MRAS

The MRAS gene resides on chromosome 3 at the band 3q22.3 and includes 10 exons. This gene produces 2 isoforms through alternative splicing.{{Cite web|url=https://www.uniprot.org/uniprot/O14807|title=MRAS - Ras-related protein M-Ras precursor - Homo sapiens (Human) - MRAS gene & protein|website=www.uniprot.org|access-date=2016-10-10}}

M-Ras is a member of the small GTPase superfamily under the Ras family, which also includes Rap1, Rap2, R-Ras, and R-Ras2 (TC21). This protein spans a length of 209 residues. Its N-terminal amino acid sequence shares 60-75% identity with that in the Ras protein while its effector region is identical with that in Ras. M-Ras shares a similar structure with H-Ras and Rap2A with the exception of its switch 1 conformation when bound to guanosine 5'-(beta,gamma-imido)triphosphate (Gpp(NH)p). Of the two states M-Ras can switch between, M-Ras is predominantly found in its state 1 conformation, which does not bind Ras effectors.{{cite journal | vauthors = Ye M, Shima F, Muraoka S, Liao J, Okamoto H, Yamamoto M, Tamura A, Yagi N, Ueki T, Kataoka T | title = Crystal structure of M-Ras reveals a GTP-bound "off" state conformation of Ras family small GTPases | journal = The Journal of Biological Chemistry | volume = 280 | issue = 35 | pages = 31267–75 | date = September 2005 | pmid = 15994326 | doi = 10.1074/jbc.M505503200 | doi-access = free | hdl = 20.500.14094/D1003488 | hdl-access = free }}

