title: Disinhibition of the HECT E3 ubiquitin ligase WWP2 by polymerized Dishevelled.
abstract: Dishevelled is a pivot in Wnt signal transduction, controlling both β-catenin-dependent transcription to specify proliferative cell fates, and cell polarity and other non-nuclear events in post-mitotic cells. In response to Wnt signals, or when present at high levels, Dishevelled forms signalosomes by dynamic polymerization. Its levels are controlled by ubiquitylation, mediated by various ubiquitin ligases, including NEDD4 family members that bind to a conserved PPxY motif in Dishevelled (mammalian Dvl1-3). Here, we show that Dvl2 binds to the ubiquitin ligase WWP2 and unlocks its ligase activity from autoinhibition. This disinhibition of WWP2 depends on several features of Dvl2 including its PPxY motif and to a lesser extent its DEP domain, but crucially on the ability of Dvl2 to polymerize, indicating that WWP2 is activated in Wnt signalosomes. We show that Notch intracellular domains are substrates for Dvl-activated WWP2 and their transcriptional activity is consequently reduced, providing a molecular mechanism for cross-talk between Wnt and Notch signalling. These regulatory interactions are conserved in Drosophila whose WWP2 orthologue, Suppressor-of-deltex, downregulates Notch signalling upon activation by Dishevelled in developing wing tissue. Attentuation of Notch signalling