Signaling from G protein-coupled receptors to c-Jun kinase involves beta gamma subunits of heterotrimeric G proteins acting on a Ras and Rac1-dependent pathway.
Stimulation of a variety of cell surface receptors enhances the enzymatic activity of mitogen-activated protein kinases (MAPKs). MAPKs have been classified in three subfamilies: extracellular signal-regulated kinases (ERKs), stress-activated protein kinases or c-Jun NH2-terminal kinases (SAPKs/JNKs), and p38 kinase. Whereas the pathway linking cell surface receptors to ERKs has been partially elucidated, the mechanism of activation of JNKs is still poorly understood. Recently, we have shown that stimulation of G protein-coupled receptors can effectively induce JNK in NIH 3T3 cells (Coso, O. A., Chiariello, M., Kalinec, G., Kyriakis, J. M., Woodgett, J., and Gutkind, J. S. (1995) J. Biol. Chem. 270, 5620-5624). In the present study, we have used the transient expression in COS-7 cells of m1 and m2 muscarinic receptors (mAChRs) as a model system to study the signaling pathway linking G protein-coupled receptors to JNK. We show that stimulation of either muscarinic receptor subtype leads to JNK activation; however, this effect was not mimicked by expression of activated forms of alphas, alphai2, alphaq, or alpha13 G protein alpha subunits. In contrast, overexpression of Gbetagamma subunits potently induced JNK activity. Furthermore, we show that signaling from m1 and m2 mAChRs to JNK involves betagamma subunits of heterotrimeric G proteins, acting on a Ras and Rac1-dependent pathway.
Coso
O A
OA
Molecular Signaling Unit, Laboratory of Cell Development and Oncology, NIDR NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA.
Teramoto
H
H
Simonds
W F
WF
Gutkind
J S
JS
D016475:3T3 Cells; D000818:Animals; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D002522:Chlorocebus aethiops; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D015870:Gene Expression; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D046911:Macromolecular Substances; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D010957:Plasmids; D011976:Receptors, Muscarinic / Q000096:biosynthesis / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D020744:rac GTP-Binding Proteins; D018631:ras Proteins / Q000378:metabolism*
D046911:Macromolecular Substances; D011976:Receptors, Muscarinic; D011994:Recombinant Proteins; D002217:Carbachol; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins; D018631:ras Proteins