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 smallGTPases which mediates cell differentiation, survival and oncogenic transformation , , , . Guanine nucleotide exchange factors (GEFs) are essential for M-RAS activationby promoting GTP loading on M-RAS. GTPase activating proteins (GAPs) negativelyregulates 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 guaninenucleotide-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 activityof p120GAP , . RAS p21 protein activator 2 (RASA2 ) also exhibits GAP activity towards M-RAS. RASA2 isactivated by Inositol 1,3,4,5-tetrakisphosphate binding or G-protein alpha-12family signaling . Another known M-RAS GAP is Neurofibromin 1( Neurofibromin ) . GTP-bound M-RAS can stimulate the Raf kinase family members v-raf-1 murineleukemia viral oncogene homolog 1 ( c-Raf-1), v-raf murine sarcoma viral oncogenehomolog 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 , .