title: Differential regulation of the Hippo pathway by adherens junctions and apical-basal cell polarity modules.
abstract: Adherens junctions (AJs) and cell polarity complexes are key players in the establishment and maintenance of apical-basal cell polarity. Loss of AJs or basolateral polarity components promotes tumor formation and metastasis. Recent studies in vertebrate models show that loss of AJs or loss of the basolateral component Scribble (Scrib) cause deregulation of the Hippo tumor suppressor pathway and hyperactivation of its downstream effectors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). However, whether AJs and Scrib act through the same or independent mechanisms to regulate Hippo pathway activity is not known. Here, we dissect how disruption of AJs or loss of basolateral components affect the activity of the Drosophila YAP homolog Yorkie (Yki) during imaginal disc development. Surprisingly, disruption of AJs and loss of basolateral proteins produced very different effects on Yki activity. Yki activity was cell-autonomously decreased but non-cell-autonomously elevated in tissues where the AJ components E-cadherin (E-cad) or α-catenin (α-cat) were knocked down. In contrast, scrib knockdown caused a predominantly cell-autonomous activation of Yki. Moreover, disruption of AJs or basolateral proteins had different effects on cell polarity and tissue size. Simultaneous knockdown of α-cat and scrib induced both cell-autonomous and non-cell-autonomous Yki activity. In mammalian cells, knockdown of E-cad or α-cat caused nuclear accumulation and activation of YAP without overt effects on Scrib localization and vice versa. Therefore, our results indicate the existence of multiple, genetically separable inputs from AJs and cell polarity complexes into Yki/YAP regulation.
authors.affiliation: Departments of Biochemistry and Molecular Biology and Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030; Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Chih-Chao
authors.initials: CC
authors.lastname: Yang
authors.affiliation: Departments of Biochemistry and Molecular Biology and.
authors.forename: Hillary K
authors.initials: HK
authors.lastname: Graves
authors.affiliation: Vlaams Instituut voor Biotechnologie Center for the Biology of Disease and Katholieke Universiteit Leuven Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium; and.
authors.forename: Ivan M
authors.initials: IM
authors.lastname: Moya
authors.affiliation: Departments of Biochemistry and Molecular Biology and.
authors.forename: Chunyao
authors.initials: C
authors.lastname: Tao
authors.affiliation: Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Fisun
authors.initials: F
authors.lastname: Hamaratoglu
authors.affiliation: Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030; Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Gladden
authors.affiliation: Departments of Biochemistry and Molecular Biology and Program in Genes and Development, The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030; Vlaams Instituut voor Biotechnologie Center for the Biology of Disease and Katholieke Universiteit Leuven Center for Human Genetics, University of Leuven, 3000 Leuven, Belgium; and georg.halder@vib.be.
authors.forename: Georg
authors.initials: G
authors.lastname: Halder
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism*; D000818:Animals; D018938:Caco-2 Cells; D015820:Cadherins / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics; D016764:Cell Polarity / Q000502:physiology*; D003433:Crosses, Genetic; D017931:DNA Primers / Q000235:genetics; D004285:Dogs; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D060227:Imaginal Discs / Q000254:growth & development*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D008565:Membrane Proteins; D009024:Morphogenesis / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000091102:YAP-Signaling Proteins; D051178:alpha Catenin / Q000235:genetics; D000099317:Hippo Kinases
chemical_list: D015820:Cadherins; D015815:Cell Adhesion Molecules; D017931:DNA Primers; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; D051178:alpha Catenin; C502521:Dis3 protein, Drosophila; C404683:Scrib protein, Drosophila; C503814:Yki protein, Drosophila; C081439:alpha-Cat protein, Drosophila; C501889:shg protein, Drosophila; C499474:hpo protein, Drosophila; D000099317:Hippo Kinases
keywords: Drosophila imaginal discs; Hippo pathway; adherens junction; apical–basal cell polarity; basolateral protein