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Analysis of mRNA Nuclear Export Kinetics in Mammalian Cells by Microinjection
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Analysis of mRNA Nuclear Export Kinetics in Mammalian Cells by Microinjection

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

Yoonmi Lee1,2, Nam Hee Kim2, Eunae Sandra Cho1

  • 1Department of Oral Pathology, Yonsei University College of Dentistry, Seoul, 03722, Korea.

Nature Communications
|June 14, 2018
PubMed

Insights

Dishevelled (DVL) mediates the cytoplasmic translocation of phosphorylated YAP, a key Hippo pathway component. Loss of tumor suppressors like p53 or LKB1 disrupts this, impacting Wnt and YAP activity in cancer.

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.

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