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

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Abstract

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.
Original languageEnglish
Pages (from-to)413-420
Number of pages8
JournalMolecular Pharmacology
Volume58
Issue number2
Publication statusPublished - 1 Aug 2000

Keywords

  • animals
  • cells, cultured
  • dynamins
  • enzyme activation
  • GTP phosphohydrolases
  • GTP-binding protein alpha subunits, Gi-Go
  • GTP-binding proteins
  • guinea pigs
  • insulin receptor substrate proteins
  • mitogen-activated protein kinase 1
  • muscle, smooth
  • phosphatidylinositol 3-kinases
  • phosphoproteins
  • phosphorylation
  • receptors, platelet-derived growth factor
  • tyrosine

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