Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Short Communication RASSF5 (Ras association (RalGDS/AF -6) domain family member 5) Lee Schmidt, Geoffrey J Clark University of Louisville, Room 119C, Baxter II Research Building, 580 S Preston Street, Louisville, KY 40202, USA (LS, GJC) Published in Atlas Database: October 2011 Online updated version : http://AtlasGeneticsOncology.org/Genes/RASSF5ID42059ch1q32.html DOI: 10.4267/2042/47279 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2012 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity DNA/RNA Other names: MGC10823, MGC17344, Maxp1, Description NORE1, NORE1A, NORE1B, RAPL, RASSF3 The human gene for RASSF5 is 81 kb in length and is HGNC (Hugo): RASSF5 located on chromosome 1(q32.1). The gene can Location: 1q32.1 produce 4 protein isoforms, two via differential exon usage, a third via differential promoter usage and the genesis of the 4 th (which can be found as an EST clone) is not yet clear. The largest isoform, A, is 418 amino acids long and has a molecular weight of about 47 kD. The protein structure of RASSF5A contains a proline- rich region at the N-terminus which contains potential SH3 binding sites and a nuclear localization signal. This is followed by a cystein rich domain, sometimes Note referred to as a zinc finger. Next is the Ras association Murine RASSF5 originally named Nore1a. Nore1B domain and this is followed by sequence containing the independently identified and designated RAPL. Rat SARAH motif required for binding to the pro-apoptotic RASSF5 also cloned independently and designated kinases MST1 and MST2. A second nuclear Maxp1. localization sequence has been reported between amino acids 200-260 and a nuclear export sequence between amino acids 260-300. Figure 1. Isoform A is shown as the longest isoform with 6 exons. Isoform B, without an alternate exon, shows that the frameshift gives a shortened and unique C-terminus. Isoform C is shown with a special 5' UTR and lacks an in-frame coding region leading to a unique N- terminus. The total coding sequence for Isoform A is about 1260 bases with the other isoforms being smaller. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 212 RASSF5 (Ras association (RalGDS/AF-6) domain family member 5) Schmidt L, Clark GJ Figure 2. A figure showing the processed mRNA as well as the amino acid sequence for isoforms A-D followed by motif explanation of isoform A (Nore1a). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 213 RASSF5 (Ras association (RalGDS/AF-6) domain family member 5) Schmidt L, Clark GJ Protein References Description Vavvas D, Li X, Avruch J, Zhang XF. Identification of Nore1 as a potential Ras effector. J Biol Chem. 1998 Mar The full length cDNA (for isoform A) encodes for a 47- 6;273(10):5439-42 kDa protein which contains a proline-rich region at the Khokhlatchev A, Rabizadeh S, Xavier R, Nedwidek M, Chen T, N-terminus followed by a putative Zhang XF, Seed B, Avruch J. Identification of a novel Ras- diacylglycerol/phorbol ester binding domain. This is regulated proapoptotic pathway. Curr Biol. 2002 Feb followed by the Ras association (RA) domain and then 19;12(4):253-65 the domain containing a SARAH motif. This later is Chen J, Lui WO, Vos MD, Clark GJ, Takahashi M, Schoumans responsible for binding to the pro-apoptotic kinases J, Khoo SK, Petillo D, Lavery T, Sugimura J, Astuti D, Zhang MST1 and MST2. C, Kagawa S, Maher ER, Larsson C, Alberts AS, Kanayama HO, Teh BT. The t(1;3) breakpoint-spanning genes LSAMP Expression and NORE1 are involved in clear cell renal cell carcinomas. Cancer Cell. 2003 Nov;4(5):405-13 Nore1a mRNA is expressed in the lung, kidney, liver, brain, spleen, thymus and heart. Hesson L, Dallol A, Minna JD, Maher ER, Latif F. NORE1A, a homologue of RASSF1A tumour suppressor gene is Localisation inactivated in human cancers. Oncogene. 