Related Experiment Video

Updated: Jun 6, 2026

Co-immunoprecipitation Assay for Studying Functional Interactions Between Receptors and Enzymes
09:40

Co-immunoprecipitation Assay for Studying Functional Interactions Between Receptors and Enzymes

Published on: September 28, 2018

A hotspot phosphorylation site on SHP2 drives oncoprotein activation and drug resistance

Prashath Karunaraj1,2,3, Remkes Scheele1, Malcolm L Wells4

  • 1Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA.

Nature Communications
|March 3, 2026
PubMed

Insights

Phosphorylation of SHP2 at tyrosine 62 (pY62) by SRC family kinases activates MAPK signaling, causing resistance to SHP2 inhibitors. This pY62 site represents a novel cancer drug target.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • SHP2 phosphatase is crucial for receptor tyrosine kinase (RTK)-driven RAS/mitogen-activated protein kinase (MAPK) signaling.
  • SHP2 inhibitors show limited clinical efficacy, with resistance mechanisms unclear.

Purpose of the Study:

  • To investigate the role of SHP2 phosphorylation in mediating resistance to SHP2 inhibitors.
  • To identify novel mechanisms of SHP2 activation and potential therapeutic targets.

Main Methods:

  • Proteomic analysis to identify SHP2 phosphorylation hotspots.
  • Biochemical assays to determine kinase activity and protein interactions.
  • Biophysical analyses to characterize SHP2 conformation and activation.

Main Results:

  • Phosphorylation of SHP2 at tyrosine 62 (pY62) was identified as a hotspot in RTK-driven tumors.
  • SRC family kinases directly phosphorylate SHP2 at Y62.
  • SHP2Y62D mutation mimics constitutive activation, leading to MAPK pathway activation and resistance to SHP2 inhibitors.

Conclusions:

  • SHP2 pY62 phosphorylation is a mechanism of primary resistance to SHP2 inhibitors, phenocopying mutational activation.
  • Targeting SHP2 pY62 offers a distinct therapeutic strategy separate from wildtype SHP2 inhibition.

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