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A new link between the c-Abl tyrosine kinase and phosphoinositide signalling through PLC-γ1

Nature Cell Biology volume 5, pages 309–319 (2003)Cite this article

An Erratum to this article was published on 01 May 2003

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-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.

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Figure 1: c-Abl activation by PDGF is dependent on PLC-γ1 activity.
Figure 2: PtdIns(4,5)P2 inhibits c-Abl kinase activity.
Figure 3: c-Abl and PLC-γ1 function together to regulate chemotaxis.
Figure 4: PLC-γ1 and c-Abl form a complex.
Figure 5: c-Abl induces Tyr phosphorylation of PLC-γ1 in vivo.
Figure 6: c-Abl phosphorylates PLC-γ1 in vitro.
Figure 7: c-Abl phosphorylation of PLC-γ1 causes downregulation of PLC activity.
Figure 8: Model of the interaction between c-Abl and PLC-γ1 signalling pathways.

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Acknowledgements

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.

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Author notes

  1. Brenda J. Irvin

    Present address: Department of Biochemistry Vanderbilt University Nashville, TN 37232, USA

  2. Shuling Guo

    Present address: Howard Hughes Medical Institute Dept. of Microbiology, Immunology, & Molecular Genetics, University of California at Los Angeles, CA 90095, USA

  3. Robert T. Abraham

    Present address: The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA

Authors and Affiliations

  1. Department of Pharmacology and Cancer Biology Duke University Medical Center Durham, 27710, NC, USA

    Rina Plattner, Brenda J. Irvin, Shuling Guo, Robert T. Abraham, John D. York & Ann Marie Pendergast

  2. Proteomic Technologies GlaxoSmithKline Research Triangle Park, 27709, NC, USA

    Kevin Blackburn

  3. Schepens Eye Research Institute Harvard Medical School Boston, 02114, MA, USA

    Andrius Kazlauskas

  4. Howard Hughes Medical Institute Duke University Medical Center Durham, 27710, NC, USA

    John D. York

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Plattner, R., Irvin, B., Guo, S. et al. A new link between the c-Abl tyrosine kinase and phosphoinositide signalling through PLC-γ1. Nat Cell Biol 5, 309–319 (2003). https://doi.org/10.1038/ncb949

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