Pathway Map Details

G-protein signaling_G-Protein alpha-q signaling cascades



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Object list (links open in MetaCore):

GRB2, PLC-beta, Ca('2+) = Ca('2+), Ca('2+) cytosol, I-kB, 3.1.4.11, PI3K cat class IA, PtdIns(3,4,5)P3, G-protein beta/gamma, PtdIns(4,5)P2, Pyk2(FAK2), IP3, SOS, PKC-epsilon, DAG, NF-kB, RGS2, IP3 receptor, Ca('2+) endoplasmic reticulum lumen, 2.7.1.153, IKK (cat), RhoA, LARG, G-protein alpha-q/11, PLC-gamma, H-Ras, Shc, RGS3, PDK (PDPK1), GRK2, IKK-alpha, AKT(PKB), ROCK, Btk

Description:

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 )/ S on 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