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Osmotic stress-induced phosphorylation by NLK at Ser128 activates YAP

Audrey W Hong1, Zhipeng Meng1, Hai-Xin Yuan1,2

  • 1Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.

EMBO Reports
|December 17, 2016
PubMed

Insights

Osmotic stress activates YAP, a key protein in cell growth, by triggering its nuclear entry through NLK kinase. This process enhances cellular adaptation to stress, revealing a novel link between osmotic stress and the Hippo pathway.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The Hippo pathway regulates organ size and cell growth, with YAP as its main effector.
  • Dysregulated YAP activity is linked to human cancers.
  • YAP's function is controlled by its localization between the nucleus and cytoplasm.

Purpose of the Study:

  • To investigate the effect of osmotic stress on YAP activity.
  • To elucidate the molecular mechanism by which osmotic stress influences YAP.
  • To understand the role of YAP regulation in cellular stress adaptation.

Main Methods:

  • Investigated YAP phosphorylation and localization under osmotic stress conditions.
  • Utilized kinase assays to identify the role of NLK in YAP regulation.
  • Assessed the impact of YAP nuclear accumulation on downstream gene expression.

Main Results:

  • Osmotic stress induces transient YAP nuclear localization and activity, independent of Ser127 phosphorylation.
  • NLK kinase phosphorylates YAP at Ser128, disrupting 14-3-3 binding.
  • YAP Ser128 phosphorylation leads to nuclear accumulation and increased expression of target genes, enhancing stress adaptation.

Conclusions:

  • NLK-mediated YAP Ser128 phosphorylation is a critical regulatory mechanism.
  • Osmotic stress and the Hippo pathway exhibit crosstalk.
  • This pathway activation contributes to cellular adaptation to osmotic stress.
Keywords:
14‐3‐3HippoNLKYAPosmotic stress

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