YAP-Dependent Proliferation by a Small Molecule Targeting Annexin A2
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Yang, Peng-Yu
Grzelak, Edyta M.
Nutsch, Kayla
Shao, Sida
Zambaldo, Claudio
Ibrahim, Lara
Stanton, Caroline
Chadwick, Stormi R.
Chen, Emily
Hull, Mitchell
Chatterjee, Arnab K.
Shen, Weijun
Bollong, Michael J.
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https://doi.org/10.1038/s41589-021-00755-0Metadata
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Shalhout, Sophia Z, Peng-Yu Yang, Edyta M Grzelak, Kayla Nutsch, Sida Shao, Claudio Zambaldo, Jonathan Iaconelli, et al. 2021. “YAP-Dependent Proliferation by a Small Molecule Targeting Annexin A2.” Nature Chemical Biology 17 (7): 767–75.Abstract
The transcriptional coactivator YAP orchestrates a pro-proliferative 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 upon topical administration of drug. 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, non-phosphorylated, and transcriptionally active form of YAP. This work reveals ANXA2 to be a previously undescribed, druggable component of the Hippo pathway and suggests a mechanistic rationale for promoting YAP-dependent regenerative repair in disease.Citable link to this page
https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37374379
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