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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, NORE1, NORE1A, NORE1B, RAPL, RASSF3 HGNC (Hugo): RASSF5 Location: 1q32.1 Description The human gene for RASSF5 is 81 kb in length and is located on chromosome 1(q32.1). The gene can produce 4 protein isoforms, two via differential exon usage, a third via differential promoter usage and the genesis of the 4th (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 prolinerich 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 referred to as a zinc finger. Next is the Ras association domain and this is followed by sequence containing the SARAH motif required for binding to the pro-apoptotic kinases MST1 and MST2. A second nuclear localization sequence has been reported between amino acids 200-260 and a nuclear export sequence between amino acids 260-300. Note Murine RASSF5 originally named Nore1a. Nore1B independently identified and designated RAPL. Rat RASSF5 also cloned independently and designated Maxp1. 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 Nterminus. 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 6;273(10):5439-42 The full length cDNA (for isoform A) encodes for a 47kDa protein which contains a proline-rich region at the N-terminus followed by a putative diacylglycerol/phorbol ester binding domain. This is followed by the Ras association (RA) domain and then the domain containing a SARAH motif. This later is responsible for binding to the pro-apoptotic kinases MST1 and MST2. Khokhlatchev A, Rabizadeh S, Xavier R, Nedwidek M, Chen T, Zhang XF, Seed B, Avruch J. Identification of a novel Rasregulated proapoptotic pathway. Curr Biol. 2002 Feb 19;12(4):253-65 Chen J, Lui WO, Vos MD, Clark GJ, Takahashi M, Schoumans J, Khoo SK, Petillo D, Lavery T, Sugimura J, Astuti D, Zhang C, Kagawa S, Maher ER, Larsson C, Alberts AS, Kanayama HO, Teh BT. The t(1;3) breakpoint-spanning genes LSAMP and NORE1 are involved in clear cell renal cell carcinomas. Cancer Cell. 2003 Nov;4(5):405-13 Expression 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 inactivated in human cancers. Oncogene. 2003 Feb 13;22(6):947-54 Localisation 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 proapoptotic Ras effector Nore1 may serve as a Ras-regulated tumor suppressor in the lung. J Biol Chem. 2003 Jun 13;278(24):21938-43 Function RASSF5A is a pro-apoptotic Ras effector that can bind and relocalize the pro-apoptotic MST kinases in the presence of activated Ras. It can also promote cell cycle arrest and modulate the activity of p53 by regulating its' nuclear localization. Knockdown of RASSF5A promotes cellular proliferation and soft agar growth. Thus, RASSF5A appears to function as a Ras regulated tumor suppressor. Analysis of human tumors has found little evidence of somatic mutation but the gene is frequently inactivated by promoter methylation in a broad range of human tumors. RASSF5C (also known as Nore1b or RAPL) has been reported to modulate cellular adhesion and to be regulated by the Ras related protein Rap1a. RASSF5C has also been implicated as serving as an adaptor protein to facilitate the interaction of Ras and CARMA1. Aoyama Y, Avruch J, Zhang XF. Nore1 inhibits tumor cell growth independent of Ras or the MST1/2 kinases. Oncogene. 2004 Apr 22;23(19):3426-33 Praskova M, Khoklatchev A, Ortiz-Vega S, Avruch J. Regulation of the MST1 kinase by autophosphorylation, by the growth inhibitory proteins, RASSF1 and NORE1, and by Ras. Biochem J. 2004 Jul 15;381(Pt 2):453-62 Avruch J, Praskova M, Ortiz-Vega S, Liu M, Zhang XF. Nore1 and RASSF1 regulation of cell proliferation and of the MST1/2 kinases. Methods Enzymol. 2006;407:290-310 Calvisi DF, Ladu S, Gorden A, Farina M, Conner EA, Lee JS, Factor VM, Thorgeirsson SS. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology. 2006 Apr;130(4):1117-28 Donninger H, Vos MD, Clark GJ. The RASSF1A tumor suppressor. J Cell Sci. 2007 Sep 15;120(Pt 18):3163-72 Kumari G, Singhal PK, Rao MR, Mahalingam S. Nuclear transport of Ras-associated tumor suppressor proteins: different transport receptor binding specificities for arginine-rich nuclear targeting signals. J Mol Biol. 2007 Apr 13;367(5):1294311 Mutations Note No tumor mutations yet reported. Calvisi DF, Donninger H, Vos MD, Birrer MJ, Gordon L, Leaner V, Clark GJ. NORE1A tumor suppressor candidate modulates p21CIP1 via p53. Cancer Res. 2009 Jun 1;69(11):4629-37 Implicated in Clear cell renal carcinoma Richter AM, Pfeifer GP, Dammann RH. The RASSF proteins in cancer; from epigenetic silencing to functional characterization. Biochim Biophys Acta. 2009 Dec;1796(2):114-28 Note RASSF5 is frequently down-regulated by promoter methylation in a variety of tumors including clear cell renal carcinomas. Moreover, a rare hereditary form of kidney cancer has been reported that maps with a translocation inactivating the RASSF5 gene. Bee C, Moshnikova A, Mellor CD, Molloy JE, Koryakina Y, Stieglitz B, Khokhlatchev A, Herrmann C. Growth and tumor suppressor NORE1A is a regulatory node between Ras signaling and microtubule nucleation. J Biol Chem. 2010 May 21;285(21):16258-66 Kumari G, Singhal PK, Suryaraja R, Mahalingam S. Functional interaction of the Ras effector RASSF5 with the tyrosine kinase Lck: critical role in nucleocytoplasmic transport and cell cycle regulation. J Mol Biol. 2010 Mar 19;397(1):89-109 Various cancers Note Nore1a is frequently inactivated by promoter methylation in renal carcinoma, breast cancer, lung cancer, liver cancer and neurological tumors. Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) Park J, Kang SI, Lee SY, Zhang XF, Kim MS, Beers LF, Lim DS, Avruch J, Kim HS, Lee SB. Tumor suppressor ras 214 RASSF5 (Ras association (RalGDS/AF-6) domain family member 5) association domain family 5 (RASSF5/NORE1) mediates death receptor ligand-induced apoptosis. J Biol Chem. 2010 Nov 5;285(45):35029-38 This article should be referenced as such: Schmidt L, Clark GJ. RASSF5 (Ras association (RalGDS/AF6) domain family member 5). Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3):212-215. Overmeyer JH, Maltese WA. Death pathways triggered by activated Ras in cancer cells. Front Biosci. 2011 Jan 1;16:1693-713 Atlas Genet Cytogenet Oncol Haematol. 2012; 16(3) Schmidt L, Clark GJ 215