YAP-dependent proliferation by a small molecule targeting annexin A2

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.