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

Hansen, Klaus; Johnell, Matilda; Siegbahn, Agneta; Rorsman, Charlotte; Engström, Ulla; Wernstedt, Christer; Heldin, Carl-Henrik and Rönnstrand, Lars LU (1996) In EMBO Journal 15(19). p.5299-5313
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... (More)
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. (Less)
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@article{9e9bf984-83bd-4ca7-9900-900de6c12a02,
  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.},
  author       = {Hansen, Klaus and Johnell, Matilda and Siegbahn, Agneta and Rorsman, Charlotte and Engström, Ulla and Wernstedt, Christer and Heldin, Carl-Henrik and Rönnstrand, Lars},
  issn         = {1460-2075},
  keyword      = {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},
  language     = {eng},
  number       = {19},
  pages        = {5299--5313},
  publisher    = {Oxford University Press},
  series       = {EMBO Journal},
  title        = {Mutation of a Src phosphorylation site in the PDGF beta-receptor leads to increased PDGF-stimulated chemotaxis but decreased mitogenesis},
  volume       = {15},
  year         = {1996},
}