The MRAS gene is expressed specifically in brain, heart, myoblasts, myotubes, fibroblasts, skeletal muscles, and uterus, suggesting a specific role of M-Ras in these tissue and cells.{{cite journal | vauthors = Matsumoto K, Asano T, Endo T | title = Novel small GTPase M-Ras participates in reorganization of actin cytoskeleton | journal = Oncogene | volume = 15 | issue = 20 | pages = 2409–17 | date = November 1997 | pmid = 9395237 | doi = 10.1038/sj.onc.1201416 | s2cid = 12357144 | doi-access = }}{{cite journal | vauthors = Kimmelman A, Tolkacheva T, Lorenzi MV, Osada M, Chan AM | title = Identification and characterization of R-ras3: a novel member of the RAS gene family with a non-ubiquitous pattern of tissue distribution | journal = Oncogene | volume = 15 | issue = 22 | pages = 2675–85 | date = November 1997 | pmid = 9400994 | doi = 10.1038/sj.onc.1201674 | doi-access = free }} M-Ras is involved in many biological processes by activating a wide variety of proteins. For instance, it is activated by Ras guanine nucleotide exchange factors and can bind/activate some Ras protein effectors.{{cite journal | vauthors = Rebhun JF, Castro AF, Quilliam LA | title = Identification of guanine nucleotide exchange factors (GEFs) for the Rap1 GTPase. Regulation of MR-GEF by M-Ras-GTP interaction | journal = The Journal of Biological Chemistry | volume = 275 | issue = 45 | pages = 34901–8 | date = November 2000 | pmid = 10934204 | doi = 10.1074/jbc.M005327200 | doi-access = free }} M-Ras also weakly stimulates the mitogen-activated protein kinase (MAPK) activity and ERK2 activity, but modestly stimulates trans-activation from different nuclear response elements which bind transcription factors, such as SRF, ETS/TCF, Jun/Fos, and NF- kB/Rel.{{cite journal | vauthors = Quilliam LA, Castro AF, Rogers-Graham KS, Martin CB, Der CJ, Bi C | title = M-Ras/R-Ras3, a transforming ras protein regulated by Sos1, GRF1, and p120 Ras GTPase-activating protein, interacts with the putative Ras effector AF6 | journal = The Journal of Biological Chemistry | volume = 274 | issue = 34 | pages = 23850–7 | date = August 1999 | pmid = 10446149 | doi=10.1074/jbc.274.34.23850| doi-access = free }} M-Ras has been found to induce Akt kinase activity in the PI3-K pathway, and it may play a role in cell survival of neural-derived cells.{{cite journal | vauthors = Kimmelman AC, Osada M, Chan AM | title = R-Ras3, a brain-specific Ras-related protein, activates Akt and promotes cell survival in PC12 cells | journal = Oncogene | volume = 19 | issue = 16 | pages = 2014–22 | date = April 2000 | pmid = 10803462 | doi = 10.1038/sj.onc.1203530 | s2cid = 25048933 | doi-access = }} Moreover, M-Ras plays a crucial role in the downregulation of OCT4 and NANOG protein levels upon differentiation and has been demonstrated to modulate cell fate at early steps of development during neurogenesis.{{cite journal | vauthors = Mathieu ME, Faucheux C, Saucourt C, Soulet F, Gauthereau X, Fédou S, Trouillas M, Thézé N, Thiébaud P, Boeuf H | title = MRAS GTPase is a novel stemness marker that impacts mouse embryonic stem cell plasticity and Xenopus embryonic cell fate | journal = Development | volume = 140 | issue = 16 | pages = 3311–22 | date = August 2013 | pmid = 23863483 | doi = 10.1242/dev.091082 | doi-access = free }} M-Ras, induced and activated by BMP-2 signaling, also participates in the osteoblastic determination, differentiation, and transdifferentiation under p38 MAPK and JNK regulation.{{cite journal | vauthors = Watanabe-Takano H, Takano K, Keduka E, Endo T | title = M-Ras is activated by bone morphogenetic protein-2 and participates in osteoblastic determination, differentiation, and transdifferentiation | journal = Experimental Cell Research | volume = 316 | issue = 3 | pages = 477–90 | date = February 2010 | pmid = 19800879 | doi = 10.1016/j.yexcr.2009.09.028 }} M-Ras is involved in TNF-alpha-stimulated and Rap1-mediated LFA-1 activation in splenocytes.{{cite journal | vauthors = Yoshikawa Y, Satoh T, Tamura T, Wei P, Bilasy SE, Edamatsu H, Aiba A, Katagiri K, Kinashi T, Nakao K, Kataoka T | title = The M-Ras-RA-GEF-2-Rap1 pathway mediates tumor necrosis factor-alpha dependent regulation of integrin activation in splenocytes | journal = Molecular Biology of the Cell | volume = 18 | issue = 8 | pages = 2949–59 | date = August 2007 | pmid = 17538012 | doi = 10.1091/mbc.E07-03-0250 | pmc=1949361}} More generally, cells transfected with M-Ras exhibit dendritic appearances with microspikes, suggesting that M-Ras may participate in reorganization of the actin cytoskeleton. In addition, it is reported that M-Ras forms a complex with SCRIB and SHOC2, a polarity protein with tumor suppressor properties, and may play a key role in tumorigenic growth.{{cite journal | vauthors = Young LC, Hartig N, Muñoz-Alegre M, Oses-Prieto JA, Durdu S, Bender S, Vijayakumar V, Vietri Rudan M, Gewinner C, Henderson S, Jathoul AP, Ghatrora R, Lythgoe MF, Burlingame AL, Rodriguez-Viciana P | title = An MRAS, SHOC2, and SCRIB complex coordinates ERK pathway activation with polarity and tumorigenic growth | journal = Molecular Cell | volume = 52 | issue = 5 | pages = 679–92 | date = December 2013 | pmid = 24211266 | doi = 10.1016/j.molcel.2013.10.004 | doi-access = free }}

