Mutation of a Src phosphorylation site in the PDGF beta-receptor leads to increased PDGF-stimulated chemotaxis but decreased mitogenesis

EMBO J. 1996 Oct 1;15(19):5299-313.

Abstract

Ligand induced activation of the beta-receptor for platelet-derived growth factor (PDGF) leads to activation of Src family tyrosine kinases. We have explored the possibility that the receptor itself is a substrate for Src. We show that Tyr934 in the kinase domain of the PDGF receptor is phosphorylated by Src. Cell lines expressing a beta-receptor mutant, in which Tyr934 was replaced with a phenyalanine residue, showed reduced mitogenic signaling in response to PDGF-BB. In contrast, the mutant receptor mediated increased signals for chemotaxis and actin reorganization. Whereas the motility responses of cells expressing wild-type beta-receptors were attenuated by inhibition of phosphatidylinositol 3'-kinase, those of cells expressing the mutant receptor were only slightly influenced. In contrast, PDGF-BB-induced chemotaxis of the cells with the mutant receptor was attenuated by inhibition of protein kinase C, whereas the chemotaxis of cells expressing the wild-type beta-receptor was less affected. Moreover, the PDGF-BB-stimulated tyrosine phosphorylation of phospholipase C-gamma was increased in the mutant receptor cells compared with wild-type receptor cells. In conclusion, the characteristics of the Y934F mutant suggest that the phosphorylation of Tyr934 by Src negatively modulates a signal transduction pathway leading to motility responses which involves phospholipase C-gamma, and shifts the response to increased mitogenicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Amino Acid Sequence
  • Becaplermin
  • Cell Division
  • Cell Line
  • Chemotaxis / physiology*
  • Chromones / pharmacology
  • Enzyme Inhibitors / pharmacology
  • HeLa Cells
  • Humans
  • Isoenzymes / metabolism
  • Kinetics
  • Molecular Sequence Data
  • Morpholines / pharmacology
  • Mutation
  • Peptides / chemical synthesis
  • Peptides / metabolism
  • Phosphatidylinositol 3-Kinases
  • Phospholipase C gamma
  • Phosphorylation / drug effects
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Platelet-Derived Growth Factor / pharmacology
  • Protein Binding
  • Protein Kinase C / antagonists & inhibitors
  • Proto-Oncogene Proteins c-sis
  • Proto-Oncogene Proteins pp60(c-src) / metabolism*
  • Receptor, Platelet-Derived Growth Factor beta
  • Receptors, Platelet-Derived Growth Factor / genetics
  • Receptors, Platelet-Derived Growth Factor / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / physiology
  • Type C Phospholipases / metabolism
  • Tyrosine / metabolism
  • src Homology Domains

Substances

  • Actins
  • Chromones
  • Enzyme Inhibitors
  • Isoenzymes
  • Morpholines
  • Peptides
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-sis
  • Recombinant Fusion Proteins
  • Becaplermin
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Tyrosine
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor)
  • Receptor, Platelet-Derived Growth Factor beta
  • Receptors, Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins pp60(c-src)
  • Protein Kinase C
  • Type C Phospholipases
  • Phospholipase C gamma