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WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional

Rami I Aqeilan1, Valentina Donati, Alexey Palamarchuk

  • 1Human Cancer Genetics Program, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43220, USA. rami.aqeilan@osumc.edu

Cancer Research
|August 3, 2005
PubMed

Insights

The tumor suppressor WWOX protein interacts with ErbB-4, preventing YAP from activating transcription. WWOX antagonizes YAP

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • The WW domain-containing oxidoreductase (WWOX) is a known tumor suppressor.
  • WWOX suppresses the transcriptional activity of p73 and AP-2gamma.
  • Yes-associated protein (YAP) enhances p73 transcriptional activity and coactivates the ErbB-4 receptor tyrosine kinase.

Purpose of the Study:

  • To investigate the interaction between WWOX and ErbB-4.
  • To determine the effect of WWOX on YAP's transcriptional coactivation of ErbB-4.
  • To elucidate the role of WWOX in regulating YAP's function.

Main Methods:

  • Coexpression of WWOX and ErbB-4 in HeLa cells.
  • Treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) to induce ErbB-4 cleavage.
  • Analysis of ErbB-4 localization in cytoplasm and nucleus.
  • Dose-dependent assays to assess transcriptional coactivation suppression.
  • Use of a mutant WWOX form lacking ErbB-4 interaction.

Main Results:

  • WWOX physically associates with full-length ErbB-4 via its first WW domain.
  • WWOX coexpression with ErbB-4 leads to ErbB-4 retention in the cytoplasm upon TPA stimulation.
  • WWOX suppresses YAP-mediated transcriptional coactivation of ErbB-4's COOH-terminal fragment (CTF) in a dose-dependent manner.
  • WWOX inhibits YAP-mediated coactivation of p73.

Conclusions:

  • WWOX antagonizes YAP's function by competing for interaction with ErbB-4 and other targets.
  • WWOX negatively regulates YAP's transcriptional activity.
  • WWOX interaction with ErbB-4 impacts its cellular localization and downstream signaling.

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