Abstract
The c-Abl tyrosine (Tyr) kinase is activated after platelet-derived-growth factor receptor (PDGFR) stimulation in a manner that is partially dependent on Src kinase activity. However, the activity of Src kinases alone is not sufficient for activation of c-Abl by PDGFR. Here we show that functional phospholipase C-gamma1 (PLC-gamma1) is required for c-Abl activation by PDGFR. Decreasing cellular levels of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) by PLC-gamma1-mediated hydrolysis or dephosphorylation by an inositol polyphosphate 5-phosphatase (Inp54) results in increased Abl kinase activity. c-Abl functions downstream of PLC-gamma1, as expression of kinase-inactive c-Abl blocks PLC-gamma1-induced chemotaxis towards PDGF-BB. PLC-gamma1 and c-Abl form a complex in cells that is enhanced by PDGF stimulation. After activation, c-Abl phosphorylates PLC-gamma1 and negatively modulates its function in vivo. These findings uncover a newly discovered functional interdependence between non-receptor Tyr kinase and lipid signalling pathways.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Binding Sites / genetics
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Cells, Cultured
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Chemotaxis / genetics
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Eukaryotic Cells / enzymology*
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Gene Expression Regulation, Enzymologic / physiology
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Mutation / physiology
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Phosphatidylinositol 4,5-Diphosphate / genetics
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Phosphatidylinositol 4,5-Diphosphate / metabolism*
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Phospholipase C gamma
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Phosphorylation
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Platelet-Derived Growth Factor / genetics
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Platelet-Derived Growth Factor / metabolism*
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Protein Structure, Tertiary / genetics
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Proto-Oncogene Proteins c-abl / genetics
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Proto-Oncogene Proteins c-abl / metabolism*
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Receptor, Platelet-Derived Growth Factor beta / genetics
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Receptor, Platelet-Derived Growth Factor beta / metabolism*
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Recombinant Fusion Proteins / genetics
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Signal Transduction / physiology*
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Type C Phospholipases / antagonists & inhibitors
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Type C Phospholipases / deficiency*
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Type C Phospholipases / genetics
Substances
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Enzyme Inhibitors
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Phosphatidylinositol 4,5-Diphosphate
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Platelet-Derived Growth Factor
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Recombinant Fusion Proteins
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Receptor, Platelet-Derived Growth Factor beta
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Proto-Oncogene Proteins c-abl
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Type C Phospholipases
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Phospholipase C gamma