (bottom) roughly aligned with its corresponding functional protein domains (top). Boxes represent individual exons with widths roughly relative to the base-pair length; connecting lines between exon boxes represent introns, which are drawn approximately 10-fold smaller to better align with the protein domains. The open-ended boxes of exons 1 and 20 indicate untranslated regions (not shown). Exon 10, which can be removed via alternative splicing, encodes an extracellular region at the C-terminal end of the second FNIII domain.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1065 AXL (AXL receptor tyrosine kinase) Migdall J, Graham DK

The diagram on the top depicts the domain organization of the AXL receptor tyrosine kinase. The intracellular kinase domain includes the seven-residue sequence conserved among TAM family receptor tyrosine kinases: at positions 3 and 5 within this conserved sequence, AXL and MERTK contain isoleucine (I) residues, while TYRO3 contains leucine (L) residues. Proteolytic cleavage of residues between the transmembrane and closest FNIII domains renders a soluble isoform of AXL, which contains its fully functioning extracellular domains. The diagram on the bottom depicts the domain structure of GAS6, the AXL ligand. GAS6 is activated by vitamin K-dependent carboxylation of the gamma-carboxyglutamic acid (Gla) domain.

Carboxy-terminal to the second FNIII domain, fourteen Protein amino acids (aa 438-451 in the longer variant) serve as Description a proteolytic cleavage site, yielding an 80 kD soluble form of AXL with only the extracellular domains of the The full-length AXL protein contains 894 amino acids full-length protein. As this cleavage site translates from and has a molecular weight of 104 kDa. As the exon 11, proteins from both transcript variants are extracellular domain contains six N-linked subject to proteolysis. The intact ligand-binding glycosylation sites, two other post-translationally domains in this soluble form highlight its potential role modified forms weighing 120 and 140 kDa - in signal transduction as an inhibitor of the membrane- representing partial and complete glycosylation, bound receptor (O'Bryan et al., 1995). respectively- have been identified. The extracellular The intracellular tyrosine kinase domain of AXL component of the AXL receptor contains two Ig-like contains the sequence KW(I/L)A(I/L)ES (aa 714-720), domains (aa 37-124 for domain 1, 141-212 for domain which is conserved among all TAM family RTKs. 2) followed by two FNIII domains (aa 224-322 for Within this signature motif, the third and fifth amino domain 1, 325-428 for domain 2) (O'Bryan et al., acids are isoleucine (I) in both AXL and MERTK, 1991). This particular tandem arrangement defines while leucine (L) occupies these positions in TYRO3 AXL as part of the TAM family of receptor tyrosine (Graham et al., 1994). Activation of the AXL receptor kinases (RTKs), which also includes TYRO3 and occurs within its intracellular domain and is MERTK (Graham et al., 1994). All three TAM family characterized by the phosphorylation of tyrosine proteins bind the ligand GAS6, a vitamin K-dependent residues at sites that have yet to be defined. MERTK is protein structurally similar to Protein S (PROS1), the only TAM family member with validated tyrosine which activates MERTK and TYRO3 but not AXL autophosphorylation sites; AXL also has three tyrosine (Prasad et al., 2006). Like all TAM family members, residues -Y697, Y702, and Y703- conserved in each immunoglobulin domain of the AXL receptor sequence context within its kinase domain, but no provides a binding site for each of the two laminin G- evidence exists implicating their role in like (LG) domains of GAS6, the only identified ligand autophosphorylation (Ling et al., 1996). Numerous for AXL as of yet (Sasaki et al., 2006).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1066 AXL (AXL receptor tyrosine kinase) Migdall J, Graham DK

mass spectrometry analyses confirm that these and Homology several other tyrosine residues are, in fact, AXL and the two other TAM family members, phosphorylated (Hornbeck et al., 2004), and a recent MERTK and TYRO3, share 31-36% and 54-59% study demonstrated that phosphorylation occurs at sequence identities in the extracellular and intracellular Y702 and Y703 upon GAS6 stimulation (Pao-Chun et regions, respectively (Graham et al., 1995). al., 2009). However, neither of these sites has been shown to directly regulate or interact with the downstream effectors of AXL activation. Mutations Three other tyrosine residues within the AXL Note intracellular domain -Y779, Y821, and Y866- mediate Although AXL overexpression is implicated in binding of various substrates, suggesting that they may oncogenesis, no mutations in the gene have been be more likely candidates for autophosphorylation identified as the underlying cause. sites. Y779 partially contributes to binding PI3K, while Y866 plays an integral role in binding PLC. Y821 has Implicated in been shown to be a critical docking site for multiple substrates, including PI3K, PLC, GRB2, c-SRC, and Malignancy LCK (Braunger et al., 1997). Despite this evidence, an Disease in vivo study refuted the significance of Y821 in AXL The transforming properties of AXL were first autophosphorylation and activation, as mutants without identified in patients with chronic myelogenous Y821 display normal GAS6-stimulated tyrosine leukemia (O'Bryan et al., 1991). AXL overexpression phosphorylation (Fridell et al., 1996). has also been reported in glioblastoma, melanoma, Along with conventional ligand-induced dimerization osteosarcoma, erythroid and megakaryocytic and autophosphorylation, AXL activation can also leukemias, and uterine, colon, prostate, thyroid, occur through ligand-independent pathways. AXL ovarian, and liver cancers (Linger et al., 2008). overexpression causes homophilic binding between its AXL overexpression positively correlates with tumor extracellular domains on neighboring cells and leads to metastasis and invasiveness in a number of tumor increased phosphorylation of its intracellular domain types, including renal cell carcinoma (Chung et al., (Bellosta et al., 1995). AXL also engages in cross-talk 2003), glioblastoma (Hutterer et al., 2008), and breast with the IL-15 receptor, which transactivates AXL and (Meric et al., 2002), gastric (Wu et al., 2002), lung requires it for survival from TNF-alpha-mediated (Shieh et al., 2005), and prostate cancers (Sainaghi et apoptosis (Budagian et al., 2005). al., 2005). AXL expression increases in response to Expression both targeted therapeutics and traditional AXL is expressed throughout all tissue and cell types chemotherapy, conferring drug resistance in (O'Bryan et al., 1991). Higher expression is observed in gastrointestinal stromal tumors (Mahadevan et al., endothelial cells, heart and skeletal muscle, liver, 2007) and acute myeloid leukemia (Hong et al., 2008). kidney, testis, platelets, myelomonocytic cells, Along with other signaling molecules -including some hippocampus, and cerebellum (Neubauer et al., 1994; that function with AXL to mediate drug resistance- Bellosta et al., 1995; Graham et al., 1995; Angelillo- AXL plays an important role in breast cancer epithelial- Scherrer et al., 2001). Relative to normal expression to-mesenchymal transition (EMT), a key program in levels, AXL is increased in a number of disease states metastasis induction (Gjerdrum et al., 2009). as reviewed by Linger et al (2008). The effects of AXL inhibition on cancer cells make AXL an attractive target for cancer treatment. In mouse Localisation xenografts of human breast cancer, RNAi-mediated AXL is a transmembrane receptor tyrosine kinase. AXL inhibition decreases angiogenesis by impairing Function endothelial cell migration, proliferation, and tube formation (Holland et al., 2005). Antibodies against the Activation of the AXL receptor initiates various extracellular AXL domain decrease tumor growth and signaling pathways involved in cell survival, invasion in in vitro models of breast and lung cancer proliferation, apoptosis inhibition, migration, cell (Zhang et al., 2008; Li et al., 2009). More recently, adhesion, and cytokine production. This is mediated via several small molecules have been identified as interactions with a spectrum of signaling molecules, promising AXL inhibitors: MP470 has cytotoxic effects including PI3K/Akt, ERK1/ERK2, GRB2, RAS, RAF1, on gastrointestinal stromal tumors and synergizes with MEK-1, and SOCS-1. Beyond its overexpression and other standard treatments (Mahadevan et al., 2007). In oncogenic potential in numerous cancers, AXL has also breast cancer, 3-quinolinecarbonitrile compounds been implicated in angiogenesis and metastasis (Linger decrease motility and invasion (Zhang et al., 2008), and et al., 2008). R428 selectively blocks AXL and its ability to promote angiogenesis and metastasis (Holland et al., 2010).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1067 AXL (AXL receptor tyrosine kinase) Migdall J, Graham DK

Autoimmune disease receptor tyrosine kinase Axl and its ligand Gas6 in rheumatoid arthritis: evidence for a novel endothelial cell survival pathway. Disease Am J Pathol. 1999 Apr;154(4):1171-80 Mice devoid of TYRO3, AXL, and MERTK develop Angelillo-Scherrer A, de Frutos P, Aparicio C, Melis E, Savi P, autoimmune diseases, including rheumatoid arthritis Lupu F, Arnout J, Dewerchin M, Hoylaerts M, Herbert J, Collen and lupus, with more pronounced susceptibility to D, Dahlbäck B, Carmeliet P. Deficiency or inhibition of Gas6 autoimmunity in triple-knockout (relative to single- or causes platelet dysfunction and protects mice against thrombosis. Nat Med. 2001 Feb;7(2):215-21 double-knockout) TAM mutants (Cohen et al., 2002; Lemke and Lu, 2003). Transgenic mice with ectopic Cohen PL, Caricchio R, Abraham V, Camenisch TD, Jennette JC, Roubey RA, Earp HS, Matsushima G, Reap EA. Delayed AXL expression develop noninsulin-dependent apoptotic cell clearance and lupus-like autoimmunity in mice diabetes mellitus and have increased levels of TNF- lacking the c-mer membrane tyrosine kinase. J Exp Med. 2002 alpha (Augustine et al., 1999). In humans, AXL Jul 1;196(1):135-40 promotes survival of endothelial cells in the synovial Meric F, Lee WP, Sahin A, Zhang H, Kung HJ, Hung MC. joints of patients with rheumatoid arthritis (O'Donnell Expression profile of tyrosine kinases in breast cancer. Clin et al., 1999) and mediates injury-induced chemotaxis Cancer Res. 2002 Feb;8(2):361-7 and vascular remodeling (Fridell et al., 1998). Wu CW, Li AF, Chi CW, Lai CH, Huang CL, Lo SS, Lui WY, Lin WC. Clinical significance of AXL kinase family in gastric References cancer. Anticancer Res. 2002 Mar-Apr;22(2B):1071-8 Chung BI, Malkowicz SB, Nguyen TB, Libertino JA, McGarvey O'Bryan JP, Frye RA, Cogswell PC, Neubauer A, Kitch B, TW. Expression of the proto-oncogene Axl in renal cell Prokop C, Espinosa R 3rd, Le Beau MM, Earp HS, Liu ET. axl, carcinoma. DNA Cell Biol. 2003 Aug;22(8):533-40 a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase. Mol Lemke G, Lu Q. Macrophage regulation by Tyro 3 family Cell Biol. 1991 Oct;11(10):5016-31 receptors. Curr Opin Immunol. 2003 Feb;15(1):31-6 Graham DK, Dawson TL, Mullaney DL, Snodgrass HR, Earp Hornbeck PV, Chabra I, Kornhauser JM, Skrzypek E, Zhang B. HS. Cloning and mRNA expression analysis of a novel human PhosphoSite: A bioinformatics resource dedicated to protooncogene, c-mer. Cell Growth Differ. 1994 Jun;5(6):647- physiological protein phosphorylation. Proteomics. 2004 57 Jun;4(6):1551-61 Neubauer A, Fiebeler A, Graham DK, O'Bryan JP, Schmidt CA, Budagian V, Bulanova E, Orinska Z, Thon L, Mamat U, Barckow P, Serke S, Siegert W, Snodgrass HR, Huhn D. Bellosta P, Basilico C, Adam D, Paus R, Bulfone-Paus S. A Expression of axl, a transforming receptor tyrosine kinase, in promiscuous liaison between IL-15 receptor and Axl receptor normal and malignant hematopoiesis. Blood. 1994 Sep tyrosine kinase in cell death control. EMBO J. 2005 Dec 15;84(6):1931-41 21;24(24):4260-70 Bellosta P, Costa M, Lin DA, Basilico C. The receptor tyrosine Holland SJ, Powell MJ, Franci C, Chan EW, Friera AM, kinase ARK mediates cell aggregation by homophilic binding. Atchison RE, McLaughlin J, Swift SE, Pali ES, Yam G, Wong Mol Cell Biol. 1995 Feb;15(2):614-25 S, Lasaga J, Shen MR, Yu S, Xu W, Hitoshi Y, Bogenberger J, Nör JE, Payan DG, Lorens JB. Multiple roles for the receptor Graham DK, Bowman GW, Dawson TL, Stanford WL, Earp tyrosine kinase axl in tumor formation. Cancer Res. 2005 Oct HS, Snodgrass HR. Cloning and developmental expression 15;65(20):9294-303 analysis of the murine c-mer tyrosine kinase. Oncogene. 1995 Jun 15;10(12):2349-59 Sainaghi PP, Castello L, Bergamasco L, Galletti M, Bellosta P, Avanzi GC. Gas6 induces proliferation in prostate carcinoma O'Bryan JP, Fridell YW, Koski R, Varnum B, Liu ET. The cell lines expressing the Axl receptor. J Cell Physiol. 2005 transforming receptor tyrosine kinase, Axl, is post- Jul;204(1):36-44 translationally regulated by proteolytic cleavage. J Biol Chem. 1995 Jan 13;270(2):551-7 Shieh YS, Lai CY, Kao YR, Shiah SG, Chu YW, Lee HS, Wu CW. Expression of axl in lung adenocarcinoma and correlation Fridell YW, Jin Y, Quilliam LA, Burchert A, McCloskey P, Spizz with tumor progression. Neoplasia. 2005 Dec;7(12):1058-64 G, Varnum B, Der C, Liu ET. Differential activation of the Ras/extracellular-signal-regulated protein kinase pathway is Prasad D, Rothlin CV, Burrola P, Burstyn-Cohen T, Lu Q, responsible for the biological consequences induced by the Axl Garcia de Frutos P, Lemke G. TAM receptor function in the receptor tyrosine kinase. Mol Cell Biol. 1996 Jan;16(1):135-45 retinal pigment epithelium. Mol Cell Neurosci. 2006 Sep;33(1):96-108 Ling L, Templeton D, Kung HJ. Identification of the major autophosphorylation sites of Nyk/Mer, an NCAM-related Sasaki T, Knyazev PG, Clout NJ, Cheburkin Y, Göhring W, receptor tyrosine kinase. J Biol Chem. 1996 Aug Ullrich A, Timpl R, Hohenester E. Structural basis for Gas6-Axl 2;271(31):18355-62 signalling. EMBO J. 2006 Jan 11;25(1):80-7 Braunger J, Schleithoff L, Schulz AS, Kessler H, Lammers R, Mahadevan D, Cooke L, Riley C, Swart R, Simons B, Della Ullrich A, Bartram CR, Janssen JW. Intracellular signaling of Croce K, Wisner L, Iorio M, Shakalya K, Garewal H, Nagle R, the Ufo/Axl receptor tyrosine kinase is mediated mainly by a Bearss D. A novel tyrosine kinase switch is a mechanism of multi-substrate docking-site. Oncogene. 1997 Jun imatinib resistance in gastrointestinal stromal tumors. 5;14(22):2619-31 Oncogene. 2007 Jun 7;26(27):3909-19 Fridell YW, Villa J Jr, Attar EC, Liu ET. GAS6 induces Axl- Hong CC, Lay JD, Huang JS, Cheng AL, Tang JL, Lin MT, Lai mediated chemotaxis of vascular smooth muscle cells. J Biol GM, Chuang SE. Receptor tyrosine kinase AXL is induced by Chem. 1998 Mar 20;273(12):7123-6 chemotherapy drugs and overexpression of AXL confers drug resistance in acute myeloid leukemia. Cancer Lett. 2008 Sep O'Donnell K, Harkes IC, Dougherty L, Wicks IP. Expression of 18;268(2):314-24

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1068 AXL (AXL receptor tyrosine kinase) Migdall J, Graham DK

