Diacylglycerol kinase-α phosphorylation by Src on Y335 is required for activation, membrane recruitment and Hgf-induced cell motility

G. Baldanzi, S. Cutrupi, F. Chianale, V. Gnocchi, E. Rainero, P. Porporato, N. Filigheddu, W. J. Van Blitterswijk, O. Parolini, F. Bussolino, F. Sinigaglia, A. Graziani

Research output: Contribution to journalArticlepeer-review

Abstract

Diacylglycerol (DAG) kinases (Dgk), which phosphorylate DAG to generate phosphatidic acid, act as either positive or negative key regulators of cell signaling. We previously showed that Src mediates growth factors-induced activation of Dgk-α, whose activity is required for cell motility, proliferation and angiogenesis. Here, we demonstrate that both hepatocytes growth factor (HGF) stimulation and v-Src transformation induce tyrosine phosphorylation of Dgk-α on Y335, through a mechanism requiring its proline-rich C-terminal sequence. Moreover, we show that both proline-rich sequence and phosphorylation of Y335 of Dgk-α mediate: (i) its enzymatic activation, (ii) its ability to interact respectively with SH3 and SH2 domains of Src, (iii) its recruitment to the membrane. In addition, we show that phosphorylation of Dgk-α on Y335 is required for HGF-induced motility, while its constitutive recruitment at the membrane by myristylation is sufficient to trigger spontaneous motility in absence of HGF. Providing the first evidence that tyrosine phosphorylation of Dgk-α is required for growth-factors-induced activation and membrane recruitment, these findings underscore its relevance as a rheostat, whose activation is a threshold to elicit growth factors-induced migratory signaling.

Original languageEnglish
Pages (from-to)942-956
Number of pages15
JournalOncogene
Volume27
Issue number7
DOIs
Publication statusPublished - Feb 7 2008

Keywords

  • Cell migration
  • Diacylglycerol kinase
  • Hepatocyte growth factor
  • Signal transduction
  • Src
  • Tyrosine kinase

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

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