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Phosphorylation-dependent binding of 14-3-3 terminates signalling by the Gab2 docking protein

Tilman Brummer1, Mark Larance, Maria Teresa Herrera Abreu

  • 1Cancer Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.

The EMBO Journal
|January 28, 2009
PubMed

Insights

Growth factor-induced phosphorylation of Gab2 (Grb2-associated binder 2) recruits 14-3-3 proteins, attenuating signalling. This novel negative-feedback mechanism involves Gab2 dissociation from Grb2, impacting tyrosine kinase pathways.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Oncogenesis

Background:

  • Grb2-associated binder (Gab)2 acts as a docking platform for signal transducers downstream of tyrosine kinases.
  • Gab2 signaling is crucial for normal physiology and oncogenesis, often mediated by Grb2 adaptor protein.
  • Mechanisms for attenuating Gab2 signaling have been poorly understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms that attenuate Gab2 signaling.
  • To investigate the role of Gab2 phosphorylation in negative-feedback regulation.
  • To understand how Gab2 signaling termination impacts cell proliferation and transformation.

Main Methods:

  • Investigated growth factor-induced phosphorylation of Gab2 at specific residues (S210 and T391).
  • Utilized site-directed mutagenesis to create Gab2(S210A/T391A) and constitutive 14-3-3-binding mutants.
  • Assessed receptor association, signaling, Grb2 binding, and cell proliferation/transformation.

Main Results:

  • Phosphorylation of Gab2 at S210 and T391 recruits 14-3-3 proteins, mediating negative feedback.
  • Gab2(S210A/T391A) mutants showed sustained receptor association, signaling, and promoted cell proliferation/transformation.
  • Constitutive 14-3-3 binding sites rendered Gab2 refractory to receptor activation, reducing Grb2 binding.

Conclusions:

  • Site-selective 14-3-3 protein binding is sufficient to terminate Gab2 signaling.
  • 14-3-3 proteins promote Gab2 dissociation from Grb2, uncoupling it from the receptor complex.
  • This represents a novel regulatory mechanism for tyrosine kinase signaling systems with implications in cancer.

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