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Grb2 controls phosphorylation of FGFR2 by inhibiting receptor kinase and Shp2 phosphatase activity

Zamal Ahmed1, Chi-Chuan Lin, Kin M Suen

  • 1Department of Biochemistry and Molecular Biology and Center for Biomolecular Structure and Function, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. zahmed@mdanderson.org

The Journal of Cell Biology
|February 20, 2013
PubMed

Insights

Growth factor receptor-bound protein 2 (Grb2) regulates fibroblast growth factor receptor 2 (FGFR2) and SH2 domain-containing protein tyrosine phosphatase 2 (Shp2) activity. This maintains a non-signaling state until growth factors trigger receptor activation and downstream signaling.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Signal transduction pathways

Background:

  • Receptor tyrosine kinases (RTKs) require precise regulation of kinase and phosphatase activity.
  • Aberrant signaling can lead to uncontrolled cell growth and disease.
  • Adaptor proteins play crucial roles in modulating RTK signaling networks.

Purpose of the Study:

  • To elucidate the role of growth factor receptor-bound protein 2 (Grb2) in regulating fibroblast growth factor receptor 2 (FGFR2) and SH2 domain-containing protein tyrosine phosphatase 2 (Shp2) activity.
  • To understand the dynamic mechanism controlling FGFR2 signaling in the absence of extracellular stimulation.
  • To identify how Grb2 maintains a homeostatic, signaling-incompetent state.

Main Methods:

  • Investigated the interplay between FGFR2, Grb2, and Shp2 using biochemical assays.
  • Analyzed the phosphorylation and dephosphorylation states of FGFR2, Grb2, and Shp2.
  • Studied the binding dynamics between FGFR2 and Grb2 under various conditions.

Main Results:

  • FGFR2 and Shp2 exhibit reciprocal cycling of enzymatic activity, regulated by Grb2 binding.
  • Grb2 binding to FGFR2 inhibits both FGFR2 kinase and Shp2 phosphatase activity.
  • FGFR2-mediated phosphorylation of Grb2 disrupts its binding, activating both FGFR2 and Shp2.
  • Shp2-mediated dephosphorylation of Grb2 restores the FGFR2-Grb2 complex, re-establishing the inhibited state.
  • Growth factor stimulation dissociates Grb2, leading to increased FGFR2 phosphorylation and downstream signaling.

Conclusions:

  • Grb2 acts as a constitutive regulator of the mutually dependent activities of FGFR2 and Shp2.
  • A dynamic cycling mechanism maintains FGFR2 signaling in a basal, non-signaling state.
  • Growth factor-induced Grb2 dissociation is essential for initiating downstream signaling pathways.

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