2. Academic Validation
  3. YAP-dependent proliferation by a small molecule targeting annexin A2

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.
Sophia Z Shalhout  # 1 2 3,  Peng-Yu Yang  # 4 5,  Edyta M Grzelak  # 4,  Kayla Nutsch 4,  Sida Shao 4,  Claudio Zambaldo 4,  Jonathan Iaconelli 4,  Lara Ibrahim 4,  Caroline Stanton 4,  Stormi R Chadwick 4,  Emily Chen 5,  Michael DeRan 6,  Sijia Li 5,  Mitchell Hull 5,  Xu Wu 6,  Arnab K Chatterjee 5,  Weijun Shen 7,  Fernando D Camargo 8 9 10,  Peter G Schultz 11 12,  Michael J Bollong 13
Affiliations

Affiliations

  • 1 Stem Cell Program, Boston Children's Hospital, Boston, MA, USA.
  • 2 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
  • 3 Harvard Stem Cell Institute, Boston, MA, USA.
  • 4 Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • 5 Calibr, a division of Scripps Research, La Jolla, CA, USA.
  • 6 Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
  • 7 Calibr, a division of Scripps Research, La Jolla, CA, USA. wshen@scripps.edu.
  • 8 Stem Cell Program, Boston Children's Hospital, Boston, MA, USA. fernando.camargo@childrens.harvard.edu.
  • 9 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. fernando.camargo@childrens.harvard.edu.
  • 10 Harvard Stem Cell Institute, Boston, MA, USA. fernando.camargo@childrens.harvard.edu.
  • 11 Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. schultz@scripps.edu.
  • 12 Calibr, a division of Scripps Research, La Jolla, CA, USA. schultz@scripps.edu.
  • 13 Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA. mbollong@scripps.edu.
  • # Contributed equally.
PMID: 33723431 DOI: 10.1038/s41589-021-00755-0
Abstract

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.

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