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Development and Application of Rapamycin-regulated Tyrosine Phosphatases
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Gab2 phosphorylation by RSK inhibits Shp2 recruitment and cell motility

Xiaocui Zhang1, Genevieve Lavoie, Loic Fort

  • 1Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.

Molecular and Cellular Biology
|February 13, 2013
PubMed

Insights

p90 ribosomal S6 kinase (RSK) phosphorylates Gab2, a protein overexpressed in cancers, inhibiting Shp2 recruitment and dampening cancer cell migration. This identifies RSK as a negative feedback mechanism controlling Gab2 signaling.

Area of Science:

  • Cellular signaling
  • Cancer biology
  • Molecular mechanisms

Background:

  • Gab2 (Grb2-associated binder) is a scaffolding adapter protein crucial for growth factor and cytokine signaling.
  • Gab2 overexpression in malignancies like breast cancer correlates with enhanced mammary epithelial cell migration.
  • Mechanisms regulating Gab2 inactivation remain incompletely understood.

Purpose of the Study:

  • To investigate the feedback mechanisms controlling Gab2 signaling.
  • To identify kinases responsible for Gab2 phosphorylation and inactivation.
  • To elucidate the functional consequences of Gab2 phosphorylation on cell motility.

Main Methods:

  • Investigated Gab2 phosphorylation by the Ras/mitogen-activated protein kinase (MAPK) pathway.
  • Utilized in vivo and in vitro assays to demonstrate RSK (p90 ribosomal S6 kinase) phosphorylation of Gab2 on specific residues.
  • Assessed the impact of Gab2 phosphorylation on Shp2 recruitment and cell motility using mutant Gab2 in mammary epithelial cells.

Main Results:

  • Activation of the Ras/MAPK pathway leads to Gab2 phosphorylation by RSK.
  • Gab2 phosphorylation, specifically at three conserved residues by RSK, inhibits the recruitment of tyrosine phosphatase Shp2.
  • An unphosphorylatable Gab2 mutant promoted an invasion-like phenotype and increased cell motility in mammary epithelial cells.

Conclusions:

  • RSK acts as a negative-feedback regulator, phosphorylating Gab2 to restrict Gab2-dependent epithelial cell motility.
  • These findings suggest a broader regulatory role for RSK in diverse receptor signaling systems.
  • Understanding this RSK-Gab2 axis offers potential therapeutic targets in cancers with Gab2 overexpression.

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