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Strategies for Tracking Anastasis, A Cell Survival Phenomenon that Reverses Apoptosis
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YAP-dependent proliferation by a small molecule targeting annexin A2

Sophia Z Shalhout1,2,3, Peng-Yu Yang4,5, Edyta M Grzelak4

  • 1Stem Cell Program, Boston Children's Hospital, Boston, MA, USA.

Nature Chemical Biology
|March 16, 2021
PubMed

Insights

Researchers discovered PY-60, a small molecule that activates Yes-associated protein (YAP) transcriptional activity. This molecule promotes skin cell regeneration and reveals annexin A2 as a potential therapeutic target for regenerative medicine.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Regenerative Medicine

Background:

  • The transcriptional coactivator Yes-associated protein (YAP) regulates cell proliferation and tissue regeneration.
  • Activating YAP holds therapeutic potential for diseases with impaired regenerative repair.

Purpose of the Study:

  • To identify small molecules that activate YAP transcriptional activity.
  • To elucidate the mechanism of YAP activation and its therapeutic implications.

Main Methods:

  • In vitro assays to measure YAP transcriptional activity.
  • Topical drug administration in mice to assess epidermal keratinocyte expansion.
  • Chemical proteomics to identify the molecular target of the small molecule.

Main Results:

  • Discovery of PY-60, a small molecule that robustly activates YAP.
  • PY-60 promotes YAP-dependent epidermal keratinocyte expansion in mice.
  • Annexin A2 (ANXA2) identified as the direct target of PY-60.
  • PY-60 treatment causes ANXA2 release from the cell membrane, activating YAP.

Conclusions:

  • Annexin A2 is a novel, druggable component of the Hippo pathway.
  • PY-60 activates YAP by modulating ANXA2.
  • This study provides a mechanistic basis for promoting regenerative repair through YAP activation.

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