Grb2 binding induces phosphorylation-independent activation of Shp2

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Updated: Nov 10, 2025

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
08:45

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Published on: July 17, 2020

6.4K

Chi-Chuan Lin1, Lukasz Wieteska2, Kin Man Suen2,3

  • 1School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK. C.C.Lin@leeds.ac.uk.

Communications Biology
|April 2, 2021
PubMed

Insights

The adaptor protein Grb2 directly activates Shp2 phosphatase activity in its monomeric state, independent of external growth factors. This finding reveals a new mechanism for controlling intracellular signaling pathways crucial in cancer.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Phosphatase activity regulates intracellular signaling, particularly the mitogen-activated protein kinase (MAPK) pathway.
  • Shp2, a protein tyrosine phosphatase, is often hyperactive in cancers.
  • Grb2 adaptor protein typically functions as a dimer.

Purpose of the Study:

  • To investigate the mechanism of Shp2 activation independent of receptor tyrosine kinase signaling.
  • To elucidate the role of the Grb2 adaptor protein in regulating Shp2 activity.

Main Methods:

  • Biochemical assays to study protein-protein interactions.
  • Analysis of Shp2 and Grb2 conformations.
  • Investigating signaling in non-stimulated cells.

Main Results:

  • Monomeric Grb2 binds to both N-terminal SH2 and catalytic domains of Shp2.
  • This interaction releases Shp2 from its auto-inhibited state, initiating phosphatase activity.
  • Grb2's monomeric state is favored at low concentrations or upon phosphorylation at Y160.
  • Shp2 activation occurs without extracellular growth factor stimulation or kinase mutations.

Conclusions:

  • Direct binding of monomeric Grb2 is sufficient to activate Shp2 phosphatase.
  • This activation pathway operates independently of receptor tyrosine kinase up-regulation.
  • Grb2-mediated Shp2 activation provides a novel target for cancer therapy.

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