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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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Transforming growth factor {beta} (TGF-{beta})-Smad target gene protein tyrosine phosphatase receptor type kappa is

Shizhen Emily Wang1, Frederick Y Wu, Incheol Shin

  • 1Division of Oncology, Department of Cancer Biology, Vanderbilt University School of Medicine, 2220 Pierce Ave., 777 PRB, Nashville, TN 37232-6307, USA.

Molecular and Cellular Biology
|May 19, 2005
PubMed

Insights

Transforming growth factor beta (TGF-beta) and HER2 signaling converge on protein tyrosine phosphatase receptor type kappa (PTPRK). PTPRK is essential for TGF-beta

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Transforming growth factor beta (TGF-beta) is known to inhibit proliferation and promote cell migration.
  • HER2 overexpression is implicated in various cellular processes, including mammary epithelial cell behavior.

Purpose of the Study:

  • To identify novel Smad targets in TGF-beta-treated MCF10A mammary epithelial cells overexpressing HER2.
  • To elucidate the role of protein tyrosine phosphatase receptor type kappa (PTPRK) in TGF-beta and HER2 signaling pathways.

Main Methods:

  • Chromatin immunoprecipitation was used to identify Smad targets.
  • RNA interference (RNAi) was employed to study the function of PTPRK.
  • Western blotting and quantitative PCR were utilized to assess protein and mRNA expression levels.
  • Cell proliferation, cell cycle progression, and cell motility assays were performed.

Main Results:

  • PTPRK was identified as a novel Smad target, with TGF-beta up-regulating its expression and HER2 overexpression down-regulating it.
  • RNAi of PTPRK accelerated cell cycle progression, enhanced EGF response, and abrogated TGF-beta-mediated antimitogenesis.
  • RPTPkappa (the protein product of PTPRK) associated with EGFR and HER2, suppressing proliferation and receptor phosphorylation.
  • TGF-beta-induced cell motility, FAK phosphorylation, and F-actin assembly were dependent on RPTPkappa.
  • RPTPkappa positively regulates Src, with convergence of HER2 and TGF-beta signaling at Src.

Conclusions:

  • RPTPkappa is a key mediator of both the antiproliferative and promigratory effects of TGF-beta.
  • HER2 signaling and TGF-beta-induced RPTPkappa converge at Src, influencing cell motility and adhesion.
  • PTPRK plays a critical role in regulating mammary epithelial cell behavior in response to TGF-beta and HER2 signaling.

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