Hutterer M, Knyazev P, Abate A, Reschke M, Maier H, Li Y, Ye X, Tan C, Hongo JA, Zha J, Liu J, Kallop D, Ludlam Stefanova N, Knyazeva T, Barbieri V, Reindl M, Muigg A, MJ, Pei L. Axl as a potential therapeutic target in cancer: role Kostron H, Stockhammer G, Ullrich A. Axl and growth arrest- of Axl in tumor growth, metastasis and angiogenesis. specific gene 6 are frequently overexpressed in human Oncogene. 2009 Oct 1;28(39):3442-55 gliomas and predict poor prognosis in patients with glioblastoma multiforme. Clin Cancer Res. 2008 Jan Pao-Chun L, Chan PM, Chan W, Manser E. Cytoplasmic ACK1 1;14(1):130-8 interaction with multiple receptor tyrosine kinases is mediated by Grb2: an analysis of ACK1 effects on Axl signaling. J Biol Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor Chem. 2009 Dec 11;284(50):34954-63 tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv Cancer Res. Gjerdrum C, Tiron C, Høiby T, Stefansson I, Haugen H, Sandal 2008;100:35-83 T, Collett K, Li S, McCormack E, Gjertsen BT, Micklem DR, Akslen LA, Glackin C, Lorens JB. Axl is an essential epithelial- Zhang YX, Knyazev PG, Cheburkin YV, Sharma K, Knyazev YP, Orfi L, Szabadkai I, Daub H, Kéri G, Ullrich A. AXL is a to-mesenchymal transition-induced regulator of breast cancer potential target for therapeutic intervention in breast cancer metastasis and patient survival. Proc Natl Acad Sci U S A. progression. Cancer Res. 2008 Mar 15;68(6):1905-15 2010 Jan 19;107(3):1124-9 Hubbard TJ, Aken BL, Ayling S, Ballester B, Beal K, Bragin E, Holland SJ, Pan A, Franci C, Hu Y, Chang B, Li W, Duan M, Brent S, Chen Y, Clapham P, Clarke L, Coates G, Fairley S, Torneros A, Yu J, Heckrodt TJ, Zhang J, Ding P, Apatira A, Fitzgerald S, Fernandez-Banet J, Gordon L, Graf S, Haider S, Chua J, Brandt R, Pine P, Goff D, Singh R, Payan DG, Hitoshi Hammond M, Holland R, Howe K, Jenkinson A, Johnson N, Y. R428, a selective small molecule inhibitor of Axl kinase, Kahari A, Keefe D, Keenan S, Kinsella R, Kokocinski F, blocks tumor spread and prolongs survival in models of Kulesha E, Lawson D, Longden I, Megy K, Meidl P, Overduin metastatic breast cancer. Cancer Res. 2010 Feb B, Parker A, Pritchard B, Rios D, Schuster M, Slater G, 15;70(4):1544-54 Smedley D, Spooner W, Spudich G, Trevanion S, Vilella A, Vogel J, White S, Wilder S, Zadissa A, Birney E, Cunningham This article should be referenced as such: F, Curwen V, Durbin R, Fernandez-Suarez XM, Herrero J, Migdall J, Graham DK. AXL (AXL receptor tyrosine kinase). Kasprzyk A, Proctor G, Smith J, Searle S, Flicek P. Ensembl Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1065- 2009. Nucleic Acids Res. 2009 Jan;37(Database issue):D690- 1069. 7

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1069 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

BAK1 (BCL2-antagonist/killer 1) Grant Dewson, Ruth Kluck The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville 3050, Melbourne, Australia (GD, RK)

Published in Atlas Database: February 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/BAK1ID752ch6p21.html DOI: 10.4267/2042/44896 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

proteins, several agents that target the prosurvival Identity proteins are being developed as novel cancer Other names: BAK; BAK-LIKE; BCL2L7; Bcl2-L-7; therapeutics. CDN1; MGC117255; MGC3887 HGNC (Hugo): BAK1 DNA/RNA Location: 6p21.31 Description Local order: Orientation: minus strand. The BAK1 gene, with 7748 bases in length, and Located approximately 380 kb centromeric to the contains 6 exons. The first exon is non-coding, and human major histocompatibility complex (MHC) class most of the largest, final exon is untranslated. II region. Transcription Note The BAK1 gene transcribes a 211 aa protein Bak. A The BAK1 gene produces the Bak protein, a pro- possible 101 aa splice variant, called BAK-like, apoptotic protein from the Bcl-2 protein family. Either contains BH1, BH2 and TM domains, but no BH3 Bak or Bax is required to permeabilize the domain, with a 2.4 kb transcript of BAK-like detected mitochondrial outer membrane during the in most human tissues and exhibiting pro-apoptotic mitochondrial (intrinsic) pathway of apoptotic cell activity. Two other human BAK1 mRNA variants are death. Bak is a single-pass membrane protein that present in GenBak but may not be expressed: the BakM localises to the mitochondrial outer membrane in variant would be 190 aa and lack 21 amino acids in the healthy cells, while Bax moves to mitochondria during linker region between alpha-helices 1 and 2; another apoptosis. Both Bak and Bax convert to the activated, would be 153 aa with the stop codon upstream of a pro-apoptotic form by undergoing a large splice junction and therefore predicted to be subject to conformational change before oligomerising to form nonsense-mediated mRNA decay. However in mice, a apoptotic pores in the mitochondrial outer membrane. similar 151 aa N-Bak that contains only the BH3 Pore formation allows the release of cytochrome c, domain is reportedly expressed in neurons. Smac and other proteins that promote protease (caspase) activity to kill the cell. Thus, Bak/Bax pore Pseudogene formation is a major point of no return in cell death. There are two pseudogenes: Bak2 (chromosome 20) The activation of Bak (and Bax) is initiated when the and Bak3 (chromosome 11). cell up-regulates the pro-apoptotic BH3-only members of the Bcl-2 family. Bak activation is blocked if Protein sufficient prosurvival (anti-apoptotic) Bcl-2 family members (e.g. Bcl-xL, Mcl-1, Bcl-2 and A1) are Note present to sequester the BH3-only proteins and also The BAK1 gene encodes for a 23409 Da protein, perhaps the activated Bak and Bax proteins. As cancer named Bak. The Bak cDNA was isolated by three cells often express high levels of these prosurvival groups by virtue of its protein product interacting with the adenovirus E1B 19K protein, or its homo-

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1070 BAK1 (BCL2-antagonist/killer 1) Dewson G, Kluck R

The human Bak protein is 211 aa in length. Bcl-2 homology (BH) domains indicate regions of sequence homology with other Bcl-2 family members, with the BH3 domain being present in all members. The structure of non-activated Bak is similar to that of the prosurvival Bcl-2 family members, with alpha helices 1-9 indicated. The oligomerization domain is important for homo-oligomerization and pore formation, while the transmembrane domain anchors Bak in the mitochondrial outer membrane. logy to the BH1 and BH2 domains of Bcl-2. The BH3 aneurysms, and cervical, colorectal and gastric cancers, domain of Bak is essential for its binding to a although the causal relationship is not clear. In hydrophobic surface groove on the prosurvival proteins addition, around 200 SNPs, with unknown clinical Bcl-xL and Mcl-1. The Bak BH3 domain is also association have been reported in Entrez SNP database. important for binding to a similar hydrophobic groove Somatic in another activated Bak molecule to form Bak oligomers and the formation of pores. Somatic mutations were increased in uterine cervical carcinoma (6 from 42) compared with non-neoplastic Expression tissue (0 from 32). While an early study reported BAK1 mRNA is expressed widely in different tissues somatic mutations in 17% of samples of colorectal and as an approximately 2.4 kb transcript. Highest mRNA gastric cancers in Korean patients, a later study levels are in the heart and skeletal muscle. reported no somatic mutations in 192 colorectal and Localisation gastric cancers. The Bak protein is inserted in the mitochondrial outer Implicated in membrane in healthy cells, while its close homologue Bax translocates to mitochondria after an apoptotic Lymphoma and leukemia stimulus. A small proportion of Bak has also been Note detected at the endoplasmic reticulum membrane. Lymphomas and leukemias have high levels of Bcl-2 Function prosurvival proteins that prevent Bak (and Bax) from Bak (or Bax) is required to form pores in the inducing apoptosis. New anti-cancer therapies that mitochondrial outer membrane during apoptotic cell target prosurvival proteins can activate Bak (or Bax) to death. The killing activity of Bak is regulated by other re-instate apoptotic cell death. In one example, a new members of the Bcl-2 family. For example, certain drug, GX15-070, was found to induce apoptosis in BH3-only proteins (Bim and Bid) are reported to mantle cell lymphoma cell lines by binding to Mcl-1 directly bind Bak to convert it into the activated and assist in Bak activation (Pérez-Galán et al., 2007). conformation, while the prosurvival proteins (e.g. Bcl- This drug is in clinical trials for refractory chronic xL and Mcl-1) can sequester activated Bak and so lymphocytic leukemia (Storey, 2008), and is prevent Bak homo-oligomerization and pore formation. presumably acting by indirectly activating Bak (or The role of Bak at the ER membrane is unclear. Bax). Homology Gastric and colorectal cancer Human Bak shares 99.5% amino acid identity with Pan Note troglodytes, 91.9% identity with Canis lupus familiaris, The first report of Bak mutations being associated with 86.2% with Bos taurus, 77.2% with Rattus norvegicus. gastrointestinal cancers was of missense BAK1 BAK1 is not found in the Danio rerio genome. Human mutations in 3 of 24 gastric cancers and 2 of 20 Bak has 53% amino-acid sequence identity with the colorectal cancers, with mutations observed only in BH1 and BH2 domains of Bcl-2. Over the full advanced-stage cancers (Kondo et al., 2000). In another sequence, Bak is 25, 33 and 19% identical to Bcl-2, study, BAK1 mutations were also rare (3/107) in Bcl-xL and Bax, respectively. patients with gastric adenocarcinomas, and were each associated with late stage disease (Kim et al., 2003). Mutations However, no somatic mutations were found in 192 patients with colorectal and gastric cancers, and the Note rare single-nucleotide substitutions (4/129) were also Several Bak single point mutations have been found in the corresponding normal tissue samples associated with autoimmune diseases, aortic (Sakamoto et al., 2004).

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1071 BAK1 (BCL2-antagonist/killer 1) Dewson G, Kluck R

Uterine cervical carcinoma Multiple sclerosis Note Note Possible role for Bak mutation in uterine cervical Bak mRNA levels were increased in the autoimmune carcinoma was reported (Wani et al., 2003). In a study lesions of patients with multiple sclerosis (Banisor and of 42 patients, 6 missense (M60V, D30N, D57N, Kalman, 2004). V74M, I80T and V191A) and one silent mutations in Ataxia telangiectasia the coding region of BAK1 were found, with no mutations detected in 32 non-neoplastic cervix tissue Note samples. Mutations were associated with late-stage BAK1 mutations were observed in 8 of 50 patients with disease and with resistance to chemotherapy, but were ataxia telangiectasia, and were each a silent mutation in not statistically significant due to sample size. exon 2 in codon 14 (TGC>TGT), while none of the healthy controls had such an alteration (Isaian et al., Melanoma 2009). Note Transient platelet loss In patients with superficial-spreading melanoma high Bak levels corresponded to improved survival (10-year Note survival of 62%), while low Bak correlated with low Bak can be activated to kill platelets as a side effect of survival (10-year survival of 10%) (Fecker et al., new anti-cancer treatments (Mason et al., 2007; 2006). Bax levels correlated in a similar way. Oltersdorf et al., 2005). The small molecule ABT-737 is a BH3-mimetic that binds specifically to prosurvival Autoimmune diseases proteins (Bcl-2, Bcl-xL, Bcl-w) that are commonly Note over-expressed in cancers. As platelets contain Bcl-xL Severe autoimmune disease occurs in adult mice as the predominant prosurvival protein guarding Bak, following deletion of both Bak and its close relative ABT-737 causes Bak activation and transient loss of Bax (Takeuchi et al., 2005). The mice accumulate platelets. excess memory B- and T-cells in lymphoid and Age-related hearing loss mesenchymal organs, leading to hepato-splenomegaly, lymphadenopathy, and thymic selection impairment. In Note humans, similar deletion of two copies of BAK1 (and In mice, Bak-mediated apoptosis exacerbated age- BAX) does not occur, however less marked changes in related hearing loss (Someya et al., 2009; Someya et Bak protein levels, as well as BAK1 mutations, have al., 2007). Moreover, hearing loss was decreased if Bak been associated with autoimmune disease in rare cases was deleted, if mice were kept on a calorie restriction (see below). diet, or given oral supplementation with antioxidants. In keeping with oxidative stress was proposed to induce Sjogren's syndrome Bak expression in primary cells from cochlear cells. Note Aortic aneurysms The Bak protein and its gene mutation may participate in the pathology and susceptibility of Sjogren's Note syndrome, as Bak was over-expressed in patient A possible role for Bak mutation in aortic aneurysms autoimmune lesions (Anaya et al., 2005). In a later was evident in a study of 31 patients with abdominal study three polymorphisms in BAK1 were associated aortic aneurysms (Gottlieb et al., 2009). Two single with Sjogren's syndrome (Delgado-Vega et al., 2009). nucleotide polymorphisms (R42H and V52A) in the BAK1 gene were present in both diseased (31 cases) Coeliac disease and healthy aortic tissue (5 cases), but not in matching Note blood samples. The authors propose that multiple A significant increase in Bak mRNA and protein levels variants of a gene such as BAK1 might pre-exist within was found in the intestinal lesions of patients with disease-susceptible tissues, and can be selected for untreated coeliac disease (Chernavsky et al., 2002). The during disease progression. increase in Bak and in apoptosis of enterocytes may be due to increased IFN-gamma signalling. To be noted Graves' disease Note Note The Bak protein plays a role in many diseases due to its Differential expression of Bak (and Bcl-2 and Bax) was central role in apoptotic cell death. However, most Bak associated with apoptosis in thyrocytes and lymphoid dysregulation is not due to mutations in Bak, but rather follicles, implicating Bak in the pathology of Grave's to altered expression or mutation of Bak regulators (e.g. disease (Hiromatsu et al., 2004). Bcl-xL and Mcl-1). If Bak (and its homologue Bax) fail

