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

P Gual1, S Giordano, S Anguissola

  • 1Institute for Cancer Research and Treatment (IRCC), University of Torino Medical School, Str. Prov. 142, Km 3.95, 10060 Candiolo, Italy.

Oncogene
|April 21, 2001
PubMed

Insights

Hepatocyte Growth Factor (HGF) signaling involves Gab1 protein. Serine/threonine phosphorylation of Gab1 negatively regulates HGF-induced invasive growth, offering a new therapeutic target.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Hepatocyte Growth Factor (HGF) receptor signaling, mediated by the MET oncogene tyrosine kinase, drives invasive growth in epithelial cells.
  • Sustained tyrosine phosphorylation of the adaptor protein Gab1 is crucial for HGF-induced cellular responses.

Purpose of the Study:

  • To investigate the role of serine/threonine phosphorylation of Gab1 in regulating HGF signaling.
  • To identify mechanisms controlling HGF-induced invasive growth.

Main Methods:

  • Treatment with okadaic acid, an inhibitor of protein phosphatases PP1 and PP2A.
  • Analysis of Gab1 phosphorylation status (serine/threonine and tyrosine).
  • Assessment of HGF-induced biological responses and recruitment of signaling molecules like PI3 kinase.

Main Results:

  • Inhibition of PP1 and PP2A led to serine/threonine hyper-phosphorylation and tyrosine hypo-phosphorylation of Gab1.
  • Gab1's reduced tyrosine phosphorylation impaired its ability to recruit SH2-domain containing proteins, such as PI3 kinase.
  • Protein kinase C (PKC)-alpha and PKC-beta1 were identified as key kinases involved in Gab1 serine/threonine phosphorylation and negative regulation.
  • These events severely inhibited HGF-induced invasive growth.

Conclusions:

  • Gab1 serine/threonine phosphorylation represents a novel negative feedback mechanism in HGF receptor signaling.
  • PKC-alpha and PKC-beta1 play critical roles in this negative regulation.
  • Targeting these kinases could offer a strategy to inhibit invasive growth in cancers driven by HGF/MET signaling.

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