Ras-related protein M-Ras, also known as muscle RAS oncogene homolog and R-Ras3, is aprotein that in humans is encoded by theMRASgene onchromosome 3.[5][6][7] It is ubiquitously expressed in many tissues and cell types.[8] This protein functions as asignal transducer for a wide variety of signaling pathways, including those promotingneural andbone formation as well astumor growth.[9][10][11][12] TheMRAS gene also contains one of 27SNPs associated with increased risk ofcoronary artery disease.[13]
M-Ras is a member of thesmall GTPase superfamily under theRas family, which also includesRap1, Rap2,R-Ras, andR-Ras2 (TC21).[14] This protein spans a length of 209residues. ItsN-terminal amino acid sequence shares 60-75% identity with that in theRas protein while itseffector region is identical with that in Ras. M-Ras shares a similar structure withH-Ras andRap2A 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.[15]
The MRAS gene is expressed specifically inbrain,heart,myoblasts,myotubes,fibroblasts,skeletal muscles, anduterus, suggesting a specific role of M-Ras in these tissue and cells.[16][17] M-Ras is involved in many biological processes by activating a wide variety of proteins. For instance, it is activated by Rasguanine nucleotide exchange factors and can bind/activate some Ras protein effectors.[18] M-Ras also weakly stimulates themitogen-activated protein kinase (MAPK) activity andERK2 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.[17][19] M-Ras has been found to induceAkt kinase activity in thePI3-K pathway, and it may play a role in cell survival of neural-derived cells.[20] Moreover, M-Ras plays a crucial role in the downregulation ofOCT4 andNANOG protein levels upon differentiation and has been demonstrated to modulate cell fate at early steps of development duringneurogenesis.[21] M-Ras, induced and activated byBMP-2 signaling, also participates in the osteoblastic determination, differentiation, and transdifferentiation underp38 MAPK andJNK regulation.[22] M-Ras is involved inTNF-alpha-stimulated andRap1-mediatedLFA-1 activation insplenocytes.[23] More generally, cells transfected with M-Ras exhibit dendritic appearances with microspikes, suggesting that M-Ras may participate in reorganization of theactincytoskeleton.[16] In addition, it is reported that M-Ras forms a complex withSCRIB andSHOC2, a polarity protein with tumor suppressor properties, and may play a key role in tumorigenic growth.[24]
In humans, other members of the Ras subfamilies carry mutations in human cancers.[25] Furthermore, the Ras proteins are not only involved in tumorigenesis but also in many developmental disorders.[25] 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.[26][27][28][29] 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.[30]
A multi-locus genetic risk score study based on a combination of 27 loci, including theMRAS 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).[31]
^Kimmelman AC, Osada M, Chan AM (April 2000). "R-Ras3, a brain-specific Ras-related protein, activates Akt and promotes cell survival in PC12 cells".Oncogene.19 (16):2014–22.doi:10.1038/sj.onc.1203530.PMID10803462.S2CID25048933.
^Watanabe-Takano H, Takano K, Keduka E, Endo T (February 2010). "M-Ras is activated by bone morphogenetic protein-2 and participates in osteoblastic determination, differentiation, and transdifferentiation".Experimental Cell Research.316 (3):477–90.doi:10.1016/j.yexcr.2009.09.028.PMID19800879.
^abMatsumoto K, Asano T, Endo T (November 1997). "Novel small GTPase M-Ras participates in reorganization of actin cytoskeleton".Oncogene.15 (20):2409–17.doi:10.1038/sj.onc.1201416.PMID9395237.S2CID12357144.
^Kimmelman AC, Osada M, Chan AM (April 2000). "R-Ras3, a brain-specific Ras-related protein, activates Akt and promotes cell survival in PC12 cells".Oncogene.19 (16):2014–22.doi:10.1038/sj.onc.1203530.PMID10803462.S2CID25048933.
^Watanabe-Takano H, Takano K, Keduka E, Endo T (February 2010). "M-Ras is activated by bone morphogenetic protein-2 and participates in osteoblastic determination, differentiation, and transdifferentiation".Experimental Cell Research.316 (3):477–90.doi:10.1016/j.yexcr.2009.09.028.PMID19800879.
^Cox AD, Brtva TR, Lowe DG, Der CJ (November 1994). "R-Ras induces malignant, but not morphologic, transformation of NIH3T3 cells".Oncogene.9 (11):3281–8.PMID7936652.
^Huang Y, Saez R, Chao L, Santos E, Aaronson SA, Chan AM (October 1995). "A novel insertional mutation in the TC21 gene activates its transforming activity in a human leiomyosarcoma cell line".Oncogene.11 (7):1255–60.PMID7478545.
^Ortiz-Vega S, Khokhlatchev A, Nedwidek M, Zhang XF, Dammann R, Pfeifer GP, Avruch J (February 2002). "The putative tumor suppressor RASSF1A homodimerizes and heterodimerizes with the Ras-GTP binding protein Nore1".Oncogene.21 (9):1381–90.doi:10.1038/sj.onc.1205192.PMID11857081.S2CID240243.
^Ehrhardt GR, Leslie KB, Lee F, Wieler JS, Schrader JW (October 1999). "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".Blood.94 (7):2433–44.doi:10.1182/blood.V94.7.2433.419k31_2433_2444.PMID10498616.S2CID40024826.
Matsumoto K, Asano T, Endo T (November 1997). "Novel small GTPase M-Ras participates in reorganization of actin cytoskeleton".Oncogene.15 (20):2409–17.doi:10.1038/sj.onc.1201416.PMID9395237.S2CID12357144.
Louahed J, Grasso L, De Smet C, Van Roost E, Wildmann C, Nicolaides NC, Levitt RC, Renauld JC (September 1999). "Interleukin-9-induced expression of M-Ras/R-Ras3 oncogene in T-helper clones".Blood.94 (5):1701–10.doi:10.1182/blood.V94.5.1701.PMID10477695.
Ehrhardt GR, Leslie KB, Lee F, Wieler JS, Schrader JW (October 1999). "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".Blood.94 (7):2433–44.doi:10.1182/blood.V94.7.2433.419k31_2433_2444.PMID10498616.S2CID40024826.
Kimmelman AC, Osada M, Chan AM (April 2000). "R-Ras3, a brain-specific Ras-related protein, activates Akt and promotes cell survival in PC12 cells".Oncogene.19 (16):2014–22.doi:10.1038/sj.onc.1203530.PMID10803462.S2CID25048933.
Ortiz-Vega S, Khokhlatchev A, Nedwidek M, Zhang XF, Dammann R, Pfeifer GP, Avruch J (February 2002). "The putative tumor suppressor RASSF1A homodimerizes and heterodimerizes with the Ras-GTP binding protein Nore1".Oncogene.21 (9):1381–90.doi:10.1038/sj.onc.1205192.PMID11857081.S2CID240243.
Roberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi VA, Li L, Yassin Y, Tamburino AM, Neel BG, Kucherlapati RS (January 2007). "Germline gain-of-function mutations in SOS1 cause Noonan syndrome".Nature Genetics.39 (1):70–4.doi:10.1038/ng1926.PMID17143285.S2CID10222262.
