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PTPN3 acts as a tumor suppressor and boosts TGF-β signaling independent of its phosphatase activity

Bo Yuan1, Jinquan Liu1, Jin Cao1

  • 1The MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China.

The EMBO Journal
|July 16, 2019
PubMed

Insights

Protein tyrosine phosphatase non-receptor 3 (PTPN3) enhances transforming growth factor-beta (TGF-β) signaling by stabilizing the TGF-β type I receptor. Mutations in PTPN3 are linked to cancer, highlighting its role in disease.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Transforming growth factor-beta (TGF-β) signaling is crucial for development and its dysregulation is implicated in diseases like cancer.
  • Tight regulation of TGF-β signaling pathways is essential for maintaining cellular homeostasis and preventing pathogenesis.

Purpose of the Study:

  • To investigate the role of protein tyrosine phosphatase non-receptor 3 (PTPN3) in regulating TGF-β signaling.
  • To elucidate the mechanism by which PTPN3 influences TGF-β pathway activity.
  • To examine the impact of PTPN3 mutations on TGF-β signaling and tumor suppression.

Main Methods:

  • Biochemical assays to assess PTPN3's phosphatase activity and its effect on TGF-β signaling components.
  • Co-immunoprecipitation to analyze the interaction between PTPN3, Smurf2, and the TGF-β type I receptor (TβRI).
  • Analysis of TGF-β-induced R-Smad phosphorylation and downstream transcriptional responses.
  • Investigation of the functional consequences of a specific PTPN3 mutation (L232R) found in intrahepatic cholangiocarcinoma (ICC).

Main Results:

  • PTPN3 potentiates TGF-β signaling independently of its phosphatase activity.
  • PTPN3 stabilizes TβRI by preventing its interaction with Smurf2.
  • PTPN3 enhances TGF-β-induced R-Smad phosphorylation and downstream cellular responses.
  • The PTPN3 L232R mutation abrogates its ability to enhance TGF-β signaling and impairs its tumor-suppressive function in ICC.

Conclusions:

  • PTPN3 plays a critical role in potentiating TGF-β signaling through TβRI stabilization.
  • PTPN3 acts as a key regulator of TGF-β pathway activity in both normal physiology and disease.
  • The PTPN3 L232R mutation represents a mechanism by which aberrant TGF-β signaling contributes to ICC development.
Keywords:
Smurf2TGF-β signalingTβRIcholangiocarcinomaphosphatase

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