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Published on: July 17, 2020

Protein tyrosine phosphatase PTPN13 negatively regulates Her2/ErbB2 malignant signaling

J-H Zhu1, R Chen, W Yi

  • 1Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.

Oncogene
|November 6, 2007
PubMed

Insights

Protein tyrosine phosphatase PTPN13 dephosphorylates the Her2 (Human Epidermal growth factor Receptor 2) signaling domain, inhibiting its oncogenic activity. Mutations in PTPN13 elevate Her2’s potential, promoting cancer cell invasiveness and metastasis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The Her2/ErbB2 receptor tyrosine kinase is a key driver of tumorigenesis and progression in various human cancers.
  • Oncogenic signaling by Her2 is mediated through phosphorylation of its cytosolic domain.
  • Understanding cellular mechanisms that regulate Her2 phosphorylation is crucial for cancer therapy.

Purpose of the Study:

  • To identify cellular phosphatases that regulate Her2 oncogenic phosphorylation.
  • To elucidate the role of PTPN13 in controlling Her2 activity and cancer cell invasiveness.
  • To investigate the impact of PTPN13 mutations on Her2-driven oncogenesis.

Main Methods:

  • Screening of a siRNA phosphatase library to identify regulators of Her2 phosphorylation.
  • Assessing the effect of PTPN13 knockdown on Her2 phosphorylation and cancer cell invasiveness.
  • Investigating the interaction between growth factor signaling, PTPN13 phosphorylation, and Her2 dephosphorylation.
  • Analyzing the phosphatase activity of wild-type and mutated PTPN13.

Main Results:

  • Silencing protein tyrosine phosphatase PTPN13 significantly enhanced growth factor-induced Her2 phosphorylation and promoted cancer cell invasiveness.
  • Growth factor-induced phosphorylation of PTPN13 was essential for Her2 dephosphorylation, indicating a negative feedback loop.
  • PTPN13 mutations found in human tumors markedly reduced its phosphatase activity, increasing Her2 oncogenic potential and cancer cell invasiveness.

Conclusions:

  • Cellular PTPN13 acts as a negative regulator of Her2 activity by dephosphorylating its signaling domain.
  • PTPN13 plays a significant role in attenuating the invasiveness and metastasis of Her2-overexpressing tumors.
  • PTPN13's tumor-associated mutations compromise its tumor-suppressive function, highlighting its importance in Her2-driven cancers.

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