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1072 BAK1 (BCL2-antagonist/killer 1) Dewson G, Kluck R

to activate and form a pore in mitochondria, the cell bak gene in uterine cervical carcinoma. Br J Cancer. 2003 May may survive when it was meant to die, and so 19;88(10):1584-6 contribute to cancer. In the opposite scenario, if Bak (or Banisor I, Kalman B. Bcl-2 and its homologues in the brain of Bax) is activated inappropriately and mitochondria are patients with multiple sclerosis. Mult Scler. 2004 Apr;10(2):176- permeabilized, excessive cell death can occur, for 81 example, in neurodegenerative disease, autoimmune Hiromatsu Y, Kaku H, Mukai T, Miyake I, Fukutani T, Koga M, disease, and platelet loss following anti-cancer Shoji S, Toda S, Koike N. Immunohistochemical analysis of bcl-2, Bax and Bak expression in thyroid glands from patients treatments. Agents that can trigger Bak-mediated with Graves' disease. Endocr J. 2004 Aug;51(4):399-405 apoptosis in a non-targeted way include most anti- cancer agents, while agents that may trigger Bak (and Kim JK, Kim KS, Ahn JY, Kim NK, Chung HM, Yun HJ, Cha KY. Enhanced apoptosis by a novel gene, Bak-like, that lacks Bax) indirectly by targeting Bcl-2, Bcl-xL, Bcl-w, Mcl- the BH3 domain. Biochem Biophys Res Commun. 2004 Mar 1 and A1, include antisense, antibody and small 26;316(1):18-23 molecule approaches (Storey, 2008). Sakamoto I, Yamada T, Ohwada S, Koyama T, Nakano T, Okabe T, Hamada K, Kawate S, Takeyoshi I, Iino Y, Morishita References Y. Mutational analysis of the BAK gene in 192 advanced gastric and colorectal cancers. Int J Mol Med. 2004 Chittenden T, Flemington C, Houghton AB, Ebb RG, Gallo GJ, Jan;13(1):53-5 Elangovan B, Chinnadurai G, Lutz RJ. A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and Anaya JM, Mantilla RD, Correa PA. Immunogenetics of protein binding functions. EMBO J. 1995 Nov 15;14(22):5589- primary Sjögren's syndrome in Colombians. Semin Arthritis 96 Rheum. 2005 Apr;34(5):735-43 Chittenden T, Harrington EA, O'Connor R, Flemington C, Lutz Aouacheria A, Brunet F, Gouy M. Phylogenomics of life-or- RJ, Evan GI, Guild BC. Induction of apoptosis by the Bcl-2 death switches in multicellular animals: Bcl-2, BH3-Only, and homologue Bak. Nature. 1995 Apr 20;374(6524):733-6 BNip families of apoptotic regulators. Mol Biol Evol. 2005 Dec;22(12):2395-416 Kiefer MC, Brauer MJ, Powers VC, Wu JJ, Umansky SR, Tomei LD, Barr PJ. Modulation of apoptosis by the widely Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, distributed Bcl-2 homologue Bak. Nature. 1995 Apr Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, 20;374(6524):736-9 Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, Herberg JA, Phillips S, Beck S, Jones T, Sheer D, Wu JJ, O'Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Prochazka V, Barr PJ, Kiefer MC, Trowsdale J. Genomic Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, structure and domain organisation of the human Bak gene. Zhang H, Fesik SW, Rosenberg SH. An inhibitor of Bcl-2 family Gene. 1998 Apr 28;211(1):87-94 proteins induces regression of solid tumours. Nature. 2005 Jun 2;435(7042):677-81 Kondo S, Shinomura Y, Miyazaki Y, Kiyohara T, Tsutsui S, Kitamura S, Nagasawa Y, Nakahara M, Kanayama S, Takeuchi O, Fisher J, Suh H, Harada H, Malynn BA, Matsuzawa Y. Mutations of the bak gene in human gastric and Korsmeyer SJ. Essential role of BAX,BAK in B cell colorectal cancers. Cancer Res. 2000 Aug 15;60(16):4328-30 homeostasis and prevention of autoimmune disease. Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11272-7 Lindsten T, Ross AJ, King A, Zong WX, Rathmell JC, Shiels HA, Ulrich E, Waymire KG, Mahar P, Frauwirth K, Chen Y, Wei Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, M, Eng VM, Adelman DM, Simon MC, Ma A, Golden JA, Evan Adams JM, Huang DC. Proapoptotic Bak is sequestered by G, Korsmeyer SJ, MacGregor GR, Thompson CB. The Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only combined functions of proapoptotic Bcl-2 family members bak proteins. Genes Dev. 2005 Jun 1;19(11):1294-305 and bax are essential for normal development of multiple tissues. Mol Cell. 2000 Dec;6(6):1389-99 Fecker LF, Geilen CC, Tchernev G, Trefzer U, Assaf C, Kurbanov BM, Schwarz C, Daniel PT, Eberle J. Loss of Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, proapoptotic Bcl-2-related multidomain proteins in primary Thompson CB, Korsmeyer SJ. tBID, a membrane-targeted melanomas is associated with poor prognosis. J Invest death ligand, oligomerizes BAK to release cytochrome c. Dermatol. 2006 Jun;126(6):1366-71 Genes Dev. 2000 Aug 15;14(16):2060-71 Hetz C, Bernasconi P, Fisher J, Lee AH, Bassik MC, Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou Antonsson B, Brandt GS, Iwakoshi NN, Schinzel A, Glimcher V, Ross AJ, Roth KA, MacGregor GR, Thompson CB, LH, Korsmeyer SJ. Proapoptotic BAX and BAK modulate the Korsmeyer SJ. Proapoptotic BAX and BAK: a requisite unfolded protein response by a direct interaction with gateway to mitochondrial dysfunction and death. Science. IRE1alpha. Science. 2006 Apr 28;312(5773):572-6 2001 Apr 27;292(5517):727-30 Karbowski M, Norris KL, Cleland MM, Jeong SY, Youle RJ. Cherñavsky AC, Rubio AE, Vanzulli S, Rubinstein N, de Rosa Role of Bax and Bak in mitochondrial morphogenesis. Nature. S, Fainboim L. Evidences of the involvement of Bak, a member 2006 Oct 12;443(7112):658-62 of the Bcl-2 family of proteins, in active coeliac disease. Autoimmunity. 2002 Feb;35(1):29-37 Mason KD, Carpinelli MR, Fletcher JI, Collinge JE, Hilton AA, Ellis S, Kelly PN, Ekert PG, Metcalf D, Roberts AW, Huang Kim SP, Hwang MS, Cho YR, Kwon SY, Kang YN, Kim IH, DC, Kile BT. Programmed anuclear cell death delimits platelet Sohn SS, Mun KC, Kwon TK, Lee SR, Suh SI. Mutations of the life span. Cell. 2007 Mar 23;128(6):1173-86 BAK gene are infrequent in advanced gastric adenocarcinomas in Koreans. Cancer Lett. 2003 May Pérez-Galán P, Roué G, Villamor N, Campo E, Colomer D. 30;195(1):87-91 The BH3-mimetic GX15-070 synergizes with bortezomib in mantle cell lymphoma by enhancing Noxa-mediated activation Wani KM, Huilgol NG, Hongyo T, Shah K, Chatterjee N, Nair of Bak. Blood. 2007 May 15;109(10):4441-9 CK, Nomura T. Genetic alterations in the coding region of the

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1073 BAK1 (BCL2-antagonist/killer 1) Dewson G, Kluck R

Someya S, Yamasoba T, Weindruch R, Prolla TA, Tanokura Gottlieb B, Chalifour LE, Mitmaker B, Sheiner N, Obrand D, M. Caloric restriction suppresses apoptotic cell death in the Abraham C, Meilleur M, Sugahara T, Bkaily G, Schweitzer M. mammalian cochlea and leads to prevention of presbycusis. BAK1 gene variation and abdominal aortic aneurysms. Hum Neurobiol Aging. 2007 Oct;28(10):1613-22 Mutat. 2009 Jul;30(7):1043-7 Willis SN, Fletcher JI, Kaufmann T, van Delft MF, Chen L, Someya S, Xu J, Kondo K, Ding D, Salvi RJ, Yamasoba T, Czabotar PE, Ierino H, Lee EF, Fairlie WD, Bouillet P, Strasser Rabinovitch PS, Weindruch R, Leeuwenburgh C, Tanokura M, A, Kluck RM, Adams JM, Huang DC. Apoptosis initiated when Prolla TA. Age-related hearing loss in C57BL/6J mice is BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. mediated by Bak-dependent mitochondrial apoptosis. Proc Natl Science. 2007 Feb 9;315(5813):856-9 Acad Sci U S A. 2009 Nov 17;106(46):19432-7 Xu JX, Hoshida Y, Hongyo T, Sasaki T, Miyazato H, Tomita Y, Delgado-Vega AM, Castiblanco J, Gómez LM, Diaz-Gallo LM, Aozasa K. Analysis of p53 and Bak gene mutations in Rojas-Villarraga A, Anaya JM. Bcl-2 antagonist killer 1 (BAK1) lymphoproliferative disorders developing in rheumatoid polymorphisms influence the risk of developing autoimmune arthritis. J Cancer Res Clin Oncol. 2007 Feb;133(2):125-33 rheumatic diseases in women. Ann Rheum Dis. 2010 Feb;69(2):462-5 Dewson G, Kratina T, Sim HW, Puthalakath H, Adams JM, Colman PM, Kluck RM. To trigger apoptosis, Bak exposes its Isaian A, Bogdanova NV, Houshmand M, Movahadi M, BH3 domain and homodimerizes via BH3:groove interactions. Aghamohammadi A, Rezaei N, Atarod L, Sadeghi-Shabestari Mol Cell. 2008 May 9;30(3):369-80 M, Tonekaboni SH, Chavoshzadeh Z, Hassani SM, Mirfakhrai R, Cheraghi T, Kalantari N, Ataei M, Dork-Bousset T, Sanati Storey S. Targeting apoptosis: selected anticancer strategies. MH. BAK, BAX, and NBK/BIK proapoptotic gene alterations in Nat Rev Drug Discov. 2008 Dec;7(12):971-2 Iranian patients with ataxia telangiectasia. J Clin Immunol. Dewson G, Kluck RM. Mechanisms by which Bak and Bax 2010 Jan;30(1):132-7 permeabilise mitochondria during apoptosis. J Cell Sci. 2009 Aug 15;122(Pt 16):2801-8 This article should be referenced as such: Dewson G, Kratina T, Czabotar P, Day CL, Adams JM, Kluck Dewson G, Kluck R. BAK1 (BCL2-antagonist/killer 1). Atlas RM. Bak activation for apoptosis involves oligomerization of Genet Cytogenet Oncol Haematol. 2010; 14(11):1070-1074. dimers via their alpha6 helices. Mol Cell. 2009 Nov 25;36(4):696-703

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1074 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Leukaemia Section Short Communication t(3;12)(q27;p13) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)

Published in Atlas Database: January 2010 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0312q27p13ID1337.html DOI: 10.4267/2042/44897 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology Protein 335 amino acids; possess a nucleotide binding site for Disease NAD+, and sites for glyceraldehyde 3-phosphate binding; catalyzes the phosphorylation and oxidation of Non Hodgkin lymphomas (NHL) glyceraldehyde-3-phosphate to 1,3-biphosphoglycerate Epidemiology (interconversion), using NAD+ as electron acceptor. One case to date, a 78-year-old female patient with a Role in endocytosis and in nuclear membrane multifocal lymphoma, CD20+ diffuse large B-cell assembly. Associates with microtubules and RAB2, lymphoma (DLBCL) type, presenting as a primary which stimulates the recruitment of dynein, to regulate central nervous system lymphoma (PCNSL) microtubule motility and cargo transport. Also binds (Montesinos-Rongen et al., 2003). PCNSL are extra mRNA and t-RNA; may participate in tRNA export nodal NHL localized to -and remaining in- the central and mRNA stability. Role in the cell cycle, in DNA nervous system. repair, and in apoptosis associated with oxidative stress (reviews in Sirover, 1999; Hara and Snyder, 2006; Hara Genes involved and proteins et al., 2006; Colell et al., 2009). BCL6 Result of the chromosomal Location anomaly 3q27 Protein Hybrid gene 706 amino acids; composed of a NH2-term BTB/POZ Description domain (amino acids 1-130 (32-99 according to Swiss- Breakpoint in the intron 2 of GAPDH; leads to the Prot) which mediates homodimerization and protein- juxtaposition of the GAPDH promotor region with the protein interactions with other corepressors (including 2 first exons and the entire BCL6, inducing deregulated HDAC1 and NCOR2/SMRT ) to constitute a large expression of BCL6. repressing complex, another transcription repression domain (191-386), PEST sequences (300-417) with a References KKYK motif (375-379), and six zinc finger at the C- Sirover MA. New insights into an old protein: the functional term (518-541, 546-568, 574-596, 602-624, 630-652, diversity of mammalian glyceraldehyde-3-phosphate 658-681), responsible for sequence specific DNA dehydrogenase. Biochim Biophys Acta. 1999 Jul binding. Transcription repressor; recognizes the 13;1432(2):159-84 consensus sequence: TTCCT(A/C)GAA (Albagli- Albagli-Curiel O. Ambivalent role of BCL6 in cell survival and Curiel, 2003). transformation. Oncogene. 2003 Jan 30;22(4):507-16 GAPDH Montesinos-Rongen M, Akasaka T, Zühlke-Jenisch R, Schaller C, Van Roost D, Wiestler OD, Siebert R, Deckert M. Molecular Location characterization of BCL6 breakpoints in primary diffuse large 12p13.3 B-cell lymphomas of the central nervous system identifies

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1075 t(3;12)(q27;p13) Huret JL

GAPD as novel translocation partner. Brain Pathol. 2003 Colell A, Green DR, Ricci JE. Novel roles for GAPDH in cell Oct;13(4):534-8 death and carcinogenesis. Cell Death Differ. 2009 Dec;16(12):1573-81 Hara MR, Cascio MB, Sawa A. GAPDH as a sensor of NO stress. Biochim Biophys Acta. 2006 May;1762(5):502-9 This article should be referenced as such: Hara MR, Snyder SH. Nitric oxide-GAPDH-Siah: a novel cell Huret JL. t(3;12)(q27;p13). Atlas Genet Cytogenet Oncol death cascade. Cell Mol Neurobiol. 2006 Jul-Aug;26(4-6):527- Haematol. 2010; 14(11):1075-1076. 38

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1076 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Leukaemia Section Short Communication t(3;3)(q25;q27) Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)

Published in Atlas Database: January 2010 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0303q25q27ID2127.html DOI: 10.4267/2042/44898 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology Protein 706 amino acids; composed of a NH2-term BTB/POZ Disease domain (amino acids 1-130 (32-99 according to Swiss- Prot) which mediates homodimerization and protein- Non Hodgkin lymphoma. protein interactions with other corepressors (including Epidemiology HDAC1 and NCOR2/SMRT to constitute a large One case of follicular lymphoma transformed to diffuse repressing complex, another transcription repression aggressive lymphoma, from a study with no individual domain (191-386), PEST sequences (300-417) with a data (Akasaka et al., 2003). KKYK motif (375-379), and six zinc finger at the C- term (518-541, 546-568, 574-596, 602-624, 630-652, Genes involved and proteins 658-681), responsible for sequence specific DNA binding. Transcription repressor; recognizes the MBNL1 consensus sequence: TTCCT(A/C)GAA (Albagli- Location: 3q25 Curiel, 2003). Protein References Various splicing forms; one isoform comprises 388 amino acids, with 4 zinc fingers at amino acids 13-41, Akasaka T, Lossos IS, Levy R. BCL6 gene translocation in 47-73, 179-207 and 215-241, according to Swiss-Prot. follicular lymphoma: a harbinger of eventual transformation to diffuse aggressive lymphoma. Blood. 2003 Aug RNA-binding protein which regulates alternative 15;102(4):1443-8 splicing of pre-mRNAs. MBNL1 has a high-affinity Albagli-Curiel O. Ambivalent role of BCL6 in cell survival and binding for UGCU motifs, but cytidines are also often transformation. Oncogene. 2003 Jan 30;22(4):507-16 present in position 1 or 4, and general MBNL1 binding site can be defined as YGCY (Goers et al., 2010). Plays Dansithong W, Paul S, Comai L, Reddy S. MBNL1 is the primary determinant of focus formation and aberrant insulin an important role in the development of myotonic receptor splicing in DM1. J Biol Chem. 2005 Feb dystrophy 1 pathology. MBNL1 and MBNL2 play a 18;280(7):5773-80 facilitatory role in insulin receptor exon 11 splicing Goers ES, Purcell J, Voelker RB, Gates DP, Berglund JA. (Dansithong et al., 2005). MBNL1 also regulates MBNL1 binds GC motifs embedded in pyrimidines to regulate sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 1 alternative splicing. Nucleic Acids Res. 2010 Apr;38(7):2467- (SERCA1), the cardiac troponin T (cTNT) , and the 84 fast troponin T (TNNT3) splicings. This article should be referenced as such: BCL6 Huret JL. t(3;3)(q25;q27). Atlas Genet Cytogenet Oncol Location: 3q27 Haematol. 2010; 14(11):1077.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1077 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Leukaemia Section Short Communication dic(7;9)(p11 -12;p12 -13) PAX5/LOC392027 Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)