2003 Feb 13;22(6):947-54 It can be detected on microtubules, in the centrosome, but appears most obvious in the nucleus. Vos MD, Martinez A, Ellis CA, Vallecorsa T, Clark GJ. The pro- apoptotic Ras effector Nore1 may serve as a Ras-regulated Function tumor suppressor in the lung. J Biol Chem. 2003 Jun 13;278(24):21938-43 RASSF5A is a pro-apoptotic Ras effector that can bind and relocalize the pro-apoptotic MST kinases in the Aoyama Y, Avruch J, Zhang XF. Nore1 inhibits tumor cell growth independent of Ras or the MST1/2 kinases. Oncogene. presence of activated Ras. It can also promote cell 2004 Apr 22;23(19):3426-33 cycle arrest and modulate the activity of p53 by Praskova M, Khoklatchev A, Ortiz-Vega S, Avruch J. regulating its' nuclear localization. Knockdown of Regulation of the MST1 kinase by autophosphorylation, by the RASSF5A promotes cellular proliferation and soft agar growth inhibitory proteins, RASSF1 and NORE1, and by Ras. growth. Thus, RASSF5A appears to function as a Ras Biochem J. 2004 Jul 15;381(Pt 2):453-62 regulated tumor suppressor. Analysis of human tumors Avruch J, Praskova M, Ortiz-Vega S, Liu M, Zhang XF. Nore1 has found little evidence of somatic mutation but the and RASSF1 regulation of cell proliferation and of the MST1/2 gene is frequently inactivated by promoter methylation kinases. Methods Enzymol. 2006;407:290-310 in a broad range of human tumors. RASSF5C (also Calvisi DF, Ladu S, Gorden A, Farina M, Conner EA, Lee JS, known as Nore1b or RAPL) has been reported to Factor VM, Thorgeirsson SS. Ubiquitous activation of Ras and modulate cellular adhesion and to be regulated by the Jak/Stat pathways in human HCC. Gastroenterology. 2006 Ras related protein Rap1a. RASSF5C has also been Apr;130(4):1117-28 implicated as serving as an adaptor protein to facilitate Donninger H, Vos MD, Clark GJ. The RASSF1A tumor the interaction of Ras and CARMA1. suppressor. J Cell Sci. 2007 Sep 15;120(Pt 18):3163-72 Kumari G, Singhal PK, Rao MR, Mahalingam S. Nuclear Mutations transport of Ras-associated tumor suppressor proteins: different transport receptor binding specificities for arginine-rich Note nuclear targeting signals. J Mol Biol. 2007 Apr 13;367(5):1294- 311 No tumor mutations yet reported. Calvisi DF, Donninger H, Vos MD, Birrer MJ, Gordon L, Leaner V, Clark GJ. NORE1A tumor suppressor candidate modulates Implicated in p21CIP1 via p53. Cancer Res. 2009 Jun 1;69(11):4629-37 Clear cell renal carcinoma Richter AM, Pfeifer GP, Dammann RH. The RASSF proteins in cancer; from epigenetic silencing to functional characterization. Note Biochim Biophys Acta. 2009 Dec;1796(2):114-28 RASSF5 is frequently down-regulated by promoter Bee C, Moshnikova A, Mellor CD, Molloy JE, Koryakina Y, methylation in a variety of tumors including clear cell Stieglitz B, Khokhlatchev A, Herrmann C. Growth and tumor renal carcinomas. Moreover, a rare hereditary form of suppressor NORE1A is a regulatory node between Ras kidney cancer has been reported that maps with a signaling and microtubule nucleation. J Biol Chem. 2010 May translocation inactivating the RASSF5 gene. 21;285(21):16258-66 Kumari G, Singhal PK, Suryaraja R, Mahalingam S. Functional Various cancers interaction of the Ras effector RASSF5 with the tyrosine kinase Note Lck: critical role in nucleocytoplasmic transport and cell cycle Nore1a is frequently inactivated by promoter regulation. J Mol Biol. 2010 Mar 19;397(1):89-109 methylation in renal carcinoma, breast cancer, lung Park J, Kang SI, Lee SY, Zhang XF, Kim MS, Beers LF, Lim cancer, liver cancer and neurological tumors. DS, Avruch J, Kim HS, Lee SB. Tumor suppressor ras Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 214 RASSF5 (Ras association (RalGDS/AF-6) domain family member 5) Schmidt L, Clark GJ association domain family 5 (RASSF5/NORE1) mediates death This article should be referenced as such: receptor ligand-induced apoptosis. J Biol Chem. 2010 Nov 5;285(45):35029-38 Schmidt L, Clark GJ. RASSF5 (Ras association (RalGDS/AF- 6) domain family member 5). Atlas Genet Cytogenet Oncol Overmeyer JH, Maltese WA. Death pathways triggered by Haematol. 2012; 16(3):212-215. activated Ras in cancer cells. Front Biosci. 2011 Jan 1;16:1693-713 Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) 215 .