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
Summary
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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