Osmotic stress‐induced phosphorylation by NLK at Ser128 activates YAP. (15th December 2016)

• Record Type: Journal Article
• Authors: Hong, Audrey W; Meng, Zhipeng; Yuan, Hai‐Xin; Plouffe, Steven W; Moon, Sungho; Kim, Wantae; Jho, Eek‐hoon; Guan, Kun‐Liang
• Is Part Of: EMBO reports. Volume 18:Number 1(2017)
• Page Start: 72
• Page End: 86
• Publication Date: 2016-12-15
• Subjects: 14‐3‐3 -- Hippo -- NLK -- osmotic stress -- YAP; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201642681
• Languages: English
• ISSNs: 1469-221X

Abstract

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. Synopsis: Yes‐associated protein (YAP) is the major transcriptional co‐activator of the Hippo pathway, and its activity is determined by its subcellular localization. This study shows that osmotic stress induces Ser128 phosphorylation of YAP by the nemo‐like kinase (NLK), which results in its nuclear accumulation and the induction of downstream targets. Osmotic stress induces transient nuclear localization of YAP, despite LATS‐dependent Ser127 phosphorylation. Osmotic stress activates NLK to phosphorylate YAP on Ser128, which interferes with 14‐3‐3 binding and increases its nuclear localization. NLK‐dependent transient YAP activation may serve as an early response for cells to adapt to osmotic stress. Abstract : Yes‐associated protein (YAP) is the major transcriptional co‐activator of the Hippo pathway, and its activity is determined by its subcellular localization. This study shows that osmotic stress induces Ser128 phosphorylation of YAP by the nemo‐like kinase (NLK), which results in its nuclear accumulation and the induction of downstream targets.