Published in Atlas Database: February 2010 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/dic0709p11p12ID1554.html DOI: 10.4267/2042/44899 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity Protein Ribosome-binding protein 1 pseudogene. Note PAX5 See also the paper on dic(9;20)(p11-13;q11). Location Clinics and pathology 9p13.2 Protein Disease Lineage-specific transcription factor; recognizes the Acute lymphoblastic leukaemia (ALL). concensus recognition sequence Phenotype/cell stem origin GNCCANTGAAGCGTGAC, where N is any nucleotide. Involved in B-cell differentiation. Entry of B-cell precursor ALL. common lymphoid progenitors into the B cell lineage Epidemiology depends on E2A, EBF1, and PAX5; activates B-cell specific genes and repress genes involved in other 13 cases to date; sex ratio was 7M/6F, median age was lineage commitments. Activates the surface cell 17 years (range 2-51 years) (An et al., 2008). receptor CD19 and repress FLT3. Pax5 physically Prognosis interacts with the RAG1/RAG2 complex, and removes No data. the inhibitory signal of the lysine-9-methylated histone H3, and induces V-to-DJ rearrangements. Genes Cytogenetics repressed by PAX5 expression in early B cells are restored in their function in mature B cells and plasma Additional anomalies cells, and PAX5 repressed (Fuxa et al., 2004; Johnson The dic(7;9) was the sole anomaly in 8 cases, et al., 2004; Zhang et al., 2006; Cobaleda et al., 2007). accompanied a t(9;22) with BCR-ABL1 involvement in 3 cases, and was accompanied with other anomaly in 2 Result of the chromosomal other cases, including a del(6q). anomaly Genes involved and proteins Hybrid gene LOC392027 Description Break in PAX5 intron 4. Out of frame fusion of 5' Location PAX5 - 3' LOC392027. 7p12

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1078 dic(7;9)(p11-12;p12-13) PAX5/LOC392027 Huret JL

Fusion protein Zhang Z, Espinoza CR, Yu Z, Stephan R, He T, Williams GS, Burrows PD, Hagman J, Feeney AJ, Cooper MD. Transcription Description factor Pax5 (BSAP) transactivates the RAG-mediated V(H)-to- The predicted fusion protein contains the DNA binding DJ(H) rearrangement of immunoglobulin genes. Nat Immunol. 2006 Jun;7(6):616-24 paired domain of PAX5. Cobaleda C, Schebesta A, Delogu A, Busslinger M. Pax5: the Oncogenesis guardian of B cell identity and function. Nat Immunol. 2007 Loss of function of PAX5 is likely to be the oncogenic May;8(5):463-70 event. An Q, Wright SL, Konn ZJ, Matheson E, Minto L, Moorman AV, Parker H, Griffiths M, Ross FM, Davies T, Hall AG, Harrison References CJ, Irving JA, Strefford JC. Variable breakpoints target PAX5 in patients with dicentric chromosomes: a model for the basis of Fuxa M, Skok J, Souabni A, Salvagiotto G, Roldan E, unbalanced translocations in cancer. Proc Natl Acad Sci U S Busslinger M. Pax5 induces V-to-DJ rearrangements and locus A. 2008 Nov 4;105(44):17050-4 contraction of the immunoglobulin heavy-chain gene. Genes Dev. 2004 Feb 15;18(4):411-22 This article should be referenced as such: Johnson K, Pflugh DL, Yu D, Hesslein DG, Lin KI, Bothwell AL, Huret JL. dic(7;9)(p11-12;p12-13) PAX5/LOC392027. Atlas Thomas-Tikhonenko A, Schatz DG, Calame K. B cell-specific Genet Cytogenet Oncol Haematol. 2010; 14(11):1078-1079. loss of histone 3 lysine 9 methylation in the V(H) locus depends on Pax5. Nat Immunol. 2004 Aug;5(8):853-61

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1079 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Leukaemia Section Short Communication dic(9;12)(p13;p12) PAX5/SLCO1B3 Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)

Published in Atlas Database: February 2010 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/dic0912p13p12ID1555.html DOI: 10.4267/2042/44900 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

GNCCANTGAAGCGTGAC, where N is any Identity nucleotide. Involved in B-cell differentiation. Entry of Note common lymphoid progenitors into the B cell lineage While dic(9;12)(p13;p12) is usually associated with depends on E2A, EBF1, and PAX5; activates B-cell PAX5/ETV6 involvement, one case has been described specific genes and repress genes involved in other with SLCO1B3 involvement instead of ETV6. lineage commitments. Activates the surface cell See also the paper on dic(9;20)(p11-13;q11). receptor CD19 and repress FLT3. Pax5 physically interacts with the RAG1/RAG2 complex, and removes Clinics and pathology the inhibitory signal of the lysine-9-methylated histone H3, and induces V-to-DJ rearrangements. Genes Disease repressed by PAX5 expression in early B cells are Acute lymphoblastic leukaemia (ALL). restored in their function in mature B cells and plasma cells, and PAX5 repressed (Fuxa et al., 2004; Johnson Phenotype/cell stem origin et al., 2004; Zhang et al., 2006; Cobaleda et al., 2007). B-cell precursor ALL. SLCO1B3 Epidemiology Location One case to date, a 1-year-old girl (An et al., 2008). 12p12.2 Prognosis Protein No data. Multi-pass membrane protein. Organic anion transporting polypeptide. Mediates the transport for Cytogenetics various molecules such as bile acids, steroids, thyroid hormones, and exogenous drugs. Normally expressed Additional anomalies in the basolateral membrane of hepatocytes around the The dic(9;12) was the sole anomaly. central vein (Hagenbuch and Meier, 2003; Briz et al., 2006). Genes involved and proteins Result of the chromosomal PAX5 anomaly Location 9p13.2 Hybrid gene Protein Description Lineage-specific transcription factor; recognizes the Break in PAX5 intron 4. Out of frame fusion of 5' concensus recognition sequence PAX5 - 3' SLCO1B3

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1080 dic(9;12)(p13;p12) PAX5/SLCO1B3 Huret JL

Fusion protein

Description cotransport of bile acids and glutathione: an export pathway for organic anions from hepatocytes? J Biol Chem. 2006 Oct The predicted fusion protein contains the DNA binding 13;281(41):30326-35 paired domain of PAX5. Zhang Z, Espinoza CR, Yu Z, Stephan R, He T, Williams GS, Oncogenesis Burrows PD, Hagman J, Feeney AJ, Cooper MD. Transcription Loss of function of PAX5 is likely to be the oncogenic factor Pax5 (BSAP) transactivates the RAG-mediated V(H)-to- event. DJ(H) rearrangement of immunoglobulin genes. Nat Immunol. 2006 Jun;7(6):616-24 References Cobaleda C, Schebesta A, Delogu A, Busslinger M. Pax5: the guardian of B cell identity and function. Nat Immunol. 2007 Hagenbuch B, Meier PJ. The superfamily of organic anion May;8(5):463-70 transporting polypeptides. Biochim Biophys Acta. 2003 Jan 10;1609(1):1-18 An Q, Wright SL, Konn ZJ, Matheson E, Minto L, Moorman AV, Parker H, Griffiths M, Ross FM, Davies T, Hall AG, Harrison Fuxa M, Skok J, Souabni A, Salvagiotto G, Roldan E, CJ, Irving JA, Strefford JC. Variable breakpoints target PAX5 in Busslinger M. Pax5 induces V-to-DJ rearrangements and locus patients with dicentric chromosomes: a model for the basis of contraction of the immunoglobulin heavy-chain gene. Genes unbalanced translocations in cancer. Proc Natl Acad Sci U S Dev. 2004 Feb 15;18(4):411-22 A. 2008 Nov 4;105(44):17050-4

Johnson K, Pflugh DL, Yu D, Hesslein DG, Lin KI, Bothwell AL, This article should be referenced as such: Thomas-Tikhonenko A, Schatz DG, Calame K. B cell-specific loss of histone 3 lysine 9 methylation in the V(H) locus Huret JL. dic(9;12)(p13;p12) PAX5/SLCO1B3. Atlas Genet depends on Pax5. Nat Immunol. 2004 Aug;5(8):853-61 Cytogenet Oncol Haematol. 2010; 14(11):1080-1081. Briz O, Romero MR, Martinez-Becerra P, Macias RI, Perez MJ, Jimenez F, San Martin FG, Marin JJ. OATP8/1B3-mediated

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1081 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Leukaemia Section Mini Review t(2;14)(p13 -16;q32) Adriana Zamecnikova Kuwait Cancer Control Center, Laboratory of Cancer Genetics, Department of Hematology, Shuwaikh, 70653, Kuwait (AZ)

Published in Atlas Database: February 2010 Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0214p13q32ID1231.html DOI: 10.4267/2042/44901 This article is an update of : Huret JL. t(2;14)(p13;q32). Atlas Genet Cytogenet Oncol Haematol 2002;4(6):289.

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Identity

(A) Partial karyotype showing the t(2;14)(p13;q32) Top - Courtesy Adriana Zamecnikova; Middle and below - Courtesy Melanie Zenger and Claudia Haferlach. (B) Fluorescence in situ hybridization with LSI IgH/MYC and LSI ALK probe showing the juxtaposition of ALK (fusion signal) from 2p23 to the region proximal to IgH locus (green signal) on chromosome 14 and translocation of IgH segments to der(2) chromosome resulting in a green signal on rearranged chromosome 2 - Courtesy Adriana Zamecnikova.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1082 t(2;14)(p13-16;q32) Zamecnikova A

domain between zinc fingers 1 and 2 and an acidic Clinics and pathology domain between 3 and 4. 835 amino acids; 91197 Da, Disease alternative splicing: 6 isoforms, sharing a common N- terminus. Originally named EV19 human homolog Identified predominantly in B-cell malignancies, BCL11A; high level of conservation across a wide including CLL/SLL, found in 20 cases of chronic range of species; highly homologous to another gene lymphocytic leukemia (CLL), 1 B-prolymphocytic (BCL11B) on chromosome 14q32.1; like BCL11A, leukemia, 1 diffuse, mixed small/large cell non BCL11B is remarkable in having a large 5' CpG island. Hodgkin lymphoma (NHL); 8 cases of acute Predominantly expressed in brain and hematopoietic lymphocytic leukemia (ALL): one T-ALL and 7 B- cells, expression is tightly regulated during B-cell ALL (two in association with t(1;19), one in Ph+ ALL, development; low-level or undetectable BCL11A RNA one with 3-way translocation); two AML (Ph+ M1 and expression in most adult tissues. BCL11A is a DNA inv(16)) cases and in one Ph+ CML case. sequence-specific transcriptional repressor, an essential CLL cases are characterized by marrow involvement, factor in lymphopoiesis, required for B-cell formation absolute lymphocytosis, lymphadenopathy, atypical in fetal liver. morphologic features; prolymphocytes may be increased. Serum lactate dehydrogenase and beta- IgH microglobulin levels are elevated, ZAP70 is expressed. Location IgV H genes are unmutaded; most cases are positive for 14q32 CD5, CD19 and CD23; weak intensity of immunoglobuline and CD20, weak or negative CD79b, Result of the chromosomal CD22, absence of FMC-7. Epidemiology anomaly Sex ratio: CLL cases 10 males and 6 females patients, 4 Fusion protein unknown; adults: aged 40-68 years, and 3 children aged Oncogenesis 6, 10 and 15 years; ALL cases (3 males, 5 females) Juxtaposition of IgH enhancer elements leading to were 1 adult 37 years old and 7 children aged 1-17 inappropriate overexpression of the partner gene years; 2 AML cases (1 male, 1 female) were 34 and 45 product. BCL11A may be activated through years old; the CML case was a 21 years old male chromosomal translocation or amplification, leading to patient. myeloid leukemias in mice and lymphoid malignancies Prognosis in humans; the conserved N-terminus of BCL11A. 8 CLL cases were dead after 27-145 months survival; deregulated expression of BCL11A may play a major from available data on 3 ALL cases: they were all dead role in the pathogenesis; gains and amplifications of the (one after 15 months, 2 after bone marrow region of chromosome 2p13-16 have been reported in transplantation). B-cell malignancies, REL, a NF-kappaB gene family member, mapping within the amplified region is Cytogenetics coamplified with BCL11A in B-NHL cases and HD lymphoma cell lines; with gains and amplifications, Cytogenetics morphological BCL11A interacts directly with BCL6, that serves a crucial role in lymphocyte development, also involved Sole anomaly in 8 documented cases; found in complex in IG translocations. karyotypes; associated with t(14;19)(q32;q13) in 2 CLL The structure of the t(2;14) translocation is a "head-to- cases, del(6)q in 4 cases, i(9)(q10) in 2 cases, +12 in 3 head" arrangement, with the breakpoints falling cases. In two pediatric ALL cases, it was associated centromeric to the first exon adjacent to a large CpG with t(1;19) and in 3 cases it was associated with Ph+ island at the 5' end; BCL11A is deregulated as a leukemia. consequence of the translocation, suggesting that BCL11A may be involved in lymphoid malignancies Genes involved and proteins through either chromosomal translocation or BCL11A amplification. Location References 2p16.1 Ueshima Y, Bird ML, Vardiman JW, Rowley JD. A 14;19 DNA/RNA translocation in B-cell chronic lymphocytic leukemia: a new Originally assigned to region 1, band 3, 2p13; it has recurring chromosome aberration. Int J Cancer. 1985 Sep subsequently been reassigned to 2p16.1. 15;36(3):287-90 Protein Nishida K, Taniwaki M, Misawa S, Abe T. Nonrandom BCL11A/EVI9 is a zinc-finger protein, containing 6 rearrangement of chromosome 14 at band q32.33 in human lymphoid malignancies with mature B-cell phenotype. Cancer Krüppel C2H2 zinc fingers as well as a proline-rich Res. 1989 Mar 1;49(5):1275-81

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1083 t(2;14)(p13-16;q32) Zamecnikova A

Uckun FM, Gajl-Peczalska KJ, Provisor AJ, Heerema NA. Sonoki T, Matsuzaki H, Satterwhite E, Nakazawa N, Hata H, Immunophenotype-karyotype associations in human acute Tucker PW, Taniwaki M, Kuribayashi N, Harada N, Matsuno F, lymphoblastic leukemia. Blood. 1989 Jan;73(1):271-80 Mitsuya H. A plasma cell leukemia patient showing bialleic 14q translocations: t(2;14) and t(11;14). Acta Haematol. Yoffe G, Howard-Peebles PN, Smith RG, Tucker PW, 1999;101(4):197-201 Buchanan GR. Childhood chronic lymphocytic leukemia with (2;14) translocation. J Pediatr. 1990 Jan;116(1):114-7 Satterwhite E, Sonoki T, Willis TG, Harder L, Nowak R, Arriola EL, Liu H, Price HP, Gesk S, Steinemann D, Schlegelberger B, Watson MS, Land VJ, Carroll AJ, Pullen J, Borowitz MJ, Link Oscier DG, Siebert R, Tucker PW, Dyer MJ. The BCL11 gene MP, Amylon M, Behm FG. t(2;14)(p13;q32): a recurring family: involvement of BCL11A in lymphoid malignancies. abnormality in lymphocytic leukemia. A Pediatric Oncology Blood. 2001 Dec 1;98(12):3413-20 Group study. Cancer Genet Cytogenet. 1992 Feb;58(2):121-4 Yin CC, Lin KI, Ketterling RP, Knudson RA, Medeiros LJ, Geisler CH, Philip P, Christensen BE, Hou-Jensen K, Barron LL, Huh YO, Luthra R, Keating MJ, Abruzzo LV. Pedersen NT, Jensen OM, Thorling K, Andersen E, Birgens Chronic lymphocytic leukemia With t(2;14)(p16;q32) involves HS, Drivsholm A, Ellegaard J, Larsen JK, Plesner T, Brown P, the BCL11A and IgH genes and is associated with atypical Andersen PK, Hansen MM. In B-cell chronic lymphocytic morphologic features and unmutated IgVH genes. Am J Clin leukaemia chromosome 17 abnormalities and not trisomy 12 Pathol. 2009 May;131(5):663-70 are the single most important cytogenetic abnormalities for the prognosis: a cytogenetic and immunophenotypic study of 480 This article should be referenced as such: unselected newly diagnosed patients. Leuk Res. 1997 Nov- Dec;21(11-12):1011-23 Zamecnikova A. t(2;14)(p13-16;q32). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1082-1084.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1084 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Solid Tumour Section Short Communication t(6;22)(p21;q12) in hidradenoma of the skin Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)

