title: ASPP2 links the apical lateral polarity complex to the regulation of YAP activity in epithelial cells.
abstract: The Hippo pathway, by tightly controlling the phosphorylation state and activity of the transcription cofactors YAP and TAZ is essential during development and tissue homeostasis whereas its deregulation may lead to cancer. Recent studies have linked the apicobasal polarity machinery in epithelial cells to components of the Hippo pathway and YAP and TAZ themselves. However the molecular mechanism by which the junctional pool of YAP proteins is released and activated in epithelial cells remains unknown. Here we report that the tumour suppressor ASPP2 forms an apical-lateral polarity complex at the level of tight junctions in polarised epithelial cells, acting as a scaffold for protein phosphatase 1 (PP1) and junctional YAP via dedicated binding domains. ASPP2 thereby directly induces the dephosphorylation and activation of junctional YAP. Collectively, this study unearths a novel mechanistic paradigm revealing the critical role of the apical-lateral polarity complex in activating this localised pool of YAP in vitro, in epithelial cells, and in vivo, in the murine colonic epithelium. We propose that this mechanism may commonly control YAP functions in epithelial tissues.
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Christophe
authors.initials: C
authors.lastname: Royer
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Sofia
authors.initials: S
authors.lastname: Koch
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Xiao
authors.initials: X
authors.lastname: Qin
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Zak
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Ludovico
authors.initials: L
authors.lastname: Buti
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Ewa
authors.initials: E
authors.lastname: Dudziec
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Shan
authors.initials: S
authors.lastname: Zhong
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Indrika
authors.initials: I
authors.lastname: Ratnayaka
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Shankar
authors.initials: S
authors.lastname: Srinivas
authors.affiliation: Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D018938:Caco-2 Cells; D018797:Cell Cycle Proteins; D016764:Cell Polarity; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000378:metabolism; D021381:Protein Transport; D019108:Tight Junctions / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C090468:TP53BP2 protein, human; D014157:Transcription Factors; C456659:YY1AP1 protein, human; D054645:Protein Phosphatase 1