YAP-dependent proliferation by a small molecule targeting annexin A2

Nat Chem Biol. 2021 Jul;17(7):767-775. doi: 10.1038/s41589-021-00755-0. Epub 2021 Mar 15.


The transcriptional coactivator Yes-associated protein 1 (YAP) orchestrates a proproliferative transcriptional program that controls the fate of somatic stem cells and the regenerative responses of certain tissues. As such, agents that activate YAP may hold therapeutic potential in disease states exacerbated by insufficient proliferative repair. Here we report the discovery of a small molecule, termed PY-60, which robustly activates YAP transcriptional activity in vitro and promotes YAP-dependent expansion of epidermal keratinocytes in mouse following topical drug administration. Chemical proteomics revealed the relevant target of PY-60 to be annexin A2 (ANXA2), a protein that directly associates with YAP at the cell membrane in response to increased cell density. PY-60 treatment liberates ANXA2 from the membrane, ultimately promoting a phosphatase-bound, nonphosphorylated and transcriptionally active form of YAP. This work reveals ANXA2 as a previously undescribed, druggable component of the Hippo pathway and suggests a mechanistic rationale to promote regenerative repair in disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Administration, Topical
  • Adult Stem Cells / drug effects
  • Adult Stem Cells / metabolism
  • Animals
  • Annexin A2 / antagonists & inhibitors*
  • Annexin A2 / metabolism
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Mice
  • Molecular Structure
  • Small Molecule Libraries / administration & dosage
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Transcription Factors / metabolism*
  • YAP-Signaling Proteins


  • Adaptor Proteins, Signal Transducing
  • Annexin A2
  • Small Molecule Libraries
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human