G-protein signaling - G-Protein beta/gamma signaling cascades

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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

  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

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