Published in Atlas Database: January 2010 Online updated version : http://AtlasGeneticsOncology.org/Tumors/t0622p21q12HidradID6281.html DOI: 10.4267/2042/44902 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology EWSR1 Location Disease 22q12 Hidradenoma or eccrine/apocrine acrospiroma, is a Protein benign adnexal tumour developing most often in adults. From N-term to C-term: a transactivation domain Epidemiology (TAD) containing multiple degenerate hexapeptide Three cases to date, 3 female patients aged 24, 63, and repeats, 3 arginine/glycine rich domains (RGG 85 years (Möller et al., 2008). regions), a RNA recognition motif, and a RanBP2 type Zinc finger. Role in transcriptional regulation for Pathology specific genes and in mRNA splicing. There was one atypical, one poroid, and one solid hidradenoma. Result of the chromosomal Prognosis anomaly Prognosis is good in this benign disease. Hybrid Gene Cytogenetics Description 5' EWSR1 - 3' POU5F1. EWSR1 exon 6 is fused in Cytogenetics Morphological frame to POU5F1 exon 2. The t(6;22)(p21;q12) was the sole anomaly in the only Fusion Protein case with karyotypic studies; the 2 other cases were detected by the presence of the fusion transcript. Description Fusion of the N terminal transactivation domain of Genes involved and proteins EWSR1 to the POU and the homeobox (DNA binding domain) of POU5F1. POU5F1 Location References 6p21 Möller E, Stenman G, Mandahl N, Hamberg H, et al. POU5F1, encoding a key regulator of stem cell pluripotency, is fused to Protein EWSR1 in hidradenoma of the skin and mucoepidermoid Homeobox protein (homeodomain in amino acids 230- carcinoma of the salivary glands. J Pathol. 2008 289 in the 360 aa isoform) with a POU domain (in aa May;215(1):78-86 138-212). Binds the sequence 5'-ATTTGCAT-3'. This article should be referenced as such: Transcription factor. Huret JL. t(6;22)(p21;q12) in hidradenoma of the skin. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1085.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1085 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Solid Tumour Section Short Communication t(6;22)(p21;q12) in mucoepidermoid carcinoma of the salivary glands Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH) Published in Atlas Database: January 2010 Online updated version : http://AtlasGeneticsOncology.org/Tumors/t0622p21q12MucoepidID6282.html DOI: 10.4267/2042/44903 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

(TAD) containing multiple degenerate hexapeptide Clinics and pathology repeats, 3 arginine/glycine rich domains (RGG Disease regions), a RNA recognition motif, and a RanBP2 type Mucoepidermoid carcinoma is the most common type Zinc finger. Role in transcriptional regulation for of malignant salivary gland tumor, mostly located to specific genes and in mRNA splicing. the parotid gland; it is associated with a t(11;19)(q21;p13) translocation with expression of Result of the chromosomal chimeric genes 5' CRTC1 - 3' MAML2 in about half of anomaly the cases, mainly associated with a highly or moderately differentiated histology and an excellent Hybrid Gene outcome. Description Epidemiology 5' EWSR1 - 3' POU5F1. EWSR1 exon 6 is fused in One case to date, an 85-year-old male patient; the frame to POU5F1 exon 2. patient died of an unrelated disease one year after Fusion Protein diagnosis (Behboudi et al., 2006; Moller et al., 2008). Description Pathology Fusion of the N terminal transactivation domain of The mucoepidermoid carcinoma was poorly EWSR1 to the POU and the homeobox (DNA binding differentiated. domain) of POU5F1. Genes involved and proteins References Behboudi A, Enlund F, Winnes M, Andrén Y, Nordkvist A, POU5F1 Leivo I, Flaberg E, Szekely L, Mäkitie A, Grenman R, Mark J, Location Stenman G. Molecular classification of mucoepidermoid 6p21 carcinomas-prognostic significance of the MECT1-MAML2 fusion oncogene. Genes Chromosomes Cancer. 2006 Protein May;45(5):470-81 Homeobox protein (homeodomain in amino acids 230- Möller E, Stenman G, Mandahl N, Hamberg H, Mölne L, van 289 in the 360 aa isoform) with a POU domain (in aa den Oord JJ, Brosjö O, Mertens F, Panagopoulos I. POU5F1, 138-212). Binds the sequence 5'-ATTTGCAT-3'. encoding a key regulator of stem cell pluripotency, is fused to Transcription factor. EWSR1 in hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands. J Pathol. 2008 EWSR1 May;215(1):78-86

Location This article should be referenced as such: 22q12 Huret JL. t(6;22)(p21;q12) in mucoepidermoid carcinoma of the Protein salivary glands. Atlas Genet Cytogenet Oncol Haematol. 2010; From N-term to C-term: a transactivation domain 14(11):1086.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1086 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Solid Tumour Section Short Communication t(6;22)(p21;q12) in undifferentiated sarcoma Jean-Loup Huret Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France (JLH)

Published in Atlas Database: January 2010 Online updated version : http://AtlasGeneticsOncology.org/Tumors/t0622p21q12UndifID5411.html DOI: 10.4267/2042/44904 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Clinics and pathology Protein From N-term to C-term: a transactivation domain Disease (TAD) containing multiple degenerate hexapeptide repeats, 3 arginine/glycine rich domains (RGG A case of undifferentiated sarcoma of the pubic bone, regions), a RNA recognition motif, and a RanBP2 type with multiple pulmonary metastases at diagnosis, was Zinc finger. Role in transcriptional regulation for described in a 39-year-old female patient. The patient specific genes and in mRNA splicing. died 6 months after diagnosis (Yamaguchi et al., 2005). Cytogenetics Result of the chromosomal anomaly Cytogenetics Morphological The t(6;22)(p21;q12) was accompanied with a marker Hybrid Gene chromosome. Description 5' EWSR1 - 3' POU5F1. Fusion of exons 1-6 of Genes involved and proteins EWSR1 to part of exon 1, and exons 2-5 of POU5F1. POU5F1 Fusion Protein Location Description 6p21 The N terminal transactivation domain of EWSR1 was fused to the DNA binding domains of POU5F1. Protein 360 amino acids in the longest isoform; contains a bipartte DNA-binding domain, composed of a POU- References specific domain (amino acids 138-212), and a Yamaguchi S, Yamazaki Y, Ishikawa Y, Kawaguchi N, Mukai homeobox (aa 230-289). Transcription factor with a H, Nakamura T. EWSR1 is fused to POU5F1 in a bone tumor with translocation t(6;22)(p21;q12). Genes Chromosomes major role during embryogenesis. Binds specifically Cancer. 2005 Jun;43(2):217-22 ATTTGCAT. EWSR1 This article should be referenced as such: Huret JL. t(6;22)(p21;q12) in undifferentiated sarcoma. Atlas Location Genet Cytogenet Oncol Haematol. 2010; 14(11):1087. 22q12

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1087 Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Deep Insight Section

Ubiquitin, ubiquitination and the ubiquitin- proteasome system in cancer Ioannis A Voutsadakis Department of Medical Oncology, University Hospital of Larissa, Larissa 41110, Greece (IAV)

Published in Atlas Database: January 2010 Online updated version : http://AtlasGeneticsOncology.org/Deep/UbiquitininCancerID20083.html DOI: 10.4267/2042/44905 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Ubiquitin: Gene and protein using energy from the conversion of ATP to ADP, Ubiquitin is a 8 kDa protein of 76 amino-acids that has binds ubiquitin and transfers it onto a second type of taken its name from its ubiquitous presence in cells. Its enzyme called E2 or Ubiquitin conjugating enzyme. covalent link to a target protein is a signal for different E2-loaded ubiquitin is then attached, with the help of a fates for this target protein. Ubiquitination (or third type of enzymes called E3 or Ubiquitin ligase, to ubiquitylation) refers to this covalent link and the ε-amino group of a lysine residue on a target represents a signal analogous to phosphorylation. protein. Two E1 enzymes exist in the human genome Ubiquitin gene exists in multiple copies in eukaryotic called Ubiquitin-activating enzyme 1 (UBE1) and cells. Ubiquitin-like modifier Activating enzyme 6 (UBA6) Ubiquitin protein contains seven lysine residues at (Groettrup et al., 2008). UBA6 is also performing the positions 6, 11, 27, 29, 33, 48 and 63 through which it activation function for fatylation, the addition of can be attached to the substrate or to one another. FAT10 to target proteins (Chiu et al., 2007). E2 Ubiquitin is characterized by a β-grasp superfold enzymes are more abundant (about 30 to 40 exist in the termed ubiquiton in which a central α-helix is human genome) and have a conserved 150 aminoacids surrounded by four β-sheets (Welchman et al., 2005). central structure that includes four β sheets and four α- This superfold defines also ubiquitin-like proteins such helices and surrounds the active cysteine residue. This as SUMO (Small Ubiquitin-like modifier) and NEDD8 cysteine accepts ubiquitin through the formation of (Neuronal Precursor cell-expressed developmentally thiol-ester bond with the final glysine residue of down-regulated protein 8). Other human ubiquitin-like ubiquitin. A signature HPN (Histidine-proline- proteins containing ubiquitons include ISG15 asparagine) sequence is found 7 to 8 amino-acids (Interferon stimulated gene 15), FAT10 (Human amino-terminal to this cysteine (Michelle et al., 2009). leukocyte antigen F-associated Transcript 10), FUB1 The formation of thiol-ester group requires ubiquitin to (Fan Ubiquitin-like protein 1) and URM1 (Ubiquitin be activated, that is linked to the E1 enzyme, while free Related Modifier 1). All ubiquitin-like proteins, ubiquitin has very low affinity for E2 enzymes. E2- although varying in amino-acid sequence, share with bound ubiquitin transfer to the target protein is ubiquitin the common structure and the common facilitated by a ubiquitin ligase or E3 enzyme. There biochemical mechanism of tagging through an are about 600 E3 ligases in human genome. This step isopeptide bond (Pickart, 2004; Pickart and Eddins, confers substrate specificity to the process of 2004). ubiquitination given that every E3 ligase can interact only with specific substrate proteins. Nevertheless this Ubiquitination specificity is partial, as several substrates can interact The covalent attachment of ubiquitin to a target protein with an E3 ligase while a specific protein undergoing is a very well controlled process that is executed with ubiquitination can interact with several E3 ligases. In the aid of three types of enzymes. A first type of addition each E3 ligase can interact with several E2 enzyme called E1 or Ubiquitin activating enzyme, enzymes and the reverse is also true given that

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1088 Ubiquitin, ubiquitination and the ubiquitin-proteasome system in cancer Voutsadakis IA

Figure 1: Enzymatic cascade of ubiquitination. each E2 can interact with several E3s (Van Wijk et al., distinct proteins, one of which is the RING domain E2- 2009). binding protein and another binds the substrate protein Two types of E3 ligases exist having a mechanistically to be ubiquitinated (Deshaies and Joazeiro, 2009). The different catalytic mode of action through which they prototype of this latter group is the cullin-RING perform ubiquitin ligation. RING (Really Interesting ubiquitin ligases (CRLs) comprised of a RING protein New Gene) type E3s act by bringing E2-bound linked through a family of proteins called cullins to a ubiquitin in close proximity with the substrate protein substrate binding sub-unit (Bosu and Kipreos, 2008). In in order for ubiquitin to be directly transferred to the addition to transferring a first ubiquitin molecule to a substrate. In addition, RING E3s probably mediate a substrate (chain initiation), RING E3 ligases perform conformational change of bound E2 that facilitates chain elongation, the attachment of further ubiquitin ubiquitin transfer (Passmore and Barford, 2004). In molecules. These are distinct reactions and chain contrast HECT (Homologous to Human Papilloma initiation is taking place in a much slower pace than the Virus E6 Carboxyterminal domain) type E3s possesses elongation step which, in many occasions, is completed an active cysteine residue that forms a thiol-ester bond 5 to 30 times quicker than the initiation (Petroski and with ubiquitin before it is transferred to the substrate. A Deshaies, 2005). In the U-box type E3 ligases the third type of E3 ligases called U-box domain E3 ligases conserved cysteines and histidine of RING type ligases is considered by many as a sub-type of RING type E3s are replaced by charged and polar residues. because U-box domain has a RING domain-like The other major type of E3s, HECT type has 28 conformation and the mechanism of action is also by members in human genome (Rotin and Kumar, 2009). bridging E2-bound ubiquitin with the substrate, All HECT ligases possess in the carboxy-terminal part similarly to RING type E3s. of their molecule a HECT domain first identified and named by E3 ligase E6-AP (Human Papilloma Virus Type RING HECT E6-Associated Protein), while their amino-terminal part is comprised of various other domains. HECT domain % human E3s about 95% about 5% has two sub-domains, one of which binds the E2 Ubiquitin conjugating enzyme and the other binds the Covalent link with Ubiquitin No Yes substrate protein. Ubiquitination is a reversible process and there are specific de-ubiquitinating enzymes that reverse it. Ubiquitination type specificity No Yes These enzymes recognize the isopeptide bond between the carboxyterminal glycine of a ubiquitin molecule Table: Comparison of two major classes of E3 ligases and the ε-aminogroup of a lysine of another ubiquitin molecule or of a target protein. There are five families RING type E3s are by far more abundant than HECT of de-ubiquitinating enzymes: the UBP (Ubiquitin- E3s and comprise about 95% of human E3s (Li et al., specific processing protease) family, the UCH 2008). RING domain has several cysteines and a (Ubiquitin Carboxy-terminal Hydrolase) family, the histidine in its core structure which binds two zinc OTU (Ovarian Tumor related proteases) family, the atoms. RING domains create the rigid platform that ataxin/Josephin group having ataxin 3 as the only constitutes the surface for the Ubiquitin conjugating member and the JAMM (Jab1/MPN domain enzyme bound with ubiquitin binding. Some E3s are metalloenzyme)/MPN+ motif proteases (Amerik and comprised of a single polypeptide that possesses both Hochstrasser, 2004). The role of de-ubiquitinating the RING E2-binding domain and the substrate binding enzymes is to maintain the ubiquitin pool in the cell domain, while other E3s are constituted by several and to perform proof-reading for proteins that had been

