Gbetagamma signaling and Ca2+ mobilization co-operate synergistically in a Sos and Rac-dependent manner in the activation of JNK by Gq-coupled receptors.
The mechanism by which G(q)-coupled receptors stimulate the c-Jun N-terminal kinase (JNK) activity has not been fully delineated. Here, we showed that stimulation of endogenous G(q)-coupled receptors in human hepatocarcinoma HepG2 cells resulted in an Src family kinase- and Ca(2+)-dependent JNK activation. Cos-7 cells transfected with HA-tagged JNK and various G(q)-coupled receptors also exhibited similar characteristics and provided further evidence for the involvement of Gbetagamma, an upstream intermediate for Src family kinases. The Ca(2+) and Gbetagamma signals operate in a high degree of independence. Transient expression of Gbetagamma subunits and elevation of cytoplasmic Ca(2+) level by thapsigargin activated JNK in a synergistic fashion. JNK activities triggered by G(q)-coupled receptors, Gbetagamma and thapsigargin were all suppressed by dominant negative (DN) mutants of Son of sevenless (Sos) and Rac. We propose that the co-operative effect between Gbetagamma-mediated signaling and the increased intracellular Ca(2+) level represents a robust mechanism for the stimulation of JNK by G(q)-coupled receptors.
Chan
Anthony S L
AS
Department of Biochemistry, the Biotechnology Research Institute, and the Molecular Neuroscience Center, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
Wong
Yung H
YH
D000818:Animals; D015153:Blotting, Western; D001920:Bradykinin / Q000378:metabolism; D019556:COS Cells; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism*; D005799:Genes, Dominant; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D020664:Son of Sevenless Proteins / Q000378:metabolism*; D013997:Time Factors; D020744:rac GTP-Binding Proteins / Q000378:metabolism
D018076:DNA, Complementary; C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D020664:Son of Sevenless Proteins; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020744:rac GTP-Binding Proteins; D001920:Bradykinin; D002118:Calcium