In humans, other members of the Ras subfamilies carry mutations in human cancers.{{cite journal | vauthors = Karnoub AE, Weinberg RA | title = Ras oncogenes: split personalities | journal = Nature Reviews Molecular Cell Biology | volume = 9 | issue = 7 | pages = 517–31 | date = July 2008 | pmid = 18568040 | doi = 10.1038/nrm2438 | pmc=3915522}} Furthermore, the Ras proteins are not only involved in tumorigenesis but also in many developmental disorders. For instance, the Ras-related proteins appear to be overexpressed in human carcinomas of the oral cavity, esophagus, stomach, skin, and breast, as well as in lymphomas.{{cite journal | vauthors = Graham SM, Oldham SM, Martin CB, Drugan JK, Zohn IE, Campbell S, Der CJ | title = TC21 and Ras share indistinguishable transforming and differentiating activities | journal = Oncogene | volume = 18 | issue = 12 | pages = 2107–16 | date = March 1999 | pmid = 10321735 | doi = 10.1038/sj.onc.1202517 | doi-access = free }}{{cite journal | vauthors = Cox AD, Brtva TR, Lowe DG, Der CJ | title = R-Ras induces malignant, but not morphologic, transformation of NIH3T3 cells | journal = Oncogene | volume = 9 | issue = 11 | pages = 3281–8 | date = November 1994 | pmid = 7936652 }}{{cite journal | vauthors = Chan AM, Miki T, Meyers KA, Aaronson SA | title = A human oncogene of the RAS superfamily unmasked by expression cDNA cloning | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 16 | pages = 7558–62 | date = August 1994 | pmid = 8052619 | pmc = 44441 | doi = 10.1073/pnas.91.16.7558| bibcode = 1994PNAS...91.7558C | doi-access = free }}{{cite journal | vauthors = Huang Y, Saez R, Chao L, Santos E, Aaronson SA, Chan AM | title = A novel insertional mutation in the TC21 gene activates its transforming activity in a human leiomyosarcoma cell line | journal = Oncogene | volume = 11 | issue = 7 | pages = 1255–60 | date = October 1995 | pmid = 7478545 }} More currently, Ras family members such as R-RAS, R-RAS2 and also R-RAS3 have also been implicated as main factors in triggering neural transformation, with R-RAS2 as the most significant element.{{cite journal | vauthors = Gutierrez-Erlandsson S, Herrero-Vidal P, Fernandez-Alfara M, Hernandez-Garcia S, Gonzalo-Flores S, Mudarra-Rubio A, Fresno M, Cubelos B | title = R-RAS2 overexpression in tumors of the human central nervous system | journal = Molecular Cancer | volume = 12 | issue = 1 | pages = 127 | date = 2013-01-01 | pmid = 24148564 | doi = 10.1186/1476-4598-12-127 | pmc=3900289 | doi-access = free }}

A multi-locus genetic risk score study based on a combination of 27 loci, including the MRAS gene, identified individuals at increased risk for both incidence and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).{{cite journal | vauthors = Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield MJ, Devlin JJ, Nordio F, Hyde CL, Cannon CP, Sacks FM, Poulter NR, Sever PS, Ridker PM, Braunwald E, Melander O, Kathiresan S, Sabatine MS | title = Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials | journal = Lancet | volume = 385 | issue = 9984 | pages = 2264–71 | date = June 2015 | pmid = 25748612 | doi = 10.1016/S0140-6736(14)61730-X | pmc=4608367}}

MRAS has been shown to interact with RASSF5{{cite journal | vauthors = Ortiz-Vega S, Khokhlatchev A, Nedwidek M, Zhang XF, Dammann R, Pfeifer GP, Avruch J | title = The putative tumor suppressor RASSF1A homodimerizes and heterodimerizes with the Ras-GTP binding protein Nore1 | journal = Oncogene | volume = 21 | issue = 9 | pages = 1381–90 | date = February 2002 | pmid = 11857081 | doi = 10.1038/sj.onc.1205192 | s2cid = 240243 | doi-access = }} and RALGDS.{{cite journal | vauthors = Ehrhardt GR, Leslie KB, Lee F, Wieler JS, Schrader JW | title = M-Ras, a widely expressed 29-kD homologue of p21 Ras: expression of a constitutively active mutant results in factor-independent growth of an interleukin-3-dependent cell line | journal = Blood | volume = 94 | issue = 7 | pages = 2433–44 | date = October 1999 | doi = 10.1182/blood.V94.7.2433.419k31_2433_2444 | pmid = 10498616 | s2cid = 40024826 }}

