A new link between the c-Abl tyrosine kinase and phosphoinositide signalling through PLC-gamma1.
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.
Plattner
Rina
R
Department of Pharmacology and Cancer Biology Duke University Medical Center Durham, NC 27710, USA.
Irvin
Brenda J
BJ
Guo
Shuling
S
Blackburn
Kevin
K
Kazlauskas
Andrius
A
Abraham
Robert T
RT
York
John D
JD
Pendergast
Ann Marie
AM
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D002633:Chemotaxis / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005057:Eukaryotic Cells / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D009154:Mutation / Q000502:physiology; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000235:genetics / Q000378:metabolism*; D051966:Phospholipase C gamma; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics
D004791:Enzyme Inhibitors; D019269:Phosphatidylinositol 4,5-Diphosphate; D010982:Platelet-Derived Growth Factor; D011993:Recombinant Fusion Proteins; D020797:Receptor, Platelet-Derived Growth Factor beta; D016315:Proto-Oncogene Proteins c-abl; D010738:Type C Phospholipases; D051966:Phospholipase C gamma