title: Osmotic stress-induced phosphorylation by NLK at Ser128 activates YAP.
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.
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: Audrey W
authors.initials: AW
authors.lastname: Hong
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: Zhipeng
authors.initials: Z
authors.lastname: Meng
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.|The Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Hai-Xin
authors.initials: HX
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Plouffe
authors.affiliation: Department of Life Science, University of Seoul, Dongdaemun-gu, Seoul, Korea.
authors.forename: Sungho
authors.identifier: 0000-0002-5938-8930
authors.initials: S
authors.lastname: Moon
authors.affiliation: Department of Life Science, University of Seoul, Dongdaemun-gu, Seoul, Korea.
authors.forename: Wantae
authors.initials: W
authors.lastname: Kim
authors.affiliation: Department of Life Science, University of Seoul, Dongdaemun-gu, Seoul, Korea.
authors.forename: Eek-Hoon
authors.identifier: 0000-0003-2414-6234
authors.initials: EH
authors.lastname: Jho
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA kuguan@ucsd.edu.
authors.forename: Kun-Liang
authors.identifier: 0000-0003-1892-0174
authors.initials: KL
authors.lastname: Guan
mesh_terms: D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002466:Cell Nucleolus; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D009997:Osmotic Pressure; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D021381:Protein Transport; D012694:Serine / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D012694:Serine; C470551:NLK protein, human; D017346:Protein Serine-Threonine Kinases
keywords: 14‐3‐3; Hippo; NLK; YAP; osmotic stress