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
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 .
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 ) , , , . CALDAG-GEFII and CALDAG-GEFIII can be activated by increased Ca(2+) cytosol and DAG levels , , . RASGRF1 is activated by Lymphocyte-specific protein tyrosine kinase ( Lck ) phosphorylation , , .
Known GAP for M-RAS is RAS p21 protein activator 1 ( p120GAP ) . Breakpoint cluster region ( BCR ) via Docking protein 1 and 2 ( DOK1 and DOK2 ) phosphorylation stimulates GAP activity of p120GAP , . Binding of RAP1A member of RAS oncogene family ( RAP-1A ) and V-src sarcoma ( c-Src ) phosphorylation suppress GAP activity of p120GAP , . 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 . Another known M-RAS GAP is Neurofibromin 1 ( Neurofibromin ) .
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 , .