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Development G-Proteins mediated regulation MARK-ERK signaling


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Development G-Proteins mediated regulation MARK-ERK signaling

G-protein-mediated regulation of MARK-ERK signaling

Guanine nucleotide binding protein ( G-proteins ) areheterotrimeric signaling molecules composed of three subunits, alpha, beta, and gamma,which dissociate receptor-induced exchange on the alpha subunit and beta/gammaheterodimer subunit. The G-protein-coupled receptors (GPCRs) initiate diverse downstreamsignaling cascades through 5 groups of G-proteins: G-protein alpha-i family,G-protein alpha-s, G-protein alpha-q/11, G-protein alpha12/13,G-protein beta/gamma. G-alpha and G-  protein beta/gamma arecapable of initiation of various downstream signaling pathways. One of distinctGPCR-induced intracellular Mitogen-activated protein kinase (MAPK) cascades areExtracellular signal-regulated kinases ( ERK ) cascade. However, each of theG-protein s seems to use a different mechanism for this purpose [1].

G-protein alpha-i induces downstream signaling via directinteraction with V-src sarcoma viral oncogene homolog ( c-Src ) kinase and RAP1GAPRAP1 GTPase activating protein ( RAP1GAP1 ) protein. G-proteinalpha-i stimulates kinase activity of c-Src, by binding to its catalyticdomain, which leads to conformation change of c-Src. In turn, c-Srcactivates v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-RAS )/V-raf-1murine leukemia viral oncogene homolog ( c-Raf ) / Mitogen-activatedprotein kinase kinase 1 and 2 ( MEK1 and MEK2 )/ ERK pathway throughphosphorylation of adaptor protein SHC transforming protein ( Shc ) , andrecruitment of adaptor protein Growth factor receptor-bound protein 2 ( GRB2 ) andpositive regulator of Son of sevenless homolog ( SOS ). Activation of MEK/ERK pathway leads to cell proliferation via phosphorylation of transcriptionfactors ELK1 member of ETS oncogene family ( Elk-1 ) and V-fos FBJ murineosteosarcoma viral oncogene homolog ( c-Fos ). G-protein alpha-iactivates MEK/ ERK pathway via activation of RAP1GAP1.RAP1GAP1 transforms RAP1A RAP1A member of RAS oncogene family ( RAP-1A )and inhibits v-raf murine sarcoma viral oncogene homolog B1 ( B-Raf )/ MEK/ ERK pathway [2]. G-protein alpha-i inhibits activity ofseveral Adenylate cyclases (such as Adenylate cyclase I ) and decreases levels ofCyclic Adenosine 3',5'-phosphate ( cAMP ) in cell. As a result, they activateMEK/ERK pathway via decreasing of RAP-1A activity by Rho guanine nucleotideexchange factor 1 ( ARH-GEF1 ), and Glia maturation factor beta ( GMF )activity by Protein kinase A ( PKA ) [3].

Unlike G-protein alpha-i, G-protein alpha-s activatesAdenylate cyclase I activity and increases cAMP level in cell. As a result,they activate MEK/ERK pathway via B-Raf, which, in turn, is activated byARH-GEF1/ RAP-1A signaling. In several cell types MEK/ ERKpathway signaling is inhibited by PKA kinase via GMF [4].

A well-established signaling pathway for G-protein alpha-q/11 isactivation of Phospholipase C beta ( PLC-beta ), which catalyzes hydrolysis ofPhosphoinositide 4,5-bisphosphate ( PtdIns(4,5)P2 ) to form Inositol1,4,5-triphosphate ( IP3 ) and Diacylglycerol ( DAG ). The IP3released into the cytoplasm mobilizes Calcium ( Ca(II) ) from internal stores,whereas DAG activates protein kinase C epsilon ( PKC-epsilon ).PKC-epsilon induces PTK2B protein tyrosine kinase 2 beta ( PYK2 )activation. PYK2 phosphorylates adaptor protein Shc and stimulates proteincascade GRB2/ SOS/ H-RAS/ c-RAF1/ MEK/ ERK. Free Ca(II) can activate CaM kinase II ( CaMK II ), which furtherphosphorylates and inhibits RAS-GTPase-activating protein ( SynGAP ) and inducesMEK/ ERK activation [5].

G-protein alpha-12 subunit activate B-Raf/ MEK/ERK pathway via direct binding to and stimulation of RAS p21 protein activator 2 (RASA2 ). RASA2 hydrolyzes the GTP-bound form of Ras proteins and returnsthem to the GDP-bound form, thereby inhibiting such small GTPases like M-Ras andR-Ras. As a result, R-Ras is incapable of activating c-Raf-1, andM-Ras is incapable of inhibiting MR-GEF. MR-GEF activatesB-Raf and inhibits c-Raf-1 via RAP-1A transformation [6].

G-protein beta/gamma subunits activate MEK/ ERKpathway via activation of c-Src. c-Src activates ERK pathwaythrough phosphorylation of Shc, and recruitment of GRB2 and SOS[7].