title: DLG5 connects cell polarity and Hippo signaling protein networks by linking PAR-1 with MST1/2.
abstract: Disruption of apical-basal polarity is implicated in developmental disorders and cancer; however, the mechanisms connecting cell polarity proteins with intracellular signaling pathways are largely unknown. We determined previously that membrane-associated guanylate kinase (MAGUK) protein discs large homolog 5 (DLG5) functions in cell polarity and regulates cellular proliferation and differentiation via undefined mechanisms. We report here that DLG5 functions as an evolutionarily conserved scaffold and negative regulator of Hippo signaling, which controls organ size through the modulation of cell proliferation and differentiation. Affinity purification/mass spectrometry revealed a critical role of DLG5 in the formation of protein assemblies containing core Hippo kinases mammalian ste20 homologs 1/2 (MST1/2) and Par-1 polarity proteins microtubule affinity-regulating kinases 1/2/3 (MARK1/2/3). Consistent with this finding, Hippo signaling is markedly hyperactive in mammalian Dlg5-/-tissues and cells in vivo and ex vivo and in Drosophila upon dlg5 knockdown. Conditional deletion of Mst1/2 fully rescued the phenotypes of brain-specific Dlg5 knockout mice. Dlg5 also interacts genetically with Hippo effectors Yap1/Taz Mechanistically, we show that DLG5 inhibits the association between MST1/2 and large tumor suppressor homologs 1/2 (LATS1/2), uses its scaffolding function to link MST1/2 with MARK3, and inhibits MST1/2 kinase activity. These data reveal a direct connection between cell polarity proteins and Hippo, which is essential for proper development of multicellular organisms.
authors.affiliation: Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
authors.forename: Julian
authors.initials: J
authors.lastname: Kwan
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Sczaniecka
authors.affiliation: Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada.|Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Emad
authors.initials: E
authors.lastname: Heidary Arash
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Liem
authors.initials: L
authors.lastname: Nguyen
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Chia-Chun
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada.|Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Srdjana
authors.initials: S
authors.lastname: Ratkovic
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Klezovitch
authors.affiliation: Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada.|Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Liliana
authors.initials: L
authors.lastname: Attisano
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada.|Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Helen
authors.initials: H
authors.lastname: McNeill
authors.affiliation: Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Emili
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.|Department of Pathology, Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Valeri
authors.initials: V
authors.lastname: Vasioukhin
mesh_terms: D000818:Animals; D016764:Cell Polarity / Q000235:genetics*; D002478:Cells, Cultured; D004330:Drosophila / Q000196:embryology / Q000201:enzymology / Q000235:genetics; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D000072417:Protein Domains; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D034622:RNA Interference; D015398:Signal Transduction / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C114461:DLG5 protein, human; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins; D017346:Protein Serine-Threonine Kinases
keywords: Drosophila development; Hippo signaling; cell polarity; functional proteomics; interaction network; mammalian development; protein complex