Linkage of G Protein-Coupled Receptors to the MAPK Signaling Pathway Through PI 3-Kinase γ

• Published in: Science (American Association for the Advancement of Science) 1997-01, Vol.275 (5298), p.394-397
• Main Authors: Lopez-Llasaca, Marco, Crespo, Piero, Pellici, P. Giuseppe, Gutkind, J. Silvio, Wetzker, Reinhard
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Androstadienes - pharmacology; Animals; Antibodies; Antiserum; Biological and medical sciences; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Carbachol - pharmacology; Cell Membrane - enzymology; Cell physiology; Cell receptors; Cellular signal transduction; COS Cells; Dental research; Enzyme Activation; Fundamental and applied biological sciences. Psychology; G proteins; GRB2 Adaptor Protein; GTP-Binding Proteins - metabolism; Guanine Nucleotide Exchange Factors; Lipids; Mitogen-Activated Protein Kinase 1; Mitogens; Molecular and cellular biology; Molecular biology; Molecules; Phosphatidylinositol 3-Kinases; Phosphatidylinositols; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Physiological aspects; Plasmids; Proteins; Proteins - metabolism; ras Guanine Nucleotide Exchange Factors; ras Proteins - metabolism; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, Muscarinic M2; Receptors; Receptors, Muscarinic - metabolism; Recombinant Fusion Proteins - metabolism; Signal Transduction; String theory; Transfection; Tyrosine - metabolism; Wortmannin
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.275.5298.394

The tyrosine kinase class of receptors induces mitogen-activated protein kinase (MAPK) activation through the sequential interaction of the signaling proteins Grb2, Sos, Ras, Raf, and MEK. Receptors coupled to heterotrimeric guanine triphosphate-binding protein (G protein) stimulate MAPK through G$_{\beta\gamma}$ subunits, but the subsequent intervening molecules are still poorly defined. Overexpression of phosphoinositide 3-kinase γ (PI3Kγ) in COS-7 cells activated MAPK in a G$_{\beta\gamma}$-dependent fashion, and expression of a catalytically inactive mutant of PI3Kγ abolished the stimulation of MAPK by G$_{\beta\gamma}$ or in response to stimulation of muscarinic (m2) G protein-coupled receptors. Signaling from PI3Kγ to MAPK appears to require a tyrosine kinase, Shc, Grb2, Sos, Ras, and Raf. These findings indicate that PI3Kγ mediates G$_{\beta\gamma}$-dependent regulation of the MAPK signaling pathway.