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
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / metabolism
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Amino Acid Sequence
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Becaplermin
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Cell Division
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Cell Line
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Chemotaxis / physiology*
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Chromones / pharmacology
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Enzyme Inhibitors / pharmacology
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HeLa Cells
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Humans
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Isoenzymes / metabolism
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Kinetics
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Molecular Sequence Data
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Morpholines / pharmacology
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Mutation
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Peptides / chemical synthesis
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Peptides / metabolism
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Phosphatidylinositol 3-Kinases
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Phospholipase C gamma
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Phosphorylation / drug effects
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Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
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Platelet-Derived Growth Factor / pharmacology
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Protein Binding
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Protein Kinase C / antagonists & inhibitors
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Proto-Oncogene Proteins c-sis
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Proto-Oncogene Proteins pp60(c-src) / metabolism*
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Receptor, Platelet-Derived Growth Factor beta
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Receptors, Platelet-Derived Growth Factor / genetics
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Receptors, Platelet-Derived Growth Factor / metabolism*
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Recombinant Fusion Proteins / metabolism
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Signal Transduction / physiology
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Type C Phospholipases / metabolism
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Tyrosine / metabolism
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src Homology Domains
Substances
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Actins
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Chromones
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Enzyme Inhibitors
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Isoenzymes
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Morpholines
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Peptides
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Platelet-Derived Growth Factor
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Proto-Oncogene Proteins c-sis
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Recombinant Fusion Proteins
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Becaplermin
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Tyrosine
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Phosphatidylinositol 3-Kinases
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Phosphotransferases (Alcohol Group Acceptor)
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Receptor, Platelet-Derived Growth Factor beta
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Receptors, Platelet-Derived Growth Factor
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Proto-Oncogene Proteins pp60(c-src)
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Protein Kinase C
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Type C Phospholipases
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Phospholipase C gamma