MRAS

Last updated
MRAS
Protein MRAS PDB 1x1r.png
Identifiers
Aliases MRAS , M-RAs, R-RAS3, RRAS3, muscle RAS oncogene homolog, NS11
External IDs OMIM: 608435 MGI: 1100856 HomoloGene: 7424 GeneCards: MRAS
Orthologs
SpeciesHumanMouse
Entrez

22808

17532

Ensembl

ENSG00000158186

ENSMUSG00000032470

UniProt

O14807

O08989

RefSeq (mRNA)

NM_008624

RefSeq (protein)

NP_032650

Location (UCSC) Chr 3: 138.35 – 138.41 Mb Chr 9: 99.27 – 99.32 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Ras-related protein M-Ras, also known as muscle RAS oncogene homolog and R-Ras3, is a protein that in humans is encoded by the MRAS gene on chromosome 3. [5] [6] [7] It is ubiquitously expressed in many tissues and cell types. [8] This protein functions as a signal transducer for a wide variety of signaling pathways, including those promoting neural and bone formation as well as tumor growth. [9] [10] [11] [12] The MRAS gene also contains one of 27 SNPs associated with increased risk of coronary artery disease. [13]

Contents

Structure

Gene

The MRAS gene resides on chromosome 3 at the band 3q22.3 and includes 10 exons. [7] This gene produces 2 isoforms through alternative splicing. [14]

Protein

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). [14] 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. [15]

Function

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. [16] [17] 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. [18] 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. [17] [19] 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. [20] 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. [21] M-Ras, induced and activated by BMP-2 signaling, also participates in the osteoblastic determination, differentiation, and transdifferentiation under p38 MAPK and JNK regulation. [22] M-Ras is involved in TNF-alpha-stimulated and Rap1-mediated LFA-1 activation in splenocytes. [23] More generally, cells transfected with M-Ras exhibit dendritic appearances with microspikes, suggesting that M-Ras may participate in reorganization of the actin cytoskeleton. [16] 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. [24]

Clinical significance

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]

Clinical marker

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). [31]

Interactions

MRAS has been shown to interact with RASSF5 [32] and RALGDS. [5] [33]

Related Research Articles

<span class="mw-page-title-main">RAS p21 protein activator 1</span> Protein-coding gene in the species Homo sapiens

RAS p21 protein activator 1 or RasGAP, also known as RASA1, is a 120-kDa cytosolic human protein that provides two principal activities:

<span class="mw-page-title-main">GRB2-associated-binding protein 1</span> Protein-coding gene in the species Homo sapiens

GRB2-associated-binding protein 1 is a protein that in humans is encoded by the GAB1 gene.

<span class="mw-page-title-main">RAPGEF1</span> Protein-coding gene in the species Homo sapiens

Rap guanine nucleotide exchange factor 1 is a protein that in humans is encoded by the RAPGEF1 gene.

<span class="mw-page-title-main">RAC3</span> Mammalian protein found in Homo sapiens

Ras-related C3 botulinum toxin substrate 3 (Rac3) is a G protein that in humans is encoded by the RAC3 gene. It is an important component of intracellular signalling pathways. Rac3 is a member of the Rac subfamily of the Rho family of small G proteins. Members of this superfamily appear to regulate a diverse array of cellular events, including the control of cell growth, cytoskeletal reorganization, and the activation of protein kinases.

<span class="mw-page-title-main">AKAP13</span> Protein-coding gene in the species Homo sapiens

A-kinase anchor protein 13 is a protein that in humans, is encoded by the AKAP13 gene. This protein is also called AKAP-Lbc because it encodes the lymphocyte blast crisis (Lbc) oncogene, and ARHGEF13/RhoGEF13 because it contains a guanine nucleotide exchange factor (GEF) domain for the RhoA small GTP-binding protein.

<span class="mw-page-title-main">RALGDS</span> Protein-coding gene in the species Homo sapiens

Ral guanine nucleotide dissociation stimulator is a protein that is encoded by the RALGDS gene in humans.

<span class="mw-page-title-main">RRAS</span> Protein-coding gene in the species Homo sapiens

Ras-related protein R-Ras is a protein that in humans is encoded by the RRAS gene.

<span class="mw-page-title-main">RAP2A</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rap-2a is a protein that in humans is encoded by the RAP2A gene. RAP2A is a member of the Ras-related protein family.

<span class="mw-page-title-main">RASSF5</span> Protein-coding gene in the species Homo sapiens

Ras association domain-containing protein 5 is a protein that in humans is encoded by the RASSF5 or F5 gene.

<span class="mw-page-title-main">ARHGEF1</span> Protein-coding gene in the species Homo sapiens

Rho guanine nucleotide exchange factor 1 is a protein that in humans is encoded by the ARHGEF1 gene. This protein is also called RhoGEF1 or p115-RhoGEF.

<span class="mw-page-title-main">RRAS2</span> Protein-coding gene in the species Homo sapiens

Ras-related protein R-Ras2 is a protein that in humans is encoded by the RRAS2 gene.

<span class="mw-page-title-main">ARHGEF12</span> Protein-coding gene in the species Homo sapiens

Rho guanine nucleotide exchange factor 12 is a protein that in humans is encoded by the ARHGEF12 gene. This protein is also called RhoGEF12 or Leukemia-associated Rho guanine nucleotide exchange factor (LARG).

<span class="mw-page-title-main">RhoG</span> Protein-coding gene in the species Homo sapiens

RhoG is a small monomeric GTP-binding protein, and is an important component of many intracellular signalling pathways. It is a member of the Rac subfamily of the Rho family of small G proteins and is encoded by the gene RHOG.

<span class="mw-page-title-main">SHC3</span> Protein-coding gene in the species Homo sapiens

SHC-transforming protein 3 is a protein that in humans is encoded by the SHC3 gene.

<span class="mw-page-title-main">RALB</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Ral-B (RalB) is a protein that in humans is encoded by the RALB gene on chromosome 2. This protein is one of two paralogs of the Ral protein, the other being RalA, and part of the Ras GTPase family. RalA functions as a molecular switch to activate a number of biological processes, majorly cell division and transport, via signaling pathways. Its biological role thus implicates it in many cancers.

<span class="mw-page-title-main">RAP2B</span> Protein-coding gene in the species Homo sapiens

Ras-related protein Rap-2b is a protein that in humans is encoded by the RAP2B gene. RAP2B belongs to the Ras-related protein family.

<span class="mw-page-title-main">VAV3</span> Protein-coding gene in the species Homo sapiens

Guanine nucleotide exchange factor VAV3 is a protein that in humans is encoded by the VAV3 gene.

<span class="mw-page-title-main">RAPGEF2</span> Protein-coding gene in the species Homo sapiens

Rap guanine nucleotide exchange factor 2 is a protein that in humans is encoded by the RAPGEF2 gene.

<span class="mw-page-title-main">RAP1GDS1</span> Protein-coding gene in the species Homo sapiens

Rap1 GTPase-GDP dissociation stimulator 1 is an enzyme that in humans is encoded by the RAP1GDS1 gene.

<span class="mw-page-title-main">RAPGEF5</span> Protein-coding gene in the species Homo sapiens

Rap guanine nucleotide exchange factor 5 is a protein that in humans is encoded by the RAPGEF5 gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000158186 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000032470 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 Kimmelman A, Tolkacheva T, Lorenzi MV, Osada M, Chan AM (November 1997). "Identification and characterization of R-ras3: a novel member of the RAS gene family with a non-ubiquitous pattern of tissue distribution". Oncogene. 15 (22): 2675–85. doi: 10.1038/sj.onc.1201674 . PMID   9400994.
  6. ↑ Quilliam LA, Castro AF, Rogers-Graham KS, Martin CB, Der CJ, Bi C (August 1999). "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". The Journal of Biological Chemistry. 274 (34): 23850–7. doi: 10.1074/jbc.274.34.23850 . PMID   10446149.
  7. 1 2 "Entrez Gene: MRAS muscle RAS oncogene homolog".
  8. ↑ "BioGPS - your Gene Portal System". biogps.org. Retrieved 2016-10-10.[ permanent dead link ]
  9. ↑ 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. PMID   10803462.
  10. ↑ Mathieu ME, Faucheux C, Saucourt C, Soulet F, Gauthereau X, Fédou S, Trouillas M, Thézé N, Thiébaud P, Boeuf H (August 2013). "MRAS GTPase is a novel stemness marker that impacts mouse embryonic stem cell plasticity and Xenopus embryonic cell fate". Development. 140 (16): 3311–22. doi: 10.1242/dev.091082 . PMID   23863483.
  11. ↑ 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. PMID   19800879.
  12. ↑ 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 (December 2013). "An MRAS, SHOC2, and SCRIB complex coordinates ERK pathway activation with polarity and tumorigenic growth". Molecular Cell. 52 (5): 679–92. doi: 10.1016/j.molcel.2013.10.004 . PMID   24211266.
  13. ↑ 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 (June 2015). "Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials". Lancet. 385 (9984): 2264–71. doi:10.1016/S0140-6736(14)61730-X. PMC   4608367 . PMID   25748612.
  14. 1 2 "MRAS - Ras-related protein M-Ras precursor - Homo sapiens (Human) - MRAS gene & protein". www.uniprot.org. Retrieved 2016-10-10.
  15. ↑ Ye M, Shima F, Muraoka S, Liao J, Okamoto H, Yamamoto M, Tamura A, Yagi N, Ueki T, Kataoka T (September 2005). "Crystal structure of M-Ras reveals a GTP-bound "off" state conformation of Ras family small GTPases". The Journal of Biological Chemistry. 280 (35): 31267–75. doi: 10.1074/jbc.M505503200 . PMID   15994326.
  16. 1 2 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. PMID   9395237.
  17. 1 2 Kimmelman A, Tolkacheva T, Lorenzi MV, Osada M, Chan AM (November 1997). "Identification and characterization of R-ras3: a novel member of the RAS gene family with a non-ubiquitous pattern of tissue distribution". Oncogene. 15 (22): 2675–85. doi: 10.1038/sj.onc.1201674 . PMID   9400994.
  18. ↑ Rebhun JF, Castro AF, Quilliam LA (November 2000). "Identification of guanine nucleotide exchange factors (GEFs) for the Rap1 GTPase. Regulation of MR-GEF by M-Ras-GTP interaction". The Journal of Biological Chemistry. 275 (45): 34901–8. doi: 10.1074/jbc.M005327200 . PMID   10934204.
  19. ↑ Quilliam LA, Castro AF, Rogers-Graham KS, Martin CB, Der CJ, Bi C (August 1999). "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". The Journal of Biological Chemistry. 274 (34): 23850–7. doi: 10.1074/jbc.274.34.23850 . PMID   10446149.
  20. ↑ 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. PMID   10803462.
  21. ↑ Mathieu ME, Faucheux C, Saucourt C, Soulet F, Gauthereau X, Fédou S, Trouillas M, Thézé N, Thiébaud P, Boeuf H (August 2013). "MRAS GTPase is a novel stemness marker that impacts mouse embryonic stem cell plasticity and Xenopus embryonic cell fate". Development. 140 (16): 3311–22. doi: 10.1242/dev.091082 . PMID   23863483.
  22. ↑ 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. PMID   19800879.
  23. ↑ Yoshikawa Y, Satoh T, Tamura T, Wei P, Bilasy SE, Edamatsu H, Aiba A, Katagiri K, Kinashi T, Nakao K, Kataoka T (August 2007). "The M-Ras-RA-GEF-2-Rap1 pathway mediates tumor necrosis factor-alpha dependent regulation of integrin activation in splenocytes". Molecular Biology of the Cell. 18 (8): 2949–59. doi:10.1091/mbc.E07-03-0250. PMC   1949361 . PMID   17538012.
  24. ↑ 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 (December 2013). "An MRAS, SHOC2, and SCRIB complex coordinates ERK pathway activation with polarity and tumorigenic growth". Molecular Cell. 52 (5): 679–92. doi: 10.1016/j.molcel.2013.10.004 . PMID   24211266.
  25. 1 2 Karnoub AE, Weinberg RA (July 2008). "Ras oncogenes: split personalities". Nature Reviews Molecular Cell Biology. 9 (7): 517–31. doi:10.1038/nrm2438. PMC   3915522 . PMID   18568040.
  26. ↑ Graham SM, Oldham SM, Martin CB, Drugan JK, Zohn IE, Campbell S, Der CJ (March 1999). "TC21 and Ras share indistinguishable transforming and differentiating activities". Oncogene. 18 (12): 2107–16. doi: 10.1038/sj.onc.1202517 . PMID   10321735.
  27. ↑ 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. PMID   7936652.
  28. ↑ Chan AM, Miki T, Meyers KA, Aaronson SA (August 1994). "A human oncogene of the RAS superfamily unmasked by expression cDNA cloning". Proceedings of the National Academy of Sciences of the United States of America. 91 (16): 7558–62. Bibcode:1994PNAS...91.7558C. doi: 10.1073/pnas.91.16.7558 . PMC   44441 . PMID   8052619.
  29. ↑ 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. PMID   7478545.
  30. ↑ Gutierrez-Erlandsson S, Herrero-Vidal P, Fernandez-Alfara M, Hernandez-Garcia S, Gonzalo-Flores S, Mudarra-Rubio A, Fresno M, Cubelos B (2013-01-01). "R-RAS2 overexpression in tumors of the human central nervous system". Molecular Cancer. 12 (1): 127. doi: 10.1186/1476-4598-12-127 . PMC   3900289 . PMID   24148564.
  31. ↑ 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 (June 2015). "Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials". Lancet. 385 (9984): 2264–71. doi:10.1016/S0140-6736(14)61730-X. PMC   4608367 . PMID   25748612.
  32. ↑ 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. PMID   11857081.
  33. ↑ 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. PMID   10498616. S2CID   40024826.

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