Dishevelled has a YAP nuclear export function in a tumor suppressor context-dependent manner.

Area of Science:

• Cell Biology
• Molecular Biology
• Oncology

Background:

• Yeast adaptor protein YAP's phosphorylation-dependent translocation is crucial for Hippo pathway signaling.
• Oncogenic YAP paradoxically suppresses Wnt activity, a mechanism not fully understood.
• The molecular players governing YAP's cytoplasmic movement remain largely undefined.

Purpose of the Study:

• To identify the molecular effectors responsible for YAP's cytoplasmic translocation.
• To elucidate the role of Dishevelled (DVL) in YAP subcellular localization.
• To investigate the interplay between Hippo, Wnt signaling, and tumor suppressor pathways in regulating YAP.

Main Methods:

• Site-directed mutagenesis to inactivate DVL's nuclear export signal.
• Immunofluorescence and Western blotting to assess YAP localization and phosphorylation.
• Analysis of YAP-TEAD transcriptional activity.
• In vivo and clinical data analysis.

Main Results:

• Dishevelled (DVL) acts as the key mediator for the cytosolic translocation of phosphorylated YAP.
• Inactivating DVL's nuclear export signal causes nuclear YAP retention and increased TEAD activity.
• DVL is essential for YAP localization changes induced by E-cadherin, α-catenin, or AMPK activation.
• YAP nuclear-cytoplasmic trafficking is regulated by p53-Lats2 and LKB1-AMPK tumor suppressor axes.
• Loss of p53 or LKB1 releases DVL-mediated inhibition between Wnt and nuclear YAP activity.

Conclusions:

• Dishevelled (DVL) is a critical regulator of YAP's subcellular localization and Hippo pathway signaling.
• The p53-Lats2 and LKB1-AMPK tumor suppressor pathways converge on DVL to control YAP activity.
• Understanding these mechanisms provides insights into developmental processes and human cancer progression.
• Targeting DVL or related pathways could offer therapeutic strategies for YAP-driven cancers.