Gab1 phosphorylation: A novel mechanism for negative regulation of HGF receptor signaling

P. Gual, S. Giordano, S. Anguissola, P. J. Parker, P. M. Comoglio

Research output: Contribution to journalArticlepeer-review

Abstract

Signal transduction by HGF receptor, the tyrosine kinase encoded by the MET oncogene, switches on a genetic program called 'invasive growth' inducing epithelial cell dissociation, migration, growth, and ultimately leading to differentiation into branched tubular structures. Sustained tyrosine phosphorylation of the downstream adaptor protein Gab1 is required for the HGF response. Here we show that serine/threonine phosphorylation of Gab1 provides a control mechanism for negative regulation. Treatment with okadaic acid, a potent inhibitor of the serine/threonine protein phosphatases PP1 and PP2A, was followed by activation of a number of serine/threonine kinases, hyper-phosphorylation in serine and threonine of Gab1 and severe inhibition of the HGF-induced biological responses. Under these conditions, Gab1 was found to be concomitantly hypophosphorylated in tyrosine, and thus endowed with reduced ability to recruit SH2 containing signal transducers such as PI3 kinase. Among the serine-threonine kinases activated by PP1 and PP2A inhibition, we found that PKC-α and PKC-β1 are required for negative regulation of Gab1. These data provide a novel negative mechanism for the HGF receptor signaling pathways and highlight a potentially useful target for inhibitors of invasive growth.

Original languageEnglish
Pages (from-to)156-166
Number of pages11
JournalOncogene
Volume20
Issue number2
DOIs
Publication statusPublished - Jan 11 2001

Keywords

  • Gab1
  • HGF
  • Invasive growth
  • Negative regulation
  • PKC
  • Ser/Thr phosphorylation

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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