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Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases
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Author Spotlight: Developing Tools to Tune the Activity of Tyrosine Phosphatases

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Time-resolved phosphoproteomics reveals scaffolding and catalysis-responsive patterns of SHP2-dependent signaling

Vidyasiri Vemulapalli1,2, Lily A Chylek3, Alison Erickson4

  • 1Department of Cancer Biology, Dana-Farber Cancer Institute Boston, Boston, United States.

Elife
|March 23, 2021
PubMed

Insights

SHP2 protein tyrosine phosphatase is crucial for cancer cell signaling. Inhibiting SHP2 reveals new substrate sites and its dual role in regulating cell responses to growth factors like EGF.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • SHP2 (a protein tyrosine phosphatase) regulates intracellular signaling pathways.
  • Mutations in SHP2 are common in human cancers, affecting cell growth.
  • SHP2's role in breast cancer and response to EGF requires further elucidation.

Purpose of the Study:

  • To investigate the function of SHP2 in breast cancer cells.
  • To analyze phosphoproteome dynamics upon SHP2 inhibition using SHP099.
  • To identify novel SHP2 substrates and understand its regulatory mechanisms.

Main Methods:

  • Allosteric inhibition of SHP2 using the compound SHP099.
  • Monitoring phosphoproteome dynamics in breast cancer cells.
  • Quantitative analysis of phosphotyrosine abundance changes.

Main Results:

  • Six distinct phosphotyrosine abundance response signatures were identified.
  • New SHP2 substrate sites were discovered on proteins including occludin, ARHGAP35, and PLCγ2.
  • SHP2 inhibition decreased phosphotyrosine abundance at specific sites, particularly those with paired phosphotyrosine residues.

Conclusions:

  • SHP2 plays a complex role in transmembrane signaling.
  • SHP2's scaffolding and catalytic activities differentially regulate signaling responses.
  • Understanding SHP2's function is critical for developing targeted cancer therapies.
Keywords:
PTPN11biochemistrychemical biologyepidermal growth factor receptorhumanmass spectrometryphosphatasesignal transduction

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