Osmotic stress-induced phosphorylation by NLK at Ser128 activates YAP

Audrey W. Hong, Zhipeng Meng, Hai Xin Yuan, Steven W. Plouffe, Sungho Moon, Wantae Kim, Eek Hoon Jho, Kun Liang Guan

Research output: Contribution to journalArticlepeer-review

106 Scopus citations

Abstract

YAP is the major downstream effector of the Hippo pathway, which controls cell growth, tissue homeostasis, and organ size. Aberrant YAP activation, resulting from dysregulation of the Hippo pathway, is frequently observed in human cancers. YAP is a transcription co-activator, and the key mechanism of YAP regulation is its nuclear and cytoplasmic translocation. The Hippo pathway component, LATS, inhibits YAP by phosphorylating YAP at Ser127, leading to 14-3-3 binding and cytoplasmic retention of YAP. Here, we report that osmotic stress stimulates transient YAP nuclear localization and increases YAP activity even when YAP Ser127 is phosphorylated. Osmotic stress acts via the NLK kinase to induce YAP Ser128 phosphorylation. Phosphorylation of YAP at Ser128 interferes with its ability to bind to 14-3-3, resulting in YAP nuclear accumulation and induction of downstream target gene expression. This osmotic stress-induced YAP activation enhances cellular stress adaptation. Our findings reveal a critical role for NLK-mediated Ser128 phosphorylation in YAP regulation and a crosstalk between osmotic stress and the Hippo pathway.

Original languageEnglish
Pages (from-to)72-86
Number of pages15
JournalEMBO Reports
Volume18
Issue number1
DOIs
StatePublished - 1 Jan 2017

Keywords

  • 14-3-3
  • Hippo
  • NLK
  • YAP
  • osmotic stress

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