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1089 Ubiquitin, ubiquitination and the ubiquitin-proteasome system in cancer Voutsadakis IA

inappropriately ubiquitinated. De-ubiquitinating Factor) and histone arginine methyltransferases such as enzyme Rpn11 of the JAMM/MPN+ family is part of CARM1 (Coactivator-associated Arginine the proteasome (see also next) and recycles ubiquitin Methyltransferase-1) and PRMT-1 (Protein Arginine from proteins that had been recognized and processed Methyltransferase-1) (Jenster et al., 1997). These for degradation. The importance of de-ubiquitination is enzymes promote histone acetylation and methylation underlined by the fact that their dysfunction is that opens nucleosomes in order for transcription associated with diverse diseases (Singhal et al., 2008). complex to obtain access to transcription factor binding Different types of ubiquitination and role sequences in target promoters. The signal for histone methylation is provided by sequential histone mono- Although ubiquitination was initially identified as a ubiquitination and de-ubiquitination (Zhang, 2003; signal that leads to proteasome degradation of the target Dover et al., 2002; Sun and Allis, 2002), a process in protein, it has become since clear that attachment of which the 19S regulatory part of the proteasome is also ubiquitin can lead to different outcomes depending on involved (Laribee et al., 2007; Ezhkova and Tansey, the type of this attachment. All lysine residues of the 2004). This process is important in transcription ubiquitin molecules can be used for isopeptide bond elongation and defines a point of regulation of formation and result to different outcomes. In addition transcription by the UPS. RING domain-containing E3 another dimension of diversification is conferred by ligase hPIRH2 (human p53-induced ring-containing whether one ubiquitin molecule or a chain of ubiquitins H2) binds transcription factors such as nuclear is attached. receptors and promotes suppression of histone A chain of at least four ubiquitin molecules linked deacetylase 1 (HDAC1) stabilizing histones in the through lysine 48 is the signal for recognition of a acetylated state (Logan et al., 2006). Histone target protein by the proteasome complex in order to be modifications are an intermediary state that promotes degraded. The entire structure that leads to degradation nucleosomal histone octamer dissociation from the of a target protein by the proteasome is called a degron promoter transcription initiation site and leave DNA and is comprised of two parts, the first being the naked for transcription machinery binding (Boeger et covalently attached ubiquitin tag and the second being al., 2005; Boeger et al., 2004). In addition an unstructured region of the target protein that is a pre- ubiquitination of co-repressors CtBP1/2 and requisite for the delivery of the recognized and NCoR/SMRT leads to their proteasome degradation captured protein to the interior of the core proteasome releasing transcriptional repression in order for the particle where the enzymatic degradation activities transcription complex to bind DNA (Perissi et al., reside (Schrader et al., 2009). Other lysines such as 2008). Many transcription factors such as nuclear lysine 6 and 11 of the ubiquitin molecule can also serve receptors undergo ubiquitination after DNA binding as anchors of proteasome-recognized ubiquitin chains. (Gaughan et al., 2005; Ramamoorthy and Nawaz, Ubiquitin chains linked through lysine 63 regulate 2008). In parallel a molecular complex called mediator processes such as DNA repair, endocytosis and protein is recruited and helps recruit, in its turn, RNA kinases activation (Hoeller et al., 2006). Proteasome polymerase II to begin transcription (Vijayvargia et al., degradation after lysine 63 poly-ubiquitination has been 2007). After a few rounds of transcription ubiquitin described in some instances to occur (Babu et al., 2005) ligases have attached four ubiquitin molecules to but most often lysine 63 poly-ubiquitination leads to transcription factor molecules which can now be proteolysis through autophagy (Li and Ye, 2008). recognized by the proteasome for degradation. Lysine 63-linked chains differ significantly in their Components of the general transcription machinery that conformation from their lysine 48-linked counterparts. possess E3 ligase activity collaborate in this Lysine 63-linked chains undertake an open ubiquitination (Conaway et al., 2002). Some conformation with little contact between ubiquitins transcription factors such as the AR (Androgen except for the covalent link (Varadan et al., 2004), Receptor) are stabilized in a transient although in solution lysine 63 chains can adopt a monoubiquitinated state by a protein called TSG101 continuum of conformations in a dynamic manner (Tumor Susceptibility Gene 101), which later is (Datta et al., 2009). In contrast, lysine 48-linked chains displaced from the AR for poly-ubiquitination to take have a more compact conformation with neighboring place (Burgdorf et al., 2004). Proteasomal degradation ubiquitins developing additional non-covalent links is a pre-requisite for the transcription process to with each other. These differences between ubiquitin continue because it frees the way for new transcription chains form the basis for divergent functions (Tenno et factor molecules to occupy the promoter as long as the al., 2004) due to recognition specificity by different signal that activates the transcription factor exists. In ubiquitin receptor proteins (Raasi et al., 2005). this way there is a strict time regulation of The Ubiquitin-Proteasome System (UPS) plays an transcription. important role in DNA transcription. Co-activators Ubiquitination plays also significant role in DNA bound to activated transcription factors recruit histone repair. Nucleotide Excision Repair (NER), one of the acetyltransferases such as CBP (CREB Binding modes of DNA repair is activated when DNA damage, Protein)/p300 and p/CAF (p300/CBP-associated for example after UV light, is detected. NER requires

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1090 Ubiquitin, ubiquitination and the ubiquitin-proteasome system in cancer Voutsadakis IA

ubiquitin-associated (UBA) domain of protein hHR23 depends on the E2 and E3 enzymes that are involved. It in order to interact with ATP activity-possessing appears that HECT type E3s due to their distinctive components of 19S proteasome (Reed and Gillette, mode of action retain the decision of the ubiquitination 2007). This interaction does not result in proteasome type while RING type E3s are more promiscuous in the degradation but promotes XPC (Xeroderma type of ubiquitination performed and depend on their Pigmentosum Complementation group C) protein E2 partner in each case to define ubiquitination type stabilization by preventing this protein from being (Ikeda and Dikic, 2008). For example, HECT domain poly-ubiquitinated and recognized by the proteasome ligase E6-AP forms lysine 48 ubiquitin chains, while for degradation (Raasi and Pickart, 2002). XPC mono- RING domain ligase BRCA1 can mono-ubiquitinate ubiquitination is at least temporarily promoted (as poly- substrates when interacting with E2 enzymes UBCH6, ubiquitination is inhibited) and may serve as the signal UBE2E2, UBCM2 and UBE2W, forms lysine 63- for further factors involved in NER recruitment. linked chains when interacting with E2 MMS2-UBC13 A role of ubiquitination exists in DNA damage and lysine 48-linked ubiquitin chains when interacting tolerance pathway. In this instance, after DNA damage with E2 UBE2K (Christensen et al., 2007). the protein PCNA (Proliferating Cell Nuclear Antigen) The proteasome is mono-ubiquitinated and recruits trans-lesion The whole proteasome structure is called 26S synthesis polymerases that bypass DNA lesion proteasome representing a complex of 2.5 MDa. It is allowing replication despite lesion existence. In localized in both the nucleus and the cytoplasm, near contrast, PCNA lysine 63 poly-ubiquitination promotes the endoplasmic reticulum and even in the centrosome recovering of stalled replication fork at sites of DNA (Fabunmi et al., 2000). 26S proteasome is comprised of damage in an error-free manner (Chiu et al., 2006). two parts: The 19S regulatory particle (RP) and the 20S Other DNA repair pathways such as base excision Core Particle (CP), comprised in their turn of several repair (BER), mismatch repair (MMR) and Double protein sub-units each. After attachment of at least four Strand Break (DSB) repair involve both proteolytic and ubiquitin molecules the target protein is recognized by non-proteolytic ubiquitin regulation (Vlachostergios et specific sub-units of 19S regulatory particle (RP) of the al., 2009). proteasome. 19S RP is a multi-protein structure that Mono-ubiquitination is a signal involved in receptor caps the two sides of the core particle (CP) of the endocytosis and lysosomal sorting. Many receptor proteasome. 19S (also known with the alternative name tyrosine kinases (RTKs) such as EGFR (Epidermal PA700) is made of two sub-complexes called the lid Growth Factor Receptor) and PDGFR (Platelet-Derived and the base and a total of 17 peptide molecules. Six of Growth Factor Receptor) undergo ligand-induced them possess ATPase activity while the 11 others are mono-ubiquitination. In this process ligand-induced non-ATPases. The lid sub-complex is comprised of phosphorylation of the receptor gives the signal for eight sub-units, six of which contain a PCI receptor ubiquitination. E3 ligase cbl facilitates [Proteasome, COP9 signalosome and eIF3 (eukaryotic receptor ubiquitination and is the major E3 ligase for Initiation Factor 3)] domain mediating interactions this purpose (Hugland et al., 2003). Ubiquitinated between them. One of the other two sub-units, S13 in receptors interact with ubiquitin-binding proteins of the mammals and Rpn11 in yeast, is the metallopeptidase endocytic pathway and are escorted through clathrin- that performs de-ubiquitination of the substrates in coated pits to clathrin-coated vesicles, endosomes and order for ubiquitin molecules to be recycled. Both S13 finally lysosomes. In this travel, surface receptors are and the eighth lid sub-unit contain a so called MPN transferred to different ubiquitin-binding proteins. (Mpr1p and Pad1p N-terminal regions) domain (Hanna Mono-ubiquitination in multiple receptor sites and Finley, 2007). Nevertheless Rpn8 lacks key (multiple mono-ubiquitination) has also been found to residues in the MPN domain and has no play a role in receptor endocytosis. Cbl E3 ligase metallopeptidase activity. mediates also multiple mono-ubiquitination. Multiple The 19S base sub-complex is made up of the six mono-ubiquitination is believed to stabilize interaction ATPases and three other peptides. ATPases belong to of receptors with ubiquitin receptors in order to the AAA (ATPases Associated with various cellular enhance their transfer to lysosomes. Some ubiquitin Activities) family and are able to hydrolyze all four receptors may also recognize only multi-ubiquitinated nucleotide triphosphates and to alter the conformation RTKs through multiple domain interactions. of protein, preventing aggregation. The type of ubiquitination performed which, as discussed, will specify the fate of the target protein

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1091 Ubiquitin, ubiquitination and the ubiquitin-proteasome system in cancer Voutsadakis IA

Figure 2: Schematic representation of the proteasome multi-protein complex.

Thus, they function to prevent aggregation of regulation of all these processes as will be discussed proteasome substrate proteins before these proteins briefly below. enter the Core Particle to be degraded. AAA ATPases Cell cycle machinery is in the heart of cell growth and have also functions independent of their membership in the final destination of growth and anti-growth signals. the proteasome structure notably in transcription and Cell cycle is regulated in multiple levels by the UPS. membranes fusion (Hanson and Whiteheart, 2005; Proteins called cyclins are associated with Cyclin- Meyer, 2005). The three other peptides of the 19S base dependent kinases (CDKs) to activate their actions of possess ubiquitin recognition domains that allow them phosphorylation of substrates for the cell to progress to recognize poly-ubiquitin chains. through the different phases of the cell cycle. In late G1 The core particle of the proteasome is a cylinder- phase, cyclin D in collaboration with CDKs 4 and 6 shaped multi-unit structure with a hollow central phosphorylates and inactivates protein Rb. As a result chamber (Rechsteiner, 2005). Inside this chamber transcription factor E2F is freed to transcribe genes enzymatic degradation of target proteins takes place necessary for the progression into the S phase. executed by three enzymatic activity-possessing Transcription of Cyclin D is induced by the β- subunits of the CP. CP consists of four seven-member catenin/TCF4 transcription factor complex. β-catenin is rings that are stacked one on the other. The two regulated by the UPS through degradation after peripheral rings are similar and are called α rings and phosphorylation and ubiquitination with the aid of E3 the two central rings are also similar and are called β ligase βTrCP (β-Transducin repeat Containing Protein). rings. Each of the seven sub-units of the α and β rings The stability of Cyclin D is also regulated directly by is distinct resulting in the CP to be comprised of two the UPS. Proteasome degradation keeps it in low levels copies each of 14 distinct sub-units. Three of the seven through the cell cycle except for its up-regulation in sub-units of the β rings, β1, β2 and β5 possess the late G1 (Kitagawa et al., 2009). Cyclins E1, E2 and A enzymatic activities of the proteasome, trypsin-like in collaboration with CDKs 1 and 2 get cell through S (post-basic residues cleavage) activity, chymotrypsin- phase into G2 and Cyclin B functions in collaboration like (post-hydrophobic residues cleavage) activity and with CDK1 at G2 phase and is degraded by the post-glutamyl (caspase-like or post-acidic residues proteasome at late mitosis (Vodermaier, 2004). CDKs cleavage) activity respectively. Resulting fragments are further regulated by CDK inhibitors such as p21 after proteasome degradation range in general between and p27, the stability of which are also determined by 4 and 14 amino-acids in length (Wolf and Hilt, 2004). proteasome degradation (Carrano et al., 1999; Carcinogenesis processes: the role of the Bornstein et al., 2003). The E3 ligase facilitating degradation of these CDK inhibitors is a RING finger UPS type E3 with four sub-units. Of these sub-units F-box Normal cells need to obtain six essential capabilities to protein Skp2 (S-phase kinase protein 2) is the substrate become malignant (Hanahan and Weinberg, 2000): Self recognition sub-unit. The same SCF type E3 is sufficiency in growth signals, insensitivity to anti- involved in the degradation of other cell cycle growth signals, inhibition of apoptosis, limitless inhibitors such as the Rb family protein p130. In replicative potential, angiogenesis potential and ability contrast, a SCF ligase with three identical sub-units but to invade and metastasize. UPS is involved in the a different substrate recognition sub-unit called Fbxw7

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1092 Ubiquitin, ubiquitination and the ubiquitin-proteasome system in cancer Voutsadakis IA

(alternatively named hCDC4 or Archipelago) is proteins of the cellular core apoptosis machinery are involved in the proteasome degradation of proliferator substrates of the proteasome. Bcl-2 family includes promoting transcription factor c-myc as well as of both pro-apoptotic and anti-apoptotic members and cyclin E (Onoyama and Nakayama, 2008). Given their both categories contain members that are proteasome respective substrates E3 ligase sub-units Skp2 and substrates. UPS regulates the balance between the pro- Fbxw7 are acting as an oncogene the former and a apoptotic and anti-apoptotic family members which in tumor suppressor the latter (Shapira et al., 2005; turn will determine ultimate cell fate after various Onoyama et al., 2007). stimuli (Yang and Yu, 2003). Another point of particular importance of cell cycle IAPs (Inhibitors of Apoptosis) are a family of RING regulation by the UPS is at the anaphase phase of finger E3 ligases that inhibit apoptosis through mitosis. At that point the chromosomes are aligned at ubiquitination and degradation of effectors of the center of the cell and develop connections through apoptosis, caspases. Apoptotic stimuli promote auto- the centromere with both poles of the mitotic spindle. ubiquitination of IAPs which leads to caspase When all chromosomes have completed their stabilization in order to perform their apoptotic attachment to both poles the signal is given for each function (Vaux and Silke, 2005; Ni et al., 2005). sister chromatid to begin moving to a pole, detached p53 is a transcription factor of importance for the from the other sister chromatid. Up to that point sister induction of apoptosis after DNA damage and thus, it chromatids are kept attached at the centromere with the has been named "the guardian of the genome". p53 is action of proteins cohesins. When all chromosomes are regulated by the UPS through ubiquitination by several attached, APC/C (Anaphase Promoting E3 ligases. Mdm2 (mouse double minute 2, also known Complex/Cyclosome), an E3 ligase, ubiquitinates the as hdm2 in humans) is the first identified E3 ligase that protein securin which is degraded by the proteasome ubiquitinates p53 for proteasomal degradation. In (Castro et al., 2003). Securin is an inhibitor of the different stress conditions, p53 degradation is inhibited enzyme separase, which, after securin destruction, is either through its phosphorylation that prevents activated and cleaves cohesins allowing sister interaction with mdm2 or through inhibition of mdm2 chromatids to be pulled to the two poles at the end of activity through interaction with inhibitor p14 ARF anaphase. In parallel APC/C promotes the destruction (Alternative Reading Frame, a name that this protein of Cyclin B allowing dephosphorylation and takes from the fact that it is transcribed from the same inactivation of CDK1, another prerequisite for DNA sequence but with a different reading frame with progression from anaphase to telophase and completion the CDK inhibitor p16INK4a at chromosome 9p). p53 of mitosis (Matyskiela et al., 2009). degradation is also prevented by de-ubiquitination by Apoptosis is another process important in the enzyme HAUSP (Herpes virus-Associated carcinogenesis that is regulated by the UPS. Many Ubiquitin Specific Protease).

Figure 3: Schematic representation of events leading to sister chromatids separation in anaphase.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1093 Ubiquitin, ubiquitination and the ubiquitin-proteasome system in cancer Voutsadakis IA

Other E3 ligases have been found to ubiquitinate p53. The existence of multiple pathways regulating p53 In papilloma virus-infected cells, the HECT domain E3 stability and degradation by the UPS allow both a strict ligase E6-AP (E6-Associated Protein) binds with viral control of its function and a versatility of its activation protein E6 and promotes p53 degradation, an event and inhibition. Nevertheless the UPS constitutes a vital that, together with degradation of tumor suppressor Rb, component of all pathways. greatly contributes to viral oncogenesis. PIRH2 (p53- In order for a cell to obtain limitless replicative induced RING H2) is a RING type E3 ligase that potential, it needs to neutralize the mechanism that promotes p53 ubiquitination independently of mdm2 shortens telomeres with each successive division and and inhibits p53 transcription (Leng et al., 2003). Like limits the total number of cell cycles that it can mdm2, PIRH2 is a p53 target gene, this fact serving in successfully undergo. A protein called TRF1 both occasions as a negative feed-back loop. Another (Telomeric Repeat binding Factor 1, alternatively ubiquitin ligase ubiquitinating p53 is ARF-BP1/Mule called PIN2- Protein Interacting with NIMA 2) binds (ARF-Binding Protein 1/Mcl1 ubiquitin ligase E3). telomeres and prevents access of telomerase, thus This is a HECT domain ubiquitin ligase that, as its physiologically preventing telomere length name implies, can be bound and inactivated by maintenance through the action of telomerase. In this p14/ARF, in a manner analogous to mdm2 (Chen et al., way, in normal cells, telomere length is decreased with 2005). ARF-BP1/Mule inactivation leads to promotion each successive cell cycle. Casein kinase 2 of apoptosis in both p53-dependent and -independent phosphorylates TRF1 and promotes its binding to ways implying that the ligase has other apoptosis telomeres (Kim et al., 2008). In contrast in neoplastic promoting substrates besides p53. In addition it cells, TRF1 is ADP-ribosylated by a poly(ADP-ribose) ubiquitinates and promotes degradation of an anti- polymerase (PARP), tankyrase and dissociates from apoptotic protein, the bcl2 family member Mcl1 telomeres (Smith and de Lange, 2000). Dissociated (Zhong et al., 2005). ARF-BP1/Mule possesses a BH3 TRF1 is then ubiquitinated with the mediation of F-box (Bcl2 homology 3) domain through which it interacts family E3 ligase Fbx4 and degraded by the proteasome with Mcl1. As a result of having both p53 and Mcl1 as (Chang et al., 2003; Lee et al., 2006). This degradation a substrate, ARF-BP1/Mule can promote or impede allows telomerase to access the telomere and perform apoptosis under different conditions (Shmueli and telomere length maintenance contributing to limitless Oren, 2005). Finally, COP1 (Constitutively replicative potential avoiding chromosome erosion that Photomorphogenic 1), a RING domain E3 ligase, is would lead to apoptosis. also promoting p53 degradation (Dornan et al., 2004).

