Pathway Map Details

G-protein signaling_G-Protein beta/gamma signaling cascades



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Object list (links open in MetaCore):

G-protein beta/gamma, PKA-reg (cAMP-dependent), PLC-beta2, SHC, PLC-gamma, AKT(PKB), 3.1.4.11, H-Ras, 2.7.1.137, IP3, Dynamin-2, PI3K cat class IB (p110-gamma), DAG, Adenylate cyclase type V, c-SRC, Adenylate cyclase type II, Btk, PKA-cat (cAMP-dependent), 4.6.1.1, G-protein alpha-15, MEK1/2, Erk (MAPK1/3), PDK (PDPK1), PI(3,4,5)P3, GRB2, Caveolin-1, PI(4,5)P2, SOS, PI3K reg class IB (p101), ATP, RGS3, cAMP

Description:

G-protein beta/gamma signaling

G proteins are critical cellular signal transducers for a variety of cell surface receptors. G-protein coupled receptors interact with the trimeric G-protein alpha-s/beta/gamma complex and trigger the exchange of GDP to GTP bound to G-protein alpha subunits leading to the dissociation of beta/gamma heterodimers.

Both G-protein alpha and G-protein beta/gamma subunits of complex are able to transduce receptor signaling independently as well. For instance, G-protein beta/gamma subunits regulate caveolae-mediated endocytosis activity and transendothelial albumin transport via transcytosis by inducing v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog ( c-Src )-mediated tyrosine phosphorylation and subsequent association of endocytic traffic proteins, Caveolin 1, caveolae protein, 22kDa ( Caveolin-1 ) and Dynamin-2 [1].

Another function of G-protein beta/gamma subunits is the activation of Mitogen-activated protein kinase 1-3 ( ERK1/2 ) pathway via the c-Src activation where c-Src activates ERK1/2 through phosphorylation of adaptor protein SHC (Src homology 2 domain containing) transforming protein 1 ( Shc ), and recruitment of adaptor protein Growth factor receptor-bound protein 2 ( GRB2 ) and Son of sevenless homolog ( SOS ).

G-protein beta/gamma signaling also regulates phosphoinositide metabolism by increasing the kinase activity of Bruton agammaglobulinemia tyrosine kinase ( Btk ), a known activator of Phospholipase C, gamma ( PLC-gamma ) [2] or by direct activation of Phospholipase C, beta 2 ( PLC-beta2 ). PLC-gamma and PLC-beta2 catalyze hydrolysis of phosphoinositide 4,5-bisphosphate ( PtdIns(4,5)P2) to form inositol 1,4,5-triphosphate ( IP3 ) and 1,2-diacyl-glycerol ( DAG ). The G-protein beta/gamma heterodimers also activate Phosphoinositide-3-kinase, regulatory subunit 5 ( PI3K reg class IB (p101) ) that leads to Phosphoinositide-3-kinase, catalytic, gamma polypeptide ( PI3K cat class IB (p110-gamma) ) -mediated conversion of phosphatidylinositol 4,5-biphosphate ( PtdIns(4,5)P2 ) to phosphatidylinositol 3,4,5-triphosphate ( PtdIns(3,4,5)P3 ) [3]. PtdIns(3,4,5)P3 is a 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 [4].

G-proteins beta/gamma can regulate Adenylate cyclase 2 ( Adenylate cyclase type II ) and Adenylate cyclase 5 ( Adenylate cyclase type V ) activity. Adenylate cyclases increase level of cAMP in cells and activate Protein kinase, cAMP-dependent, regulatory ( PKA-reg (cAMP-dependent) ) that results in Protein kinase, cAMP-dependent, catalytic ( PKA-cat (cAMP-dependent) ) activation [5].

Regulator of G-protein signaling 3 ( RGS3 ) binds G-protein beta/gamma subunits and limits their ability to trigger the production of inositol phosphates and the activation of AKT(PKB) and ERK1/2 signaling [6].

References:

  1. Shajahan AN, Tiruppathi C, Smrcka AV, Malik AB, Minshall RD
    Gbetagamma activation of Src induces caveolae-mediated endocytosis in endothelial cells. The Journal of biological chemistry 2004 Nov 12;279(46):48055-62
  2. Lowry WE, Huang XY
    G Protein beta gamma subunits act on the catalytic domain to stimulate Bruton's agammaglobulinemia tyrosine kinase. The Journal of biological chemistry 2002 Jan 11;277(2):1488-92
  3. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
    Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annual review of cell and developmental biology 2001;17:615-75
  4. Igarashi J, Michel T
    Sphingosine 1-phosphate and isoform-specific activation of phosphoinositide 3-kinase beta. Evidence for divergence and convergence of receptor-regulated endothelial nitric-oxide synthase signaling pathways. The Journal of biological chemistry 2001 Sep 28;276(39):36281-8
  5. Defer N, Best-Belpomme M, Hanoune J
    Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase. American journal of physiology. Renal physiology. 2000 Sep;279(3):F400-16
  6. Shi CS, Lee SB, Sinnarajah S, Dessauer CW, Rhee SG, Kehrl JH
    Regulator of G-protein signaling 3 (RGS3) inhibits Gbeta1gamma 2-induced inositol phosphate production, mitogen-activated protein kinase activation, and Akt activation. The Journal of biological chemistry 2001 Jun 29;276(26):24293-300