Pertussis toxin-sensitive activation of p21ras by G protein-coupled receptor agonists in fibroblasts

Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1257-61. doi: 10.1073/pnas.90.4.1257.

Abstract

Some agonists of G protein-coupled receptors, such as thrombin and lysophosphatidic acid (LPA), can promote cell proliferation via a pertussis toxin (PTX)-sensitive signaling pathway. While these agonists stimulate phospholipase C and inhibit adenylate cyclase, it appears that other, as-yet-unidentified, effector pathways are required for mitogenesis. Here we report that LPA and a thrombin receptor agonist peptide rapidly activate the protooncogene product p21ras in quiescent fibroblasts. This activation is inhibited by PTX and yet not attributable to known PTX-sensitive G protein pathways, including stimulation of phospholipases, inhibition of adenylate cyclase, or modulation of ion channels. LPA- and peptide-induced p21ras activation is inhibited by the tyrosine kinase inhibitor genistein, at doses that do not affect epidermal growth factor-induced p21ras activation. Thus, a heterotrimeric G protein of the Gi subfamily regulates activation of p21ras by LPA and thrombin, possibly through an intermediary tyrosine kinase. This pathway may critically participate in mitogenic signaling downstream from certain G protein-coupled receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylate Cyclase Toxin*
  • Animals
  • Cell Line
  • Cholera Toxin / pharmacology
  • DNA Replication / drug effects*
  • Epidermal Growth Factor / pharmacology*
  • ErbB Receptors / physiology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • GTP-Binding Proteins / metabolism*
  • Genes, ras
  • Guanosine Triphosphate / metabolism*
  • Kinetics
  • Lysophospholipids / pharmacology*
  • Pertussis Toxin*
  • Phosphates / metabolism
  • Phosphotyrosine
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • Receptors, Cell Surface / drug effects
  • Receptors, Cell Surface / physiology*
  • Receptors, Thrombin
  • Signal Transduction*
  • Suramin / pharmacology
  • Tetradecanoylphorbol Acetate / pharmacology
  • Thrombin / pharmacology*
  • Tyrosine / analogs & derivatives
  • Tyrosine / analysis
  • Virulence Factors, Bordetella / pharmacology*

Substances

  • Adenylate Cyclase Toxin
  • Lysophospholipids
  • Phosphates
  • Receptors, Cell Surface
  • Receptors, Thrombin
  • Virulence Factors, Bordetella
  • Phosphotyrosine
  • Tyrosine
  • Suramin
  • Epidermal Growth Factor
  • Guanosine Triphosphate
  • Cholera Toxin
  • Pertussis Toxin
  • ErbB Receptors
  • Thrombin
  • GTP-Binding Proteins
  • Proto-Oncogene Proteins p21(ras)
  • Tetradecanoylphorbol Acetate