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

Författare

  • Klaus Hansen
  • Matilda Johnell
  • Agneta Siegbahn
  • Charlotte Rorsman
  • Ulla Engström
  • Christer Wernstedt
  • Carl-Henrik Heldin
  • Lars Rönnstrand

Summary, in English

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.

Publiceringsår

1996

Språk

Engelska

Sidor

5299-5313

Publikation/Tidskrift/Serie

EMBO Journal

Volym

15

Issue

19

Dokumenttyp

Artikel i tidskrift

Förlag

Oxford University Press

Ämne

  • Medicinal Chemistry

Nyckelord

  • Platelet-Derived Growth Factor/genetics/*metabolism Recombinant Fusion Proteins/metabolism Signal Transduction/physiology Type C Phospholipases/metabolism Tyrosine/metabolism src Homology Domains
  • Platelet-Derived Growth Factor beta Receptors
  • Actins/metabolism Amino Acid Sequence 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/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 pp60(c-src)/*metabolism Receptor

Status

Published

ISBN/ISSN/Övrigt

  • ISSN: 1460-2075