title: Regulation of the nuclear localization of the human Nedd4-related WWP1 protein by Notch.
abstract: Nedd4 family ubiquitin ligases regulate trafficking and degradation of numerous target substrates in different cellular compartments, including at the plasma membrane, in endosomes, in the secretory pathway and in the nucleus. WWP1 is a Nedd4 family protein closely related to mouse Itch and Drosophila Su(dx), both of which have been shown to regulate the Notch receptor. To investigate the possibility that WWP1 is also associated with Notch signalling we coexpressed human Notch1 and WWP1 in mouse myoblast cells. We found that WWP1 could localize to both the nucleus and cytoplasm in a context dependent manner. Coexpression of human Notch1 (hN1) depleted WWP1 from the nucleus to colocalise with hN1 in early endosomes, dependent on the presence of the C-terminal HECT domain. Furthermore we found that full-length expressed WWP1 could interact in vitro with the cytoplasmic domain of human Notch1. The Notch receptor has multiple roles in development, mediating a short-range signal that controls cell fate and pattern formation. The canonical Notch signal involves proteolytic release of the soluble Notch intracellular domain and the activation by the latter of the transcription factor Suppressor of Hairless/CBF-1 in the nucleus. This pathway does not however account for all of the activity of Notch. The ability of Notch to regulate the nuclear localization of WWP1 suggests a possible alternative mechanism by which Notch may communicate a signal to the nucleus. Drosophila Notch similarly regulated the nuclear localization of the Drosophila Nedd4 family protein, Suppressor of deltex, implying conservation of this mechanism during evolution.
authors.affiliation: University of Manchester, Faculty of Life Sciences, Michael Smith Building, Manchester.
authors.forename: Marzena
authors.initials: M
authors.lastname: Flasza
authors.forename: Ngoc-Sa
authors.initials: NS
authors.lastname: Nguyen Huu
authors.forename: Sabine
authors.initials: S
authors.lastname: Mazaleyrat
authors.forename: Sylvaine
authors.initials: S
authors.lastname: Clémence
authors.forename: Cécile
authors.initials: C
authors.lastname: Villemant
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
authors.forename: Martin
authors.initials: M
authors.lastname: Baron
mesh_terms: D000818:Animals; D002451:Cell Compartmentation; D002466:Cell Nucleolus; D002478:Cells, Cultured; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D051379:Mice; D000075702:Nedd4 Ubiquitin Protein Ligases; D019913:Nuclear Localization Signals; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051881:Receptor, Notch1 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; C497761:NOTCH1 protein, human; D019913:Nuclear Localization Signals; D051881:Receptor, Notch1; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618483:Nedd4 protein, human; C000618461:Nedd4l protein, mouse; C119838:Su(dx) protein, Drosophila; C471642:WWP1 protein, human; D044767:Ubiquitin-Protein Ligases