G-protein signaling - G-Protein alpha-q signaling cascades

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G-Protein alpha-q signaling cascades

Activated Guanine nucleotide binding protein q receptors (G-protein alpha-q) receptors interaction with trimeric G-protein alpha-q/G-protein beta/gamma causes an exchange of GDP for GTP bound to G-protein alpha subunits, and leads to dissociation of the G-protein beta/gamma heterodimers.

Well-established G-protein alpha-q/11 signaling pathways are activation of Phospholipase C beta (PLC-beta) and activation, via kinase Bruton agammaglobulinemia tyrosine kinase (Btk), of Phospholipase C gamma (PLC-gamma), which catalyzes hydrolysis of Phosphoinositide 4,5-bisphosphate (PtdIns(4,5)P2) to form Inositol 1,4,5-triphosphate (IP3) and Diacylglycerol (DAG). IP3 released into the cytoplasm mobilizes Ca('2+) from internal stores, whereas DAG activates Protein kinase C epsilon (PKC-epsilon). PKC-epsilon induces PTK2B protein tyrosine kinase 2 beta (Pyk2(FAK2)) activation. PYK2(FAK2)activates V-akt murine thymoma viral oncogene homolog 1 (AKT(PKB)) through Phosphoinositide-3-kinase (PI3K)-dependent pathway. PYK2(FAK2) phosphorylates adaptor protein Shc and stimulates Growth factor receptor-bound protein 2 (GRB2)/Son of sevenless homolog (SOS)/v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) signaling cascade. H-Ras interacts with catalytic subunit of phosphoinositide 3-kinase class 1A (PI3K class 1A), which leads to increase in phosphoinositide enzymatic activity and catalysis of Phosphatidylinositol 4,5-biphosphate (PtdIns(4,5)P2), phosphorylation of which yields Phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3). Signaling cascade initiated via G-protein alpha-q and AKT leads to stimulation of I kappa B kinase (IKK). IKK phosphorylates nuclear factor of Kappa light polypeptide gene enhancer in B-cells inhibitor (I-kB) resulting in dissociation of I-kB from nuclear factor kappa B (NF-kB) followed by NF-kB-dependent transcription [1].

G-protein alpha-q directly stimulates Rho guanine nucleotide exchange factor 12 (LARG). LARG transforms and activates small G-protein Ras homolog gene family, member A (RhoA), which participates in reorganization of cytoskeleton via kinase Rho-associated coiled-coil containing protein kinase (ROCK) [2].

Regulators of G-protein signaling (RGS) are GTPase-activating proteins that attenuate signaling by heterotrimeric G-proteins. RGS2 and RGS3 directly bind G-protein alpha-q and selectively inhibit G-protein alpha-q function [3]. Adrenergic beta receptor kinase 1 (GRK2) binds to the active form of G-protein alpha-q and leads to selective inhibition of G-protein alpha-q mediated signaling [4].

References:

  1. Shi CS, Kehrl JH
    PYK2 links G(q)alpha and G(13)alpha signaling to NF-kappa B activation. The Journal of biological chemistry 2001 Aug 24;276(34):31845-50
  2. Booden MA, Siderovski DP, Der CJ
    Leukemia-associated Rho guanine nucleotide exchange factor promotes G alpha q-coupled activation of RhoA. Molecular and cellular biology 2002 Jun;22(12):4053-61
  3. Heximer SP
    RGS2-mediated regulation of Gqalpha. Methods in enzymology 2004;390:65-82
  4. Hains MD, Siderovski DP, Harden TK
    Application of RGS box proteins to evaluate G-protein selectivity in receptor-promoted signaling. Methods in enzymology 2004;389:71-88

  1. Shi CS, Kehrl JH
    PYK2 links G(q)alpha and G(13)alpha signaling to NF-kappa B activation. The Journal of biological chemistry 2001 Aug 24;276(34):31845-50
  2. Booden MA, Siderovski DP, Der CJ
    Leukemia-associated Rho guanine nucleotide exchange factor promotes G alpha q-coupled activation of RhoA. Molecular and cellular biology 2002 Jun;22(12):4053-61
  3. Heximer SP
    RGS2-mediated regulation of Gqalpha. Methods in enzymology 2004;390:65-82
  4. Hains MD, Siderovski DP, Harden TK
    Application of RGS box proteins to evaluate G-protein selectivity in receptor-promoted signaling. Methods in enzymology 2004;389:71-88

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