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Updated: Jan 8, 2026

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

6.6K

Mechanism of SHP2 activation by bis-Tyr-phosphorylated Gab1

Lisa Machner1, Alaa Shaikhqasem2, Tobias Gruber3

  • 1Institut für Biochemie und Biotechnologie, Martin-Luther-Universität Halle-Wittenberg, 06120 Halle (Saale), Germany; Institut für Molekulare Medizin, Martin-Luther-Universität Halle-Wittenberg, 06120 Halle (Saale), Germany; Charles-Tanford-Proteinzentrum, Martin-Luther-Universität Halle-Wittenberg, 06120 Halle (Saale), Germany.

Structure (London, England : 1993)
|December 23, 2025
PubMed

Insights

The study reveals how a specific peptide activates the SHP2 phosphatase by binding to its SH2 domains, altering enzyme dynamics and orientation. This finding illuminates SHP2

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Enzymology

Background:

  • SHP2 (PTPN11) is a non-receptor tyrosine phosphatase regulating cell signaling.
  • Its activity is crucial for processes like mitogenesis and cell migration.
  • SHP2 is autoinhibited, with mutations linked to cancer and other diseases.

Purpose of the Study:

  • To elucidate the activation mechanism of SHP2.
  • To understand how SHP2-activating peptides interact with the enzyme.
  • To provide insights for developing novel SHP2 modulators.

Main Methods:

  • Biochemical assays using a bis-phosphorylated peptide (pY627pY659-Gab1).
  • Analysis of SH2 domain dynamics and inter-domain orientations.
  • Structural and functional characterization of SHP2-peptide interactions.

Main Results:

  • The peptide binds to both SH2 domains of SHP2, inducing partial ordering.
  • Peptide binding alters SH2 domain dynamics and their relative orientations.
  • A novel SH2-SH2 interface is generated upon peptide binding.
  • An active conformation of SHP2 is proposed, potentially applicable to SHP1.

Conclusions:

  • The findings reveal a detailed mechanism of SHP2 activation by peptides.
  • The proposed active conformation offers a framework for understanding SHP1 activation.
  • This research paves the way for targeted drug development for SHP2-related diseases.
Keywords:
NMRSH2 domainX-ray crystallographyallosteric activationelectron crystallographyisothermal calorimetryprotein dynamicsprotein structuresignal transductiontyrosine phosphatase

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