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