The platelet-derived growth factor receptor stimulation of p42/p44 mitogen-activated protein kinase in airway smooth muscle involves a G-protein-mediated tyrosine phosphorylation of Gab1.
Using cultured airway smooth muscle cells, we showed previously that the platelet-derived growth factor (PDGF) receptor uses the G-protein, G(i), to stimulate Grb-2-associated phosphoinositide 3-kinase (PI3K) activity. We also showed that this was an intermediate step in the activation of p42/p44 mitogen-activated protein kinase (p42/p44 MAPK) by PDGF. We now present two lines of evidence that provide further support for this model. First, we report that PDGF stimulates the G(i)-mediated tyrosine phosphorylation of the Grb-2 adaptor protein, Gab1. This phosphorylation appears to be necessary for association of PI3K1a with the Gab1-Grb-2 complex. Second, PI3K appears to promote the subsequent association of dynamin II (which is involved in clathrin-mediated endocytic processing) with the complex. Furthermore, inhibitors of PI3K and clathrin-mediated endocytosis reduced the PDGF-dependent activation of p42/p44 MAPK, suggesting a role for PI3K in the endocytic signaling process leading to stimulation of p42/p44 MAPK. Together, these results begin to define a common signaling model for certain growth factor receptors (e.g., PDGF, insulin, insulin-like growth factor-1, and fibroblast growth factor) which use G(i) to transmit signals to p42/p44 MAPK.
Rakhit
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S
Department of Physiology and Pharmacology, Strathclyde Institute for Biomedical Sciences, University of Strathclyde, Glasgow, Scotland, United Kingdom.
Pyne
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Pyne
N J
NJ
D000818:Animals; D002478:Cells, Cultured; D034281:Dynamins; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000502:physiology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006168:Guinea Pigs; D055504:Insulin Receptor Substrate Proteins; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D009130:Muscle, Smooth / Q000201:enzymology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D019950:Mitogen-Activated Protein Kinase 1; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D034281:Dynamins