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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

SHP2 tyrosine phosphatase converts parafibromin/Cdc73 from a tumor suppressor to an oncogenic driver

Atsushi Takahashi1, Ryouhei Tsutsumi, Ippei Kikuchi

  • 1Division of Microbiology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.

Molecular Cell
|July 6, 2011
PubMed

Insights

SHP2 dephosphorylation of parafibromin (Cdc73) activates Wnt signaling by promoting β-catenin binding. This mechanism links SHP2 to both cancer and developmental disorders by controlling parafibromin

Area of Science:

  • Molecular Biology
  • Cellular Signaling
  • Oncology

Background:

  • SHP2 (PTPN11) is implicated in malignant diseases and developmental disorders.
  • SHP2's role in RAS signaling is established, but other cellular functions are unclear.
  • Parafibromin (Cdc73) is a tumor suppressor that inhibits cyclin D1 and c-myc via SUV39H1.

Purpose of the Study:

  • To elucidate the role of SHP2 in regulating parafibromin's function.
  • To investigate how SHP2 influences parafibromin's interaction with other proteins.
  • To understand the implications of SHP2-mediated parafibromin regulation in disease.

Main Methods:

  • Biochemical assays to detect SHP2-mediated dephosphorylation of parafibromin.
  • Co-immunoprecipitation to assess parafibromin binding to β-catenin and SUV39H1.
  • Analysis of Wnt target gene expression, including cyclin D1 and c-myc.

Main Results:

  • SHP2 dephosphorylates parafibromin on tyrosine residues.
  • Dephosphorylated parafibromin stably binds to β-catenin, overriding SUV39H1 recruitment.
  • SHP2-induced parafibromin/β-catenin interaction activates Wnt signaling and upregulates oncogenic genes.

Conclusions:

  • SHP2 governs the dual functions of parafibromin, switching it from tumor suppression to oncogenesis.
  • Dysregulation of this SHP2-parafibromin axis contributes to tumor development and congenital abnormalities.
  • Targeting SHP2 may offer therapeutic strategies for diseases linked to aberrant parafibromin activity.

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