Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review PLXNB1 (plexin B1) José Javier Gómez-Román, Montserrat Nicolas Martínez, Servando Lazuén Fernández, José Fernando Val-Bernal Department of Anatomical Pathology, Marques de Valdecilla University Hospital, Medical Faculty, University of Cantabria, Santander, Spain (JJGR, MN, SL, JFVB) Published in Atlas Database: March 2009 Online updated version: http://AtlasGeneticsOncology.org/Genes/PLXNB1ID43413ch3p21.html DOI: 10.4267/2042/44702 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 Pseudogene No. Other names: KIAA0407; MGC149167; OTTHUMP00000164806; PLEXIN-B1; PLXN5; SEP Protein HGNC (Hugo): PLXNB1 Location: 3p21.31 Description Local order: The Plexin B1 gene is located between 2135 Amino acids (AA). Plexins are receptors for axon FBXW12 and CCDC51 genes. molecular guidance molecules semaphorins. Plexin signalling is important in pathfinding and patterning of both neurons and developing blood vessels. Plexin-B1 is a surface cell receptor. When it binds to its ligand SEMA4D it activates several pathways by binding of cytoplasmic ligands, like RHOA activation and subsequent changes of the actin cytoskeleton, axon guidance, invasive growth and cell migration. It monomers and heterodimers with PLXNB2 after proteolytic processing. Binds RAC1 that has been activated by GTP binding. It binds PLXNA1 and by similarity ARHGEF11, Note ARHGEF12, ERBB2, MET, MST1R, RND1, NRP1 Size: 26,200 bases. and NRP2. Orientation: minus strand. This family features the C-terminal regions of various plexins. The cytoplasmic region, which has been called DNA/RNA a SEX domain in some members of this family is involved in downstream signalling pathways, by Description interaction with proteins such as Rac1, RhoD, Rnd1 and other plexins. Functioning gene. 21.00 kb; 37 Exons. Three copies of a cysteine rich repeat are found in Transcription Plexin. The function of the repeat is unknown. 7097.00 bp; Number of transcripts: 1; Type: Expression Messenger. It is highly expressed in fetal kidney, digestive system Two alternatively truncated spliced variant, coding (from esophagus to colon), thyroid, prostate and secreted proteins (lacking the part of the extracellular trachea and at slightly lower levels in fetal brain, lung, domains). female reproductive system (breast, uterus and ovary) and liver. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 249 PLXNB1 (plexin B1) Gómez-Román JJ, et al. Plexin B1 policlonal antibody in foetal human central nervous system. Positive staining in developing neurons. Localisation mutations in the cytoplasmic domain of the PLXNB1 gene in prostate cancer tissue. Mutations were found in Three isoforms have been identified: The isoform 1 is 8 (89%) of 9 prostate cancer bone metastases, in 7 located in cell membrane and the isoforms 2 and 3 are (41%) of 17 lymph node meta-stases, and in 41 (46%) secreted proteins. of 89 primary cancers. Forty percent of prostate cancers Function contained the same mutation, and the majority of the Plexin B1 has several molecular functions, like a primary tumors showed overexpression of the plexin- receptor activity, transmembrane receptor activity, B1 protein. In vitro functional expression studies of the protein binding, semaphorin receptor and semaphorin 3 most common mutations showed that the mutant receptor binding. It is implicated in the next biological proteins resulted in increased cell motility, inva-sion, processes: Signal transduction, intracellular signalling adhesion, and lamellipodia extension compared to cascade, multicellular organismal development, cell wildtype. The mutations acted by hindering RAC1 and migration and posi-tive regulation of axonogenesis. RRAS binding and GTP activity. Homology Implicated in It belongs to the plexin family and it contains 3 IPT/TIG domains and one Sema domain. Breast cancer Prognosis Mutations Loss of protein Plexin B1 expression is associated with Somatic poor outcome in breast cancer ER (estrogen positive) patients. Wong et al. (2007) identified 13 different somatic Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 250 PLXNB1 (plexin B1) Gómez-Román JJ, et al. Renal cell carcinoma Prostate carcinoma Note Note By reverse transcription-polymerase chain reaction 13 somatic missense mutations in the cytoplasmic domain of the Plexin-B1 gene have been reported. plexin B1 is expressed in nonneoplastic renal tissue, Mutations were found in cancer bone metastases, and it is severely downregulated in clear cell renal lymph node metastases, and in primary cancers. carcinomas. By immunohistochemistry on tissue Forty percent of prostate cancers contained the same microarrays it was shown that plexin B1 protein is mutation. Overexpression of the Plexin-B1 protein was absent in more than 80% of renal cell carcinomas. found in the majority of primary tumors. The mutations Otherwise, all kinds of renal tubules showed strong hinder Rac and R-Ras binding and R-RasGAP activity, membrane reactivity. resulting in an increase in cell motility, invasion, When plexin B1 expression is induced with an adhesion, and lamellipodia. expression vector in the renal adenocarcinoma cell line ACHN, a marked reduction in proliferation rate is found. Plexin B1 in normal kidney tissue. Tubular cortical and medular cells reactive The same immunostaining after blocking peptide incubation. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 251 PLXNB1 (plexin B1) Gómez-Román JJ, et al. Plexin B1 loss of expression in three cases of renal cell carcinoma (clear cell upper right and left), and papillary (bottom right). One case of renal clear cell carcinoma with PlexinB1 expression (bottom left). activation by Plexin-B1 and induces cell contraction in COS-7 Osteoarthritis cells. J Biol Chem. 2003 Jul 11;278(28):25671-7 Note Usui H, Taniguchi M, Yokomizo T, Shimizu T. Plexin-A1 and Using semi-quantitative reverse transcription plexin-B1 specifically interact at their cytoplasmic domains. polymerase chain reaction (RT-PCR) analysis, plexin Biochem Biophys Res Commun. 2003 Jan 24;300(4):927-31 B1 (PLXNB1) was confirmed to be consis-tently Conrotto P, Corso S, Gamberini S, Comoglio PM, Giordano S. expressed at lower levels in osteoarthritis. Interplay between scatter factor receptors and B plexins controls invasive growth. Oncogene. 2004 Jul 1;23(30):5131-7 Disease Degenerative bone disease. Oinuma I, Ishikawa Y, Katoh H, Negishi M. The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R- References Ras. Science. 2004 Aug 6;305(5685):862-5 Swiercz JM, Kuner R, Offermanns S. Plexin-B1/RhoGEF- Maestrini E, Tamagnone L, Longati P, Cremona O, Gulisano mediated RhoA activation involves the receptor tyrosine kinase M, Bione S, Tamanini F, Neel BG, Toniolo D, Comoglio PM. A ErbB-2. J Cell Biol. 2004 Jun 21;165(6):869-80 family of transmembrane proteins with homology to the MET- Torres-Vázquez J, Gitler AD, Fraser SD, Berk JD, Van N hepatocyte growth factor receptor. Proc Natl Acad Sci U S A. Pham, Fishman MC, Childs S, Epstein JA, Weinstein BM. 1996 Jan 23;93(2):674-8 Semaphorin-plexin signaling guides patterning of the Fujii T, Nakao F, Shibata Y, Shioi G, Kodama E, Fujisawa H, developing vasculature. Dev Cell. 2004 Jul;7(1):117-23 Takagi S. Caenorhabditis elegans PlexinA, PLX-1, interacts Basile JR, Afkhami T, Gutkind JS. Semaphorin 4D/plexin-B1 with transmembrane semaphorins and regulates epidermal induces endothelial cell migration through the activation of morphogenesis. Development. 2002 May;129(9):2053-63 PYK2, Src, and the phosphatidylinositol 3-kinase-Akt pathway. Lorenzato A, Olivero M, Patanè S, Rosso E, Oliaro A, Mol Cell Biol. 2005 Aug;25(16):6889-98 Comoglio PM, Di Renzo MF. Novel somatic mutations of the Conrotto P, Valdembri D, Corso S, Serini G, Tamagnone L, MET oncogene in human carcinoma metastases activating cell Comoglio PM, Bussolino F, Giordano S. Sema4D induces motility and invasion. Cancer Res. 2002 Dec 1;62(23):7025-30 angiogenesis through Met recruitment by Plexin B1. Blood. Oinuma I, Katoh H, Harada A, Negishi M. Direct interaction of 2005 Jun 1;105(11):4321-9 Rnd1 with Plexin-B1 regulates PDZ-RhoGEF-mediated Rho Atlas Genet Cytogenet Oncol Haematol. 2010; 14(3) 252 PLXNB1 (plexin B1) Gómez-Román JJ, et al. Basile JR, Gavard J, Gutkind JS. Plexin-B1 utilizes RhoA and B1 and the small GTPase Rac1. J Mol Biol. 2008 Apr Rho kinase to promote the integrin-dependent activation of Akt 11;377(5):1474-87 and ERK and endothelial cell motility. J Biol Chem. 2007 Nov 30;282(48):34888-95 Gómez Román JJ, Garay GO, Saenz P, Escuredo K, Sanz Ibayondo C, Gutkind S, Junquera C, Simón L, Martínez A, Harduf H, Goldman S, Shalev E. Human uterine epithelial Fernández Luna JL, Val-Bernal JF. Plexin B1 is downregulated RL95-2 and HEC-1A cell-line adhesiveness: the role of plexin in renal cell carcinomas and modulates cell growth. Transl B1. Fertil Steril. 2007 Jun;87(6):1419-27 Res. 2008 Mar;151(3):134-40 Tong Y, Chugha P, Hota PK, Alviani RS, Li M, Tempel W, Swiercz JM, Worzfeld T, Offermanns S. ErbB-2 and met Shen L, Park HW, Buck M. Binding of Rac1, Rnd1, and RhoD reciprocally regulate cellular signaling via plexin-B1. J Biol to a novel Rho GTPase interaction motif destabilizes Chem. 2008 Jan 25;283(4):1893-901 dimerization of the plexin-B1 effector domain. J Biol Chem. 2007 Dec 21;282(51):37215-24 Tong Y, Hota PK, Hamaneh MB, Buck M. Insights into oncogenic mutations of plexin-B1 based on the solution Wong OG, Nitkunan T, Oinuma I, Zhou C, Blanc V, Brown RS, structure of the Rho GTPase binding domain. 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