Figure 4: Regulation of p53 by ubiquitination. Ubiquitin ligases involved in p53 ubiquitination are depicted.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1094 Ubiquitin, ubiquitination and the ubiquitin-proteasome system in cancer Voutsadakis IA

Figure 5: The role of UPS in telomere maintenance in cancer. In normal cells (left), telomerase access to telomeres is prevented by protein TRF1 and telomeres are shortened with each cell division. In neoplastic cells (right), after ADP-ribosylation, TRF1 is displaced from the telomere and is ubiquitinated and degraded by the proteasome. As a result, telomerase can access telomeres and prevent their shortening.Angiogenesis is a crucial process in carcinogenesis and is regulated by the UPS in multiple levels. For example, the α sub- units of transcription factor HIF-1 (Hypoxia Inducible Factor-1) is kept suppressed under normoxic conditions by proteasome degradation (Corn, 2007). This degradation requires the action of oxygen sensing prolyl-hydroxylases (PHDs) that hydroxylate HIF α in two proline residues (Pro402 and Pro564) of a so-called oxygen-dependent degradation domain (ODD). Proline hydroxylation gives the signal for HIF α ubiquitination with the help of E3 ligase complex consisting of VHL (Von Hippel Lindau) protein, elongin B, elongin C, Cul2 and Rbx1. Ubiquitination is followed by HIFα proteasome degradation (Koh et al., 2008). In contrast, in hypoxia, prolyl-hydroxylases are inactive and HIF α remains hypo-hydroxylated and is stabilized in order to perform, in collaboration with constitutively present factor HIF- 1β, a transcription program which induces dozens of genes among which genes important for angiogenesis, such as VEGF, are included. VHL protein constituent of HIF α's E3 ligase is mutated in Von Hippel Lindau syndrome which encompasses increased frequency of renal cell carcinomas (RCCs), retinal and central nervous system tumors as well as in sporadic RCCs, leading to Invasive and metastatic potential is another constitutively active HIF α in this malignancy. PHDs characteristic of the neoplastic cell and is also regulated are themselves proteasome substrates and their by the UPS. Activation of several receptor tyrosine ubiquitination is mediated by E3 ligases Siah1 and 2 kinases such as EGFR, PDGFR and GDNFR (Glial cell (Seven in absentia Homolog 1 and 2) (Nakayama and line-Derived Neurotrophic Factor Receptor, also known Ronai, 2004). as ret) favour invasion. These receptor proteins are Several other control points of angiogenesis by the UPS proteasome substrates (Gur et al., 2004; Pierchala et al., exist and include, as another example, direct HIF 2006; Kim et al., 2008; Baron and Schwartz, 2000) and transcription regulation by proteasome-dependent and - the same is true for intracellular proteins that take part independent functions of ubiquitin and regulation of the in signal transduction such as Akt and ERK (Adachi et intra-cellular signal emanating from VEGFR (the al., 2003; Mikalsen et al., 2005) as well as transcription receptor of VEGF). factors that are final effectors of the pathways.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1095 Ubiquitin, ubiquitination and the ubiquitin-proteasome system in cancer Voutsadakis IA

Figure 6: Regulation of transcription factor HIF-1 by the UPS. In normoxia (left), HIF1 is hydroxyprolinated and ubiquitinated with the aid of E3 ligase VHL to be degraded by the proteasome. In hypoxia (right), hydroxylation of HIF-1 is inhibited and the transcription factor is stabilized in order to perform its transcription program.

Lysophosphatidic acid (LPA) receptors are also an mutations of genes involved in mismatch repair example of invasion and motility promoting receptors. (MMR) of DNA such as MSH2, MLH1 and PMS2 They are seven domain membrane spanning G-protein- leading to microsatellite instability (Voutsadakis, coupled receptors. GBM (Glioblastoma multiforme), a 2007). central nervous system malignancy characterized by a The FAP type sequence begins with mutations in the propensity of tissue invasion, expresses high levels of gene encoding for APC (Adenomatous Polyposis Coli) LPA receptors which are stimulated by LPA derived protein. This is a protein taking part in a complex from lysophosphatidylcholine through the action of together with scaffolding proteins axin and conductin autotaxin, an enzyme with lysophospholipase D and kinases GSK3 β (Glycogen Synthase Kinase 3 β) activity also produced and secreted by GBM cells and CKII (Casein Kinase II) that facilitates (Kishi et al., 2006; Hoelzinger et al., 2005). Autotaxin phosphorylation of transcription factor β-catenin, gene is under the control of transcription factor β- leading afterwards to ubiquitination with the help of E3 catenin which, as already mentioned, is proteasome- ligase TrCP and proteasomal degradation of β-catenin regulated (Kenny et al., 2005). (Ilyas, 2005). If APC acquires debilitating mutations in UPS role in cancer: The example of both alleles as it happens in about 85% of sporadic colorectal carcinomas, or has already a germline colorectal carcinogenesis mutation in one allele and acquires a mutation in the Colorectal cancer develops along two major pathways. other allele as it happens in FAP syndrome, β-catenin In the first pathway which takes place in about 85% of cannot be ubiquitinated and degraded by the sporadic colorectal cancer patients as well as in patients proteasome and thus, it remains constitutively active to with the hereditary syndrome Familial Adenomatous perform a proliferation program leading to formation of Polyposis (FAP), there is a sequence of molecular lesions called aberrant crypt foci (ACF) in the colon. events leading stepwise from hyperplasia to adenoma These are the first lesions in this sequence of colorectal to carcinoma. These cases have the characteristic of carcinogenesis. Subsequently, activating mutations in chromosomal instability. The remaining 15% of the oncogene k-ras promote progression of ACF to sporadic cases share molecular pathogenesis with adenoma. These mutations activate proliferation another hereditary syndrome, hereditary non-polyposis programs normally emanating from receptor tyrosine colorectal cancer (HNPCC). In these cases there are kinases without the need for receptor activation. Both

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1096 Ubiquitin, ubiquitination and the ubiquitin-proteasome system in cancer Voutsadakis IA

pathways down-stream of activated k-ras, the Fabunmi RP, Wigley WC, Thomas PJ, DeMartino GN. Activity Raf/MAPKs pathway and the PI3K/akt pathway have and regulation of the centrosome-associated proteasome. J Biol Chem. 2000 Jan 7;275(1):409-13 members that are regulated by ubiquitination and proteasome degradation, while additional intersection Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000 of k-ras-activated pathways and the UPS exist at the Jan 7;100(1):57-70 level of transcription factors activated by MAPKs such Smith S, de Lange T. Tankyrase promotes telomere elongation as AP-1 (Activated Protein 1) given that transcription is in human cells. Curr Biol. 2000 Oct 19;10(20):1299-302 a process that requires ubiquitin in both a proteasome- Conaway RC, Brower CS, Conaway JW. Emerging roles of dependent and -independent manner (Voutsadakis, ubiquitin in transcription regulation. Science. 2002 May 2008). 17;296(5571):1254-8 Next step of colorectal carcinogenesis, the transition Dover J, Schneider J, Tawiah-Boateng MA, Wood A, Dean K, from adenoma to carcinoma requires accumulation of Johnston M, Shilatifard A. Methylation of histone H3 by COMPASS requires ubiquitination of histone H2B by Rad6. J additional lesions such as p53 and Smad4 (also known Biol Chem. 2002 Aug 9;277(32):28368-71 as DPC4- Deleted in Pancreatic Carcinoma 4) mutations. These are also pathways that are UPS Sun ZW, Allis CD. Ubiquitination of histone H2B regulates H3 methylation and gene silencing in yeast. Nature. 2002 Jul regulated. As already discussed in a previous section, 4;418(6893):104-8 stability of p53 is regulated by multiple E3 ligases. Adachi M, Katsumura KR, Fujii K, Kobayashi S, Aoki H, Smad4 is part of the TGF β (Transforming Growth Matsuzaki M. Proteasome-dependent decrease in Akt by Factor β) signalling cascade and is also a proteasome growth factors in vascular smooth muscle cells. FEBS Lett. substrate for proteolytic regulation. 2003 Nov 6;554(1-2):77-80 The other sequence of colorectal carcinogenesis Bornstein G, Bloom J, Sitry-Shevah D, Nakayama K, Pagano involving lesions in MMR genes is also UPS-regulated M, Hershko A. Role of the SCFSkp2 ubiquitin ligase in the in multiple levels (Hernandez-Pigeon et al., 2004; degradation of p21Cip1 in S phase. J Biol Chem. 2003 Jul Hernandez-Pigeon et al., 2005). As mentioned in a 11;278(28):25752-7 previous paragraph, DNA repair processes in general Castro A, Vigneron S, Lorca T, Labbé JC. [Mitosis under are UPS regulated. control]. Med Sci (Paris). 2003 Mar;19(3):309-17 It becomes clear from the above discussion that several Chang W, Dynek JN, Smith S. TRF1 is degraded by ubiquitin- important lesions and pathways involved in both the mediated proteolysis after release from telomeres. Genes Dev. FAP type sequence and the MMR sequence of 2003 Jun 1;17(11):1328-33 colorectal carcinogenesis are UPS regulated. Given this Haglund K, Di Fiore PP, Dikic I. Distinct monoubiquitin signals multitude of regulations in oncogenesis by UPS, there in receptor endocytosis. Trends Biochem Sci. 2003 are multiple opportunities for therapeutic interventions. Nov;28(11):598-603 Paradoxically this same multitude may diminish the Leng RP, Lin Y, Ma W, Wu H, Lemmers B, Chung S, Parant probability that a single intervention affecting UPS JM, Lozano G, Hakem R, Benchimol S. Pirh2, a p53-induced regulation would be beneficial in a wide range of ubiquitin-protein ligase, promotes p53 degradation. Cell. 2003 Mar 21;112(6):779-91 cancers with diverse molecular lesions. In contrast there is the need for identification of sub-sets of cancer Raasi S, Pickart CM. Rad23 ubiquitin-associated domains (UBA) inhibit 26 S proteasome-catalyzed proteolysis by types with specific molecular lesions that will be sequestering lysine 48-linked polyubiquitin chains. J Biol particularly sensitive to a specific therapeutic Chem. 2003 Mar 14;278(11):8951-9 intervention affecting the UPS. Therapeutic success Yang Y, Yu X. Regulation of apoptosis: the ubiquitous way. with proteasome inhibitor bortezomib in multiple FASEB J. 2003 May;17(8):790-9 myeloma creates a hope that inhibition of UPS can be a Zhang Y. Transcriptional regulation by histone ubiquitination valid target in other types of malignancies and specific and deubiquitination. Genes Dev. 2003 Nov 15;17(22):2733-40 sub-sets of tumor locations. Further clinical trials based on the rational of solid pre-clinical data are needed to Amerik AY, Hochstrasser M. Mechanism and function of deubiquitinating enzymes. Biochim Biophys Acta. 2004 Nov identify them. 29;1695(1-3):189-207 Boeger H, Griesenbeck J, Strattan JS, Kornberg RD. Removal References of promoter nucleosomes by disassembly rather than sliding in Jenster G, Spencer TE, Burcin MM, Tsai SY, Tsai MJ, vivo. Mol Cell. 2004 Jun 4;14(5):667-73 O'Malley BW. Steroid receptor induction of gene transcription: Burgdorf S, Leister P, Scheidtmann KH. TSG101 interacts with a two-step model. Proc Natl Acad Sci U S A. 1997 Jul apoptosis-antagonizing transcription factor and enhances 22;94(15):7879-84 androgen receptor-mediated transcription by promoting its Carrano AC, Eytan E, Hershko A, Pagano M. SKP2 is required monoubiquitination. J Biol Chem. 2004 Apr 23;279(17):17524- for ubiquitin-mediated degradation of the CDK inhibitor p27. 34 Nat Cell Biol. 1999 Aug;1(4):193-9 Dornan D, Wertz I, Shimizu H, Arnott D, Frantz GD, Dowd P, Baron V, Schwartz M. Cell adhesion regulates ubiquitin- O'Rourke K, Koeppen H, Dixit VM. The ubiquitin ligase COP1 mediated degradation of the platelet-derived growth factor is a critical negative regulator of p53. Nature. 2004 May receptor beta. J Biol Chem. 2000 Dec 15;275(50):39318-23 6;429(6987):86-92

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1097 Ubiquitin, ubiquitination and the ubiquitin-proteasome system in cancer Voutsadakis IA

