G-protein signaling G-Protein beta/gamma signaling cascades
G-protein beta/gamma signaling G proteins are critical cellular signal transducers for a variety ofcell surface receptors. G-protein coupled receptors interact with the trimericG-protein alpha-s/beta/gamma complex and trigger the exchange of GDP to GTP boundto G-protein alpha subunits leading to the dissociation of beta/gammaheterodimers. Both G-protein alpha and G-protein beta/gamma subunits ofcomplex are able to transduce receptor signaling independently as well. For instance,G-protein beta/gamma subunits regulate caveolae-mediated endocytosis activity andtransendothelial albumin transport via transcytosis by inducing v-src sarcoma(Schmidt-Ruppin A-2) viral oncogene homolog ( c-Src )-mediated tyrosinephosphorylation and subsequent association of endocytic traffic proteins, Caveolin 1,caveolae protein, 22kDa ( Caveolin-1 ) and Dynamin-2 . Another function of G-protein beta/gamma subunits is theactivation of Mitogen-activated protein kinase 1-3 ( ERK1/2 ) pathway via thec-Src activation where c-Src activates ERK1/2 throughphosphorylation of adaptor protein SHC (Src homology 2 domain containing) transformingprotein 1 ( Shc ), and recruitment of adaptor protein Growth factor receptor-boundprotein 2 ( GRB2 ) and Son of sevenless homolog ( SOS ). G-protein beta/gamma signaling also regulates phosphoinositidemetabolism by increasing the kinase activity of Bruton agammaglobulinemia tyrosine kinase( Btk ), a known activator of Phospholipase C, gamma ( PLC-gamma )  or by direct activation of Phospholipase C, beta 2 ( PLC-beta2 ).PLC-gamma and PLC-beta2 catalyze hydrolysis of phosphoinositide4,5-bisphosphate ( PtdIns(4,5)P2) to form inositol 1,4,5-triphosphate ( IP3) and 1,2-diacyl-glycerol ( DAG ). The G-protein beta/gammaheterodimers also activate Phosphoinositide-3-kinase, regulatory subunit 5 ( PI3K regclass IB (p101) ) that leads to Phosphoinositide-3-kinase, catalytic, gammapolypeptide ( PI3K cat class IB (p110-gamma) ) -mediated conversion ofphosphatidylinositol 4,5-biphosphate ( PtdIns(4,5)P2 ) to phosphatidylinositol3,4,5-triphosphate ( PtdIns(3,4,5)P3 ) . PtdIns(3,4,5)P3 isa second messenger that directly binds to 3-phosphoinositide dependent protein kinase-1 (PDK(PDPK1) ) and V-akt murine thymoma viral oncogene homolog 1 ( AKT(PKB)). PDK(PDPK1) phosphorylates AKT(PKB) and activates AKT signaling. G-proteins beta/gamma can regulate Adenylate cyclase 2 ( Adenylate cyclasetype II ) and Adenylate cyclase 5 ( Adenylate cyclase type V ) activity.Adenylate cyclases increase level of cAMP in cells and activate Proteinkinase, cAMP-dependent, regulatory ( PKA-reg (cAMP-dependent) ) that results inProtein kinase, cAMP-dependent, catalytic ( PKA-cat (cAMP-dependent) ) activation. Regulator of G-protein signaling 3 ( RGS3 ) binds G-proteinbeta/gamma subunits and limits their ability to trigger the production of inositolphosphates and the activation of AKT(PKB) and ERK1/2 signaling .