GMF, IP3 receptor, Calmodulin, Ca('2+) endoplasmic reticulum lumen, PKA-reg (cAMP-dependent), MEK1(MAP2K1), PKA-cat (cAMP-dependent), MR-GEF, c-Raf-1, PtdIns(4,5)P2, CaMK II, M-Ras, Pyk2(FAK2), PLC-beta, G-protein alpha-12 family, MEK2(MAP2K2), Rap1GAP1, RAP-1A, cAMP, SOS, R-Ras, RASA2, G-protein alpha-i family, IP3, H-Ras, B-Raf, Shc, Adenylate cyclase type I, cAMP-GEFI, None, G-protein alpha-q/11, Elk-1, PKC-epsilon, ERK1 (MAPK3), c-Src, DAG, ATP cytosol, 18.104.22.168, c-Fos, Ca('2+) cytosol, GRB2, SynGAP, 22.214.171.124, G-protein beta/gamma, ERK2 (MAPK1), G-protein alpha-s
G-protein-mediated regulation of MARK-ERK signaling
Guanine nucleotide binding protein ( G-proteins ) are heterotrimeric signaling molecules composed of three subunits, alpha, beta, and gamma, which dissociate receptor-induced exchange on the alpha subunit and beta/gamma heterodimer subunit. The G-protein-coupled receptors (GPCRs) initiate diverse downstream signaling 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 are capable of initiation of various downstream signaling pathways. One of distinct GPCR-induced intracellular Mitogen-activated protein kinase (MAPK) cascades are Extracellular signal-regulated kinases ( ERK ) cascade. However, each of the G-protein s seems to use a different mechanism for this purpose .
G-protein alpha-i induces downstream signaling via direct interaction with V-src sarcoma viral oncogene homolog ( c-Src ) kinase and RAP1GAP RAP1 GTPase activating protein ( RAP1GAP1 ) protein. G-protein alpha-i stimulates kinase activity of c-Src, by binding to its catalytic domain, which leads to conformation change of c-Src. In turn, c-Src activates v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-RAS )/V-raf-1 murine leukemia viral oncogene homolog ( c-Raf ) / Mitogen-activated protein kinase kinase 1 and 2 ( MEK1 and MEK2 )/ ERK pathway through phosphorylation of adaptor protein SHC transforming protein ( Shc ) , and recruitment of adaptor protein Growth factor receptor-bound protein 2 ( GRB2 ) and positive regulator of Son of sevenless homolog ( SOS ). Activation of MEK/ ERK pathway leads to cell proliferation via phosphorylation of transcription factors ELK1 member of ETS oncogene family ( Elk-1 ) and V-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ). G-protein alpha-i activates 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 . G-protein alpha-i inhibits activity of several Adenylate cyclases (such as Adenylate cyclase I ) and decreases levels of Cyclic Adenosine 3',5'-phosphate ( cAMP ) in cell. As a result, they activate MEK/ERK pathway via decreasing of RAP-1A activity by Rho guanine nucleotide exchange factor 1 ( ARH-GEF1 ), and Glia maturation factor beta ( GMF ) activity by Protein kinase A ( PKA ) .
Unlike G-protein alpha-i, G-protein alpha-s activates Adenylate 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 by ARH-GEF1/ RAP-1A signaling. In several cell types MEK/ ERK pathway signaling is inhibited by PKA kinase via GMF .
A well-established signaling pathway for G-protein alpha-q/11 is activation of Phospholipase C beta ( PLC-beta ), which catalyzes hydrolysis of Phosphoinositide 4,5-bisphosphate ( PtdIns(4,5)P2 ) to form Inositol 1,4,5-triphosphate ( IP3 ) and Diacylglycerol ( DAG ). The IP3 released 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 protein cascade GRB2/ SOS/ H-RAS/ c-RAF1/ MEK/ ERK. Free Ca(II) can activate CaM kinase II ( CaMK II ), which further phosphorylates and inhibits RAS-GTPase-activating protein ( SynGAP ) and induces MEK/ ERK activation .
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 returns them to the GDP-bound form, thereby inhibiting such small GTPases like M-Ras and R-Ras. As a result, R-Ras is incapable of activating c-Raf-1, and M-Ras is incapable of inhibiting MR-GEF. MR-GEF activates B-Raf and inhibits c-Raf-1 via RAP-1A transformation .
G-protein beta/gamma subunits activate MEK/ ERK pathway via activation of c-Src. c-Src activates ERK pathway through phosphorylation of Shc, and recruitment of GRB2 and SOS .