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c-Abl antagonizes the YAP oncogenic function

R Keshet1, J Adler1, I Ricardo Lax1

  • 1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.

Cell Death and Differentiation
|November 1, 2014
PubMed

Insights

DNA damage triggers c-Abl kinase to phosphorylate YES-associated protein (YAP) at Y357. This phosphorylation inactivates YAP

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • YES-associated protein (YAP) is a key transcription coactivator and oncogene.
  • YAP's function shifts under DNA damage, activating pro-apoptotic genes with p73.
  • This switch is mediated by c-Abl (Abelson murine leukemia viral oncogene) through YAP phosphorylation at Y357 (pY357).

Purpose of the Study:

  • To investigate if c-Abl regulates the YAP-TEAD (transcriptional enhancer activator domain) functional module.
  • To determine the role of YAP Y357 phosphorylation in YAP's oncogenic functions.

Main Methods:

  • Investigated the effect of DNA damage and c-Abl activation on YAP-TEAD transcription.
  • Analyzed TEAD1 phosphorylation and YAP-TEAD complex integrity.
  • Utilized phosphomimetic YAP Y357E and Y357F mutations to assess TEAD coactivation.
  • Assessed YAP's role in cell transformation, migration, anchorage-independent growth, and EMT in MCF10A cells.

Main Results:

  • DNA damage, via c-Abl, significantly reduced YAP-TEAD-induced transcription.
  • c-Abl counteracts YAP's oncogenic transformation by disrupting the YAP-TEAD transcriptional program.
  • YAP Y357E mutation, unlike Y357F, impaired TEAD coactivation and YAP's oncogenic activities.
  • YAP phosphorylation at Y357 (pY357) was shown to abolish YAP's TEAD transcription activation function.

Conclusions:

  • YAP phosphorylation at Y357 by c-Abl inactivates its oncogenic function.
  • YAP Y357 phosphorylation plays a critical role in cell-fate decisions.
  • This mechanism highlights how YAP's function is regulated in response to DNA damage.

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