Ezhkova E, Tansey WP. Proteasomal ATPases link Kenny PA, Enver T, Ashworth A. Receptor and secreted ubiquitylation of histone H2B to methylation of histone H3. Mol targets of Wnt-1/beta-catenin signalling in mouse mammary Cell. 2004 Feb 13;13(3):435-42 epithelial cells. BMC Cancer. 2005 Jan 10;5:3 Gur G, Rubin C, Katz M, Amit I, Citri A, Nilsson J, Amariglio N, Meyer HH. Golgi reassembly after mitosis: the AAA family Henriksson R, Rechavi G, Hedman H, Wides R, Yarden Y. meets the ubiquitin family. Biochim Biophys Acta. 2005 Jul LRIG1 restricts growth factor signaling by enhancing receptor 10;1744(3):481-92 ubiquitylation and degradation. EMBO J. 2004 Aug 18;23(16):3270-81 Mikalsen T, Johannessen M, Moens U. Sequence- and position-dependent tagging protects extracellular-regulated Hernandez-Pigeon H, Laurent G, Humbert O, Salles B, Lautier kinase 3 protein from 26S proteasome-mediated degradation. D. Degadration of mismatch repair hMutSalpha heterodimer by Int J Biochem Cell Biol. 2005 Dec;37(12):2513-20 the ubiquitin-proteasome pathway. FEBS Lett. 2004 Mar 26;562(1-3):40-4 Ni T, Li W, Zou F. The ubiquitin ligase ability of IAPs regulates apoptosis. IUBMB Life. 2005 Dec;57(12):779-85 Nakayama K, Ronai Z. Siah: new players in the cellular response to hypoxia. Cell Cycle. 2004 Nov;3(11):1345-7 Petroski MD, Deshaies RJ. Mechanism of lysine 48-linked ubiquitin-chain synthesis by the cullin-RING ubiquitin-ligase Passmore LA, Barford D. Getting into position: the catalytic complex SCF-Cdc34. Cell. 2005 Dec 16;123(6):1107-20 mechanisms of protein ubiquitylation. Biochem J. 2004 May 1;379(Pt 3):513-25 Raasi S, Varadan R, Fushman D, Pickart CM. Diverse polyubiquitin interaction properties of ubiquitin-associated Pickart CM. Back to the future with ubiquitin. Cell. 2004 Jan domains. Nat Struct Mol Biol. 2005 Aug;12(8):708-14 23;116(2):181-90 Rechsteiner M.. The 26S Proteasome. Mayer RJ, Ciechanover Pickart CM, Eddins MJ. Ubiquitin: structures, functions, A, Rechsteiner M (eds.). Protein degradation. Wiley-VCH mechanisms. Biochim Biophys Acta. 2004 Nov 29;1695(1- Verlag 2005; (1):220-247. 3):55-72 Shapira M, Ben-Izhak O, Linn S, Futerman B, Minkov I, Tenno T, Fujiwara K, Tochio H, Iwai K, Morita EH, Hayashi H, Hershko DD. The prognostic impact of the ubiquitin ligase Murata S, Hiroaki H, Sato M, Tanaka K, Shirakawa M. subunits Skp2 and Cks1 in colorectal carcinoma. Cancer. 2005 Structural basis for distinct roles of Lys63- and Lys48-linked Apr 1;103(7):1336-46 polyubiquitin chains. Genes Cells. 2004 Oct;9(10):865-75 Shmueli A, Oren M. Life, death, and ubiquitin: taming the mule. Varadan R, Assfalg M, Haririnia A, Raasi S, Pickart C, Cell. 2005 Jul 1;121(7):963-5 Fushman D. Solution conformation of Lys63-linked di-ubiquitin chain provides clues to functional diversity of polyubiquitin Vaux DL, Silke J. IAPs, RINGs and ubiquitylation. Nat Rev Mol signaling. J Biol Chem. 2004 Feb 20;279(8):7055-63 Cell Biol. 2005 Apr;6(4):287-97 Vodermaier HC. APC/C and SCF: controlling each other and Welchman RL, Gordon C, Mayer RJ. Ubiquitin and ubiquitin- the cell cycle. Curr Biol. 2004 Sep 21;14(18):R787-96 like proteins as multifunctional signals. Nat Rev Mol Cell Biol. 2005 Aug;6(8):599-609 Wolf DH, Hilt W. The proteasome: a proteolytic nanomachine of cell regulation and waste disposal. Biochim Biophys Acta. Zhong Q, Gao W, Du F, Wang X. Mule/ARF-BP1, a BH3-only 2004 Nov 29;1695(1-3):19-31 E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell. 2005 Jul 1;121(7):1085-95 Babu JR, Geetha T, Wooten MW. Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J Chiu RK, Brun J, Ramaekers C, Theys J, Weng L, Lambin P, Neurochem. 2005 Jul;94(1):192-203 Gray DA, Wouters BG. Lysine 63-polyubiquitination guards against translesion synthesis-induced mutations. PLoS Genet. Boeger H, Bushnell DA, Davis R, Griesenbeck J, Lorch Y, 2006 Jul;2(7):e116 Strattan JS, Westover KD, Kornberg RD. Structural basis of eukaryotic gene transcription. FEBS Lett. 2005 Feb Hoeller D, Hecker CM, Dikic I.. Ubiquitin and ubiquitin-like 7;579(4):899-903 proteins in cancer pathogenesis. Nat Rev Cancer. 2006 Oct;6(10):776-88. (REVIEW) Chen D, Kon N, Li M, Zhang W, Qin J, Gu W. ARF-BP1/Mule is a critical mediator of the ARF tumor suppressor. Cell. 2005 Kishi Y, Okudaira S, Tanaka M, Hama K, Shida D, Kitayama J, Jul 1;121(7):1071-83 Yamori T, Aoki J, Fujimaki T, Arai H. Autotaxin is overexpressed in glioblastoma multiforme and contributes to Gaughan L, Logan IR, Neal DE, Robson CN. Regulation of cell motility of glioblastoma by converting androgen receptor and histone deacetylase 1 by Mdm2- lysophosphatidylcholine to lysophosphatidic acid. J Biol Chem. mediated ubiquitylation. Nucleic Acids Res. 2005;33(1):13-26 2006 Jun 23;281(25):17492-500 Hanson PI, Whiteheart SW. AAA+ proteins: have engine, will Lee TH, Perrem K, Harper JW, Lu KP, Zhou XZ. The F-box work. Nat Rev Mol Cell Biol. 2005 Jul;6(7):519-29 protein FBX4 targets PIN2/TRF1 for ubiquitin-mediated degradation and regulates telomere maintenance. J Biol Hernandez-Pigeon H, Quillet-Mary A, Louat T, Schambourg A, Chem. 2006 Jan 13;281(2):759-68 Humbert O, Selves J, Salles B, Laurent G, Lautier D. hMutS alpha is protected from ubiquitin-proteasome-dependent Logan IR, Gaughan L, McCracken SR, Sapountzi V, Leung degradation by atypical protein kinase C zeta phosphorylation. HY, Robson CN. Human PIRH2 enhances androgen receptor J Mol Biol. 2005 Apr 22;348(1):63-74 signaling through inhibition of histone deacetylase 1 and is overexpressed in prostate cancer. Mol Cell Biol. 2006 Hoelzinger DB, Mariani L, Weis J, Woyke T, Berens TJ, Sep;26(17):6502-10 McDonough WS, Sloan A, Coons SW, Berens ME. Gene expression profile of glioblastoma multiforme invasive Pierchala BA, Milbrandt J, Johnson EM Jr. Glial cell line- phenotype points to new therapeutic targets. Neoplasia. 2005 derived neurotrophic factor-dependent recruitment of Ret into Jan;7(1):7-16 lipid rafts enhances signaling by partitioning Ret from proteasome-dependent degradation. J Neurosci. 2006 Mar Ilyas M. Wnt signalling and the mechanistic basis of tumour 8;26(10):2777-87 development. J Pathol. 2005 Jan;205(2):130-44

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1098 Ubiquitin, ubiquitination and the ubiquitin-proteasome system in cancer Voutsadakis IA

Chiu YH, Sun Q, Chen ZJ. E1-L2 activates both ubiquitin and Onoyama I, Nakayama KI. Fbxw7 in cell cycle exit and stem FAT10. Mol Cell. 2007 Sep 21;27(6):1014-23 cell maintenance: insight from gene-targeted mice. Cell Cycle. 2008 Nov 1;7(21):3307-13 Christensen DE, Brzovic PS, Klevit RE. E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin Perissi V, Scafoglio C, Zhang J, Ohgi KA, Rose DW, Glass CK, chain linkages. Nat Struct Mol Biol. 2007 Oct;14(10):941-8 Rosenfeld MG. TBL1 and TBLR1 phosphorylation on regulated Corn PG. Role of the ubiquitin proteasome system in renal cell gene promoters overcomes dual CtBP and NCoR/SMRT carcinoma. BMC Biochem. 2007 Nov 22;8 Suppl 1:S4 transcriptional repression checkpoints. Mol Cell. 2008 Mar 28;29(6):755-66 Hanna J, Finley D. A proteasome for all occasions. FEBS Lett. 2007 Jun 19;581(15):2854-61 Ramamoorthy S, Nawaz Z. E6-associated protein (E6-AP) is a dual function coactivator of steroid hormone receptors. Nucl Laribee RN, Fuchs SM, Strahl BD. H2B ubiquitylation in Recept Signal. 2008 Apr 18;6:e006 transcriptional control: a FACT-finding mission. Genes Dev. 2007 Apr 1;21(7):737-43 Singhal S, Taylor MC, Baker RT. Deubiquitylating enzymes and disease. BMC Biochem. 2008 Oct 21;9 Suppl 1:S3 Onoyama I, Tsunematsu R, Matsumoto A, Kimura T, de Alborán IM, Nakayama K, Nakayama KI. Conditional Voutsadakis IA. The ubiquitin-proteasome system in colorectal inactivation of Fbxw7 impairs cell-cycle exit during T cell cancer. Biochim Biophys Acta. 2008 Dec;1782(12):800-8 differentiation and results in lymphomatogenesis. J Exp Med. 2007 Nov 26;204(12):2875-88 Yee Koh M, Spivak-Kroizman TR, Powis G. HIF-1 regulation: not so easy come, easy go. Trends Biochem Sci. 2008 Reed SH, Gillette TG. Nucleotide excision repair and the Nov;33(11):526-34 ubiquitin proteasome pathway--do all roads lead to Rome? DNA Repair (Amst). 2007 Feb 4;6(2):149-56 Datta AB, Hura GL, Wolberger C. The structure and conformation of Lys63-linked tetraubiquitin. J Mol Biol. 2009 Vijayvargia R, May MS, Fondell JD. A coregulatory role for the Oct 9;392(5):1117-24 mediator complex in prostate cancer cell proliferation and gene expression. Cancer Res. 2007 May 1;67(9):4034-41 Deshaies RJ, Joazeiro CA. RING domain E3 ubiquitin ligases. Annu Rev Biochem. 2009;78:399-434 Voutsadakis IA. Pathogenesis of colorectal carcinoma and therapeutic implications: the roles of the ubiquitin-proteasome Kitagawa K, Kotake Y, Kitagawa M. Ubiquitin-mediated control system and Cox-2. J Cell Mol Med. 2007 Mar-Apr;11(2):252-85 of oncogene and tumor suppressor gene products. Cancer Sci. 2009 Aug;100(8):1374-81 Bosu DR, Kipreos ET. Cullin-RING ubiquitin ligases: global regulation and activation cycles. Cell Div. 2008 Feb 18;3:7 Matyskiela ME, Rodrigo-Brenni MC, Morgan DO. Mechanisms of ubiquitin transfer by the anaphase-promoting complex. J Groettrup M, Pelzer C, Schmidtke G, Hofmann K. Activating Biol. 2009;8(10):92 the ubiquitin family: UBA6 challenges the field. Trends Biochem Sci. 2008 May;33(5):230-7 Michelle C, Vourc'h P, Mignon L, Andres CR. What was the set of ubiquitin and ubiquitin-like conjugating enzymes in the Ikeda F, Dikic I. Atypical ubiquitin chains: new molecular eukaryote common ancestor? J Mol Evol. 2009 Jun;68(6):616- signals. 'Protein Modifications: Beyond the Usual Suspects' 28 review series. EMBO Rep. 2008 Jun;9(6):536-42 Rotin D, Kumar S. Physiological functions of the HECT family Kim HD, Guo TW, Wu AP, Wells A, Gertler FB, Lauffenburger of ubiquitin ligases. Nat Rev Mol Cell Biol. 2009 Jun;10(6):398- DA. Epidermal growth factor-induced enhancement of 409 glioblastoma cell migration in 3D arises from an intrinsic increase in speed but an extrinsic matrix- and proteolysis- Schrader EK, Harstad KG, Matouschek A. Targeting proteins dependent increase in persistence. Mol Biol Cell. 2008 for degradation. Nat Chem Biol. 2009 Nov;5(11):815-22 Oct;19(10):4249-59 van Wijk SJ, de Vries SJ, Kemmeren P, Huang A, Boelens R, Kim MK, Kang MR, Nam HW, Bae YS, Kim YS, Chung IK. Bonvin AM, Timmers HT. A comprehensive framework of E2- Regulation of telomeric repeat binding factor 1 binding to RING E3 interactions of the human ubiquitin-proteasome telomeres by casein kinase 2-mediated phosphorylation. J Biol system. Mol Syst Biol. 2009;5:295 Chem. 2008 May 16;283(20):14144-52 Vlachostergios PJ, Patrikidou A, Daliani DD, Papandreou CN. Li W, Bengtson MH, Ulbrich A, Matsuda A, Reddy VA, Orth A, The ubiquitin-proteasome system in cancer, a major player in Chanda SK, Batalov S, Joazeiro CA. Genome-wide and DNA repair. Part 1: post-translational regulation. J Cell Mol functional annotation of human E3 ubiquitin ligases identifies Med. 2009 Sep;13(9B):3006-18 MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling. PLoS One. 2008 Jan 23;3(1):e1487 This article should be referenced as such: Li W, Ye Y. Polyubiquitin chains: functions, structures, and Voutsadakis IA. Ubiquitin, ubiquitination and the ubiquitin- mechanisms. Cell Mol Life Sci. 2008 Aug;65(15):2397-406 proteasome system in cancer. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11):1088-1099.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(11) 1099 Atlas of Genetics and Cytogenetics in Oncology and Haematology

OPEN ACCESS JOURNAL AT INIST-CNRS

Instructions to Authors Manuscripts submitted to the Atlas must be submitted solely to the Atlas. Iconography is most welcome: there is no space restriction. The Atlas publishes "cards", "deep insights", "case reports", and "educational items". Cards are structured review articles. Detailed instructions for these structured reviews can be found at: http://AtlasGeneticsOncology.org/Forms/Gene_Form.html for reviews on genes, http://AtlasGeneticsOncology.org/Forms/Leukaemia_Form.html for reviews on leukaemias, http://AtlasGeneticsOncology.org/Forms/SolidTumour_Form.html for reviews on solid tumours, http://AtlasGeneticsOncology.org/Forms/CancerProne_Form.html for reviews on cancer-prone diseases. According to the length of the paper, cards are divided, into "reviews" (texts exceeding 2000 words), "mini reviews" (between), and "short communications" (texts below 400 words). The latter category may not be accepted for indexing by bibliographic databases. Deep Insights are written as traditional papers, made of paragraphs with headings, at the author's convenience. No length restriction. Case Reports in haematological malignancies are dedicated to recurrent -but rare- chromosomes abnormalities in leukaemias/lymphomas. Cases of interest shall be: 1- recurrent (i.e. the chromosome anomaly has already been described in at least 1 case), 2- rare (previously described in less than 20 cases), 3- with well documented clinics and laboratory findings, and 4- with iconography of chromosomes. It is mandatory to use the specific "Submission form for Case reports": see http://AtlasGeneticsOncology.org/Reports/Case_Report_Submission.html. Educational Items must be didactic, give full information and be accompanied with iconography. Translations into French, German, Italian, and Spanish are welcome.

Subscription : The Atlas is FREE !

Corporate patronage, sponsorship and advertising Enquiries should be addressed to [email protected].

Rules, Copyright Notice and Disclaimer Conflicts of Interest: Authors must state explicitly whether potential conflicts do or do not exist. Reviewers must disclose to editors any conflicts of interest that could bias their opinions of the manuscript. The editor and the editorial board members must disclose any potential conflict. Privacy and Confidentiality – Iconography: Patients have a right to privacy. Identifying details should be omitted. If complete anonymity is difficult to achieve, informed consent should be obtained. Property: As "cards" are to evolve with further improvements and updates from various contributors, the property of the cards belongs to the editor, and modifications will be made without authorization from the previous contributor (who may, nonetheless, be asked for refereeing); contributors are listed in an edit history manner. Authors keep the rights to use further the content of their papers published in the Atlas, provided that the source is cited. Copyright: The information in the Atlas of Genetics and Cytogenetics in Oncology and Haematology is issued for general distribution. All rights are reserved. The information presented is protected under international conventions and under national laws on copyright and neighbouring rights. Commercial use is totally forbidden. Information extracted from the Atlas may be reviewed, reproduced or translated for research or private study but not for sale or for use in conjunction with commercial purposes. Any use of information from the Atlas should be accompanied by an acknowledgment of the Atlas as the source, citing the uniform resource locator (URL) of the article and/or the article reference, according to the Vancouver convention. Reference to any specific commercial products, process, or service by trade name, trademark, manufacturer, or otherwise, does not necessarily constitute or imply its endorsement, recommendation, or favouring. The views and opinions of contributors and authors expressed herein do not necessarily state or reflect those of the Atlas editorial staff or of the web site holder, and shall not be used for advertising or product endorsement purposes. The Atlas does not make any warranty, express or implied, including the warranties of merchantability and fitness for a particular purpose, or assumes any legal liability or responsibility for the accuracy, completeness, or usefulness of any information, and shall not be liable whatsoever for any damages incurred as a result of its use. In particular, information presented in the Atlas is only for research purpose, and shall not be used for diagnosis or treatment purposes. No responsibility is assumed for any injury and/or damage to persons or property for any use or operation of any methods products, instructions or ideas contained in the material herein. See also: "Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical Publication - Updated October 2004": http://www.icmje.org.

http://AtlasGeneticsOncology.org

© ATLAS - ISSN 1768-3262

Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS