G-protein signaling - M-RAS regulation pathway

M-RAS regulation pathway

Muscle RAS oncogene homolog (M-RAS) is a novel member of Ras family of small GTPases which mediates cell differentiation, survival and oncogenic transformation [1], [2], [3], [4].

Guanine nucleotide exchange factors (GEFs) are essential for M-RAS activation by promoting GTP loading on M-RAS. GTPase activating proteins (GAPs) negatively regulates M-RAS activity by stimulating hydrolysis of GTP to GDP [5].

Main GEFs for M-RAS are: RAS guanyl releasing proteins 1 and 3 (CALDAG-GEFII and CALDAG-GEFIII), Ras protein-specific guanine nucleotide-releasing factor 1 (RASGRF1) and Son of sevenless homolog (SOS) [5], [6], [7], [8]. CALDAG-GEFII and CALDAG-GEFIII can be activated by increased Ca(2+) cytosol and DAG levels [5], [7], [9]. RASGRF1 is activated by Lymphocyte-specific protein tyrosine kinase (Lck) phosphorylation [6], [7], [10].

Known GAP for M-RAS is RAS p21 protein activator 1 (p120GAP) [7]. Breakpoint cluster region (BCR) via Docking protein 1 and 2 (DOK1 and DOK2) phosphorylation stimulates GAP activity of p120GAP [5], [11]. Binding of RAP1A member of RAS oncogene family (RAP-1A) and V-src sarcoma (c-Src) phosphorylation suppress GAP activity of p120GAP [10], [12]. RAS p21 protein activator 2 (RASA2) also exhibits GAP activity towards M-RAS. RASA2 is activated by Inositol 1,3,4,5-tetrakisphosphate binding or G-protein alpha-12 family signaling [7]. Another known M-RAS GAP is Neurofibromin 1 (Neurofibromin) [7].

GTP-bound M-RAS can stimulate the Raf kinase family members v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1), v-raf murine sarcoma viral oncogene homolog B1 (B-Raf) and v-raf murine sarcoma 3611 viral oncogene homolog (A-Raf-1) and thus promote Mitogen-activated protein kinases 1, 3 (ERK1/2) activation [3], [13].

References:

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   R-Ras3, a brain-specific Ras-related protein, activates Akt and promotes cell survival in PC12 cells. Oncogene 2000 Apr 13;19(16):2014-22
3. Kimmelman AC, Nu?ez Rodriguez N, Chan AM
   R-Ras3/M-Ras induces neuronal differentiation of PC12 cells through cell-type-specific activation of the mitogen-activated protein kinase cascade. Molecular and cellular biology 2002 Aug;22(16):5946-61
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   Expression of activated M-Ras in hemopoietic stem cells initiates leukemogenic transformation, immortalization and preferential generation of mast cells. Oncogene 2006 Jul 13;25(30):4241-4
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   Ras and relatives--job sharing and networking keep an old family together. Experimental hematology 2002 Oct;30(10):1089-106
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   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 1999 Aug 20;274(34):23850-7
7. Ohba Y, Mochizuki N, Yamashita S, Chan AM, Schrader JW, Hattori S, Nagashima K, Matsuda M
   Regulatory proteins of R-Ras, TC21/R-Ras2, and M-Ras/R-Ras3. The Journal of biological chemistry 2000 Jun 30;275(26):20020-6
8. Ehrhardt A, David MD, Ehrhardt GR, Schrader JW
   Distinct mechanisms determine the patterns of differential activation of H-Ras, N-Ras, K-Ras 4B, and M-Ras by receptors for growth factors or antigen. Molecular and cellular biology 2004 Jul;24(14):6311-23
9. Cullen PJ, Lockyer PJ
   Integration of calcium and Ras signalling. Nature reviews. Molecular cell biology 2002 May;3(5):339-48
10. Giglione C, Gonfloni S, Parmeggiani A
    Differential actions of p60c-Src and Lck kinases on the Ras regulators p120-GAP and GDP/GTP exchange factor CDC25Mm. European journal of biochemistry / FEBS 2001 Jun;268(11):3275-83
11. Carpino N, Wisniewski D, Strife A, Marshak D, Kobayashi R, Stillman B, Clarkson B
    p62(dok): a constitutively tyrosine-phosphorylated, GAP-associated protein in chronic myelogenous leukemia progenitor cells. Cell 1997 Jan 24;88(2):197-204
12. Hata Y, Kikuchi A, Sasaki T, Schaber MD, Gibbs JB, Takai Y
    Inhibition of the ras p21 GTPase-activating protein-stimulated GTPase activity of c-Ha-ras p21 by smg p21 having the same putative effector domain as ras p21s. The Journal of biological chemistry 1990 May 5;265(13):7104-7
13. Rodriguez-Viciana P, Sabatier C, McCormick F
    Signaling specificity by Ras family GTPases is determined by the full spectrum of effectors they regulate. Molecular and cellular biology 2004 Jun;24(11):4943-54