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-γ1 (PLC-γ1) is required for c-Abl activation by PDGFR. Decreasing cellular levels of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) by PLC-γ1-mediated hydrolysis or dephosphorylation by an inositol polyphosphate 5-phosphatase (Inp54) results in increased Abl kinase activity. c-Abl functions downstream of PLC-γ1, as expression of kinase-inactive c-Abl blocks PLC-γ1-induced chemotaxis towards PDGF-BB. PLC-γ1 and c-Abl form a complex in cells that is enhanced by PDGF stimulation. After activation, c-Abl phosphorylates PLC-γ1 and negatively modulates its function in vivo. These findings uncover a newly discovered functional interdependence between non-receptor Tyr kinase and lipid signalling pathways.
|Number of pages||11|
|Journal||Nature Cell Biology|
|State||Published - Apr 1 2003|
Bibliographical noteFunding Information:
ACKNOWLEDGMENTS This work was supported by NIH grants CA70940 and GM62375 to A.M.P., NIH training grant CA09111-25 to R.P., National Institute of Health grant GM47286 to R.T.A., Howard Hughes Medical Institute funding to J. T. Y, and funded in part by GlaxoSmithKline. We thank G. Carpenter (Vanderbilt University, Nashville, TN) for the PLC-γ1 null fibroblasts, R.Van Etten (Harvard Medical School, Boston, MA) for c-Abl constructs, T. Pawson (Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Canada) for GST–PLC-γ1 fusion proteins, and A. Koleske (Yale University, New Haven, CT) for Abl/Arg null MEFs. We thank S. Finn and P. Zipfel (Duke University) for critically reading the manuscript, J. Stevensen-Paulik and A. Seeds (Duke University) for help in running the HPLC, and M. Calera (Harvard Medical School) for the PAE/PDGFR-β cell line. Correspondence and requests for materials should be addressed to A.M.P.
ASJC Scopus subject areas
- Cell Biology