Pathway Map Details

G-protein signaling_M-RAS regulation pathway

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RASGRF1, CalDAG-GEFII, DAG, M-RAS, Inositol 1,3,4,5-tetrakisphosphate cytosol, A-Raf-1, MEK1(MAP2K1), MEK2(MAP2K2), SOS, c-Src, c-Raf-1, B-Raf, G-protein alpha-12 family, Neurofibromin, RASA2, DOK2, DOK1, LCK, ERK1/2, BCR, CalDAG-GEFIII, p120GAP, RAP-1A, Ca('2+) cytosol


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 ) [6], [7], [5], [8]. CALDAG-GEFII and CALDAG-GEFIII can be activated by increased Ca(2+) cytosol and DAG levels [7], [9], [5]. 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 [11], [5]. Binding of RAP1A member of RAS oncogene family ( RAP-1A ) and V-src sarcoma ( c-Src ) phosphorylation suppress GAP activity of p120GAP [12], [10]. 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].


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    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