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• {{cite journal | vauthors = Matsumoto K, Asano T, Endo T | title = Novel small GTPase M-Ras participates in reorganization of actin cytoskeleton | journal = Oncogene | volume = 15 | issue = 20 | pages = 2409–17 | date = November 1997 | pmid = 9395237 | doi = 10.1038/sj.onc.1201416 | s2cid = 12357144 | doi-access = }}
• {{cite journal | vauthors = Louahed J, Grasso L, De Smet C, Van Roost E, Wildmann C, Nicolaides NC, Levitt RC, Renauld JC | title = Interleukin-9-induced expression of M-Ras/R-Ras3 oncogene in T-helper clones | journal = Blood | volume = 94 | issue = 5 | pages = 1701–10 | date = September 1999 | pmid = 10477695 | doi = 10.1182/blood.V94.5.1701}}
• {{cite journal | vauthors = Ehrhardt GR, Leslie KB, Lee F, Wieler JS, Schrader JW | title = M-Ras, a widely expressed 29-kD homologue of p21 Ras: expression of a constitutively active mutant results in factor-independent growth of an interleukin-3-dependent cell line | journal = Blood | volume = 94 | issue = 7 | pages = 2433–44 | date = October 1999 | pmid = 10498616 | doi = 10.1182/blood.V94.7.2433.419k31_2433_2444| s2cid = 40024826 }}
• {{cite journal | vauthors = Kimmelman AC, Osada M, Chan AM | title = R-Ras3, a brain-specific Ras-related protein, activates Akt and promotes cell survival in PC12 cells | journal = Oncogene | volume = 19 | issue = 16 | pages = 2014–22 | date = April 2000 | pmid = 10803462 | doi = 10.1038/sj.onc.1203530 | s2cid = 25048933 | doi-access = }}
• {{cite journal | vauthors = Rebhun JF, Castro AF, Quilliam LA | title = Identification of guanine nucleotide exchange factors (GEFs) for the Rap1 GTPase. Regulation of MR-GEF by M-Ras-GTP interaction | journal = The Journal of Biological Chemistry | volume = 275 | issue = 45 | pages = 34901–8 | date = November 2000 | pmid = 10934204 | doi = 10.1074/jbc.M005327200 | doi-access = free }}
• {{cite journal | vauthors = Gao X, Satoh T, Liao Y, Song C, Hu CD, Kariya Ki K, Kataoka T | title = Identification and characterization of RA-GEF-2, a Rap guanine nucleotide exchange factor that serves as a downstream target of M-Ras | journal = The Journal of Biological Chemistry | volume = 276 | issue = 45 | pages = 42219–25 | date = November 2001 | pmid = 11524421 | doi = 10.1074/jbc.M105760200 | doi-access = free }}
• {{cite journal | vauthors = Ortiz-Vega S, Khokhlatchev A, Nedwidek M, Zhang XF, Dammann R, Pfeifer GP, Avruch J | title = The putative tumor suppressor RASSF1A homodimerizes and heterodimerizes with the Ras-GTP binding protein Nore1 | journal = Oncogene | volume = 21 | issue = 9 | pages = 1381–90 | date = February 2002 | pmid = 11857081 | doi = 10.1038/sj.onc.1205192 | s2cid = 240243 | doi-access = }}
• {{cite journal | vauthors = Kimmelman AC, Nuñez Rodriguez N, Chan AM | title = R-Ras3/M-Ras induces neuronal differentiation of PC12 cells through cell-type-specific activation of the mitogen-activated protein kinase cascade | journal = Molecular and Cellular Biology | volume = 22 | issue = 16 | pages = 5946–61 | date = August 2002 | pmid = 12138204 | pmc = 133986 | doi = 10.1128/MCB.22.16.5946-5961.2002 }}
• {{cite journal | vauthors = Mitin NY, Ramocki MB, Zullo AJ, Der CJ, Konieczny SF, Taparowsky EJ | title = Identification and characterization of rain, a novel Ras-interacting protein with a unique subcellular localization | journal = The Journal of Biological Chemistry | volume = 279 | issue = 21 | pages = 22353–61 | date = May 2004 | pmid = 15031288 | doi = 10.1074/jbc.M312867200 | doi-access = free }}
• {{cite journal | vauthors = Roberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi VA, Li L, Yassin Y, Tamburino AM, Neel BG, Kucherlapati RS | title = Germline gain-of-function mutations in SOS1 cause Noonan syndrome | journal = Nature Genetics | volume = 39 | issue = 1 | pages = 70–4 | date = January 2007 | pmid = 17143285 | doi = 10.1038/ng1926 | s2cid = 10222262 }}
• {{cite journal | vauthors = Yoshikawa Y, Satoh T, Tamura T, Wei P, Bilasy SE, Edamatsu H, Aiba A, Katagiri K, Kinashi T, Nakao K, Kataoka T | title = The M-Ras-RA-GEF-2-Rap1 pathway mediates tumor necrosis factor-alpha dependent regulation of integrin activation in splenocytes | journal = Molecular Biology of the Cell | volume = 18 | issue = 8 | pages = 2949–59 | date = August 2007 | pmid = 17538012 | pmc = 1949361 | doi = 10.1091/mbc.E07-03-0250 }}

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