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Yap1 phosphorylation by c-Abl is a critical step in selective activation of proapoptotic genes in response to DNA

Dan Levy1, Yaarit Adamovich, Nina Reuven

  • 1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.

Molecular Cell
|February 19, 2008
PubMed

Insights

DNA damage triggers c-Abl kinase to phosphorylate Yap1, enhancing its stability and selective activation of proapoptotic genes with p73. This phosphorylation controls Yap1

Area of Science:

  • Cellular biology
  • Molecular mechanisms of DNA damage response
  • Gene transcription regulation

Background:

  • Cells initiate apoptosis in response to severe DNA damage.
  • c-Abl kinase phosphorylates and activates p73 under DNA damage stress.
  • The transcription coactivator Yap1 binds p73, preventing degradation and promoting proapoptotic gene transcription.

Purpose of the Study:

  • To elucidate the mechanism by which Yap1 selectively activates proapoptotic genes.
  • To investigate the role of Yap1 phosphorylation in the DNA damage response pathway.

Main Methods:

  • Investigating the interaction between c-Abl, p73, and Yap1.
  • Utilizing phosphorylation site mapping to identify Yap1 phosphorylation by c-Abl.
  • Assessing the impact of Yap1 phosphorylation on protein stability, p73 binding affinity, and target gene activation.

Main Results:

  • c-Abl directly phosphorylates Yap1 at tyrosine 357 (Y357) upon DNA damage.
  • Phosphorylated Yap1 exhibits increased stability and enhanced binding affinity to p73.
  • Yap1 phosphorylation by c-Abl leads to selective coactivation of p73 proapoptotic target genes.
  • Yap1's phosphorylation state dictates its role in switching between proapoptotic and growth arrest pathways.

Conclusions:

  • DNA damage-induced phosphorylation of Yap1 by c-Abl is a key regulatory event.
  • This modification influences the specificity of target gene activation, directing cells towards apoptosis.
  • Yap1 acts as a crucial mediator, translating DNA damage signals into specific transcriptional outcomes.

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