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

Rina Plattner; Brenda J. Irvin; Shuling Guo; Kevin Blackburn; Andrius Kazlauskas; Robert T. Abraham; John D. York; Ann Marie Pendergast

doi:10.1038/ncb949

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

Rina Plattner, Brenda J. Irvin, Shuling Guo, Kevin Blackburn, Andrius Kazlauskas, Robert T. Abraham, John D. York, Ann Marie Pendergast

Pharmacology and Nutritional Sciences

Research output: Contribution to journal › Article › peer-review

123 Scopus citations

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.

Original language	English
Pages (from-to)	309-319
Number of pages	11
Journal	Nature Cell Biology
Volume	5
Issue number	4
DOIs	https://doi.org/10.1038/ncb949
State	Published - Apr 1 2003

Bibliographical note

Funding 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

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

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.",

author = "Rina Plattner and Irvin, {Brenda J.} and Shuling Guo and Kevin Blackburn and Andrius Kazlauskas and Abraham, {Robert T.} and York, {John D.} and Pendergast, {Ann Marie}",

note = "Funding 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.",

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AU - York, John D.

AU - Pendergast, Ann Marie

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N2 - 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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A new link between the c-Abl tyrosine kinase and phosphoinositide signalling through PLC-γ1

Abstract

Bibliographical note

ASJC Scopus subject areas

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