Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
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Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
Inorganic ion
Predicted metabolite or user's structure
Generic receptor
Receptors with enzyme activity

Normal process
Pathological process
Covalent modifications
Transcription regulation
MicroRNA binding
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

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].