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JNK phosphorylates Yes-associated protein (YAP) to regulate apoptosis
V Tomlinson1, K Gudmundsdottir, P Luong
1Centre for Molecular Oncology and Imaging, Institute of Cancer, London, UK.
Cell Death & Disease
|March 3, 2011
Summary
Yes-associated protein (YAP) phosphorylation by JNK1/2 is crucial for its roles in DNA damage and cell growth. JNK-dependent YAP stabilization of ΔNp63α explains its dual function in UV response.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Yes-associated protein (YAP) is a key regulator of DNA damage response, chemosensitivity, cell growth, and cell size.
- Phosphorylation is critical for regulating YAP's diverse functions.
- Understanding novel YAP kinases can elucidate new signaling pathways and YAP's biological roles.
Purpose of the Study:
- To identify novel kinases that phosphorylate YAP through an in vitro screen.
- To investigate the functional consequences of YAP phosphorylation by newly identified kinases.
- To elucidate the mechanism behind YAP's dual role in UV response.
Main Methods:
- In vitro kinase screening to identify YAP-interacting kinases.
- Phosphorylation site mapping on YAP.
- Pharmacological inhibition and siRNA-mediated knockdown of identified kinases.
- Cellular assays assessing YAP function in response to UV irradiation.
- Co-immunoprecipitation to analyze protein-protein interactions.
Main Results:
- JNK1 and JNK2 were identified as robust YAP kinases, with multiple phosphorylation sites mapped.
- JNK was confirmed to specifically phosphorylate endogenous YAP in various cell types.
- YAP demonstrated a protective role in keratinocytes but promoted UV-induced apoptosis in squamous cell carcinoma.
- This dual role was attributed to JNK-dependent YAP stabilization of the pro-proliferative ΔNp63α isoform.
Conclusions:
- JNK1/2 are significant YAP kinases, regulating YAP phosphorylation.
- YAP's function in UV response is context-dependent and mediated by JNK-dependent stabilization of ΔNp63α.
- Assessing p63 and p73 isoform expression is vital for understanding YAP's specific functions.
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