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  • The EMBO Journal (2000) 19, 4614 - 4622
  • doi:10.1093/emboj/19.17.4614

Src-mediated activation of alpha-diacylglycerol kinase is required for hepatocyte growth factor-induced cell motility

Santina Cutrupi1,2, Gianluca Baldanzi1,2, Daniela Gramaglia3, Antonella Maffè3, Dick Schaap4, Enrico Giraudo3, Wim J. van Blitterswijk4, Federico Bussolino2,3, Paolo M. Comoglio3 and Andrea Graziani1,2,5

  1. Department of Medical Sciences, University Amedeo Avogadro of Piemonte Orientale, Novara, Italy
  2. Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy
  3. Institute for Cancer Research and Treatment (IRCC), University of Torino, Torino, Italy
  4. Division of Cellular Biochemistry, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
  5. Department of Medical Sciences, University Amedeo Avogadro, v. Solaroli 17, 28100 Novara, Italy

Correspondence to:

Andrea Graziani, E-mail: andrea@graziani.net

Received 7 June 1999; Accepted 18 July 2000; Revised 23 June 2000

Diacylglycerol kinases are involved in cell signaling, either as regulators of diacylglycerol levels or as intracellular signal-generating enzymes. However, neither their role in signal transduction nor their biochemical regulation has been elucidated. Hepatocyte growth factor (HGF), upon binding to its tyrosine kinase receptor, activates multiple signaling pathways stimulating cell motility, scattering, proliferation and branching morphogenesis. Herein we demonstrate that: (i) the enzymatic activity of alpha-diacylglycerol kinase (alphaDgk) is stimulated by HGF in epithelial, endothelial and alphaDgk-transfected COS cells; (ii) cellular expression of an alphaDgk kinase-defective mutant inhibits activation of endogenous alphaDgk acting as dominant negative; (iii) specific inhibition of alphaDgk prevents HGF-induced cell movement of endothelial cells; (iv) HGF induces the association of alphaDgk in a complex with Src, whose tyrosine kinase activity is required for alphaDgk activation by HGF; (v) Src wild type stimulates alphaDgk activity in vitro; and (vi) alphaDgk can be tyrosine phosphorylated in intact cells.

  • Keywords:

    • cell motility,
    • diacylglycerol kinase,
    • HGF,
    • phosphatidic acid,
    • Src