title: Dlg3 trafficking and apical tight junction formation is regulated by nedd4 and nedd4-2 e3 ubiquitin ligases.
abstract: The Drosophila Discs large (Dlg) scaffolding protein acts as a tumor suppressor regulating basolateral epithelial polarity and proliferation. In mammals, four Dlg homologs have been identified; however, their functions in cell polarity remain poorly understood. Here, we demonstrate that the X-linked mental retardation gene product Dlg3 contributes to apical-basal polarity and epithelial junction formation in mouse organizer tissues, as well as to planar cell polarity in the inner ear. We purified complexes associated with Dlg3 in polarized epithelial cells, including proteins regulating directed trafficking and tight junction formation. Remarkably, of the four Dlg family members, Dlg3 exerts a distinct function by recruiting the ubiquitin ligases Nedd4 and Nedd4-2 through its PPxY motifs. We found that these interactions are required for Dlg3 monoubiquitination, apical membrane recruitment, and tight junction consolidation. Our findings reveal an unexpected evolutionary diversification of the vertebrate Dlg family in basolateral epithelium formation.
authors.affiliation: Institute of Stem Cell Research, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Claude A
authors.initials: CA
authors.lastname: Van Campenhout
authors.forename: Andrea
authors.initials: A
authors.lastname: Eitelhuber
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Gloeckner
authors.forename: Patrizia
authors.initials: P
authors.lastname: Giallonardo
authors.forename: Moritz
authors.initials: M
authors.lastname: Gegg
authors.forename: Heide
authors.initials: H
authors.lastname: Oller
authors.forename: Seth G N
authors.initials: SG
authors.lastname: Grant
authors.forename: Daniel
authors.initials: D
authors.lastname: Krappmann
authors.forename: Marius
authors.initials: M
authors.lastname: Ueffing
authors.forename: Heiko
authors.initials: H
authors.lastname: Lickert
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016764:Cell Polarity / Q000502:physiology; D007758:Ear, Inner / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D005260:Female; D051528:Guanylate Kinases / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D000075702:Nedd4 Ubiquitin Protein Ligases; D021381:Protein Transport; D019108:Tight Junctions / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D008565:Membrane Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases; C491075:Dlgh3 protein, mouse; D051528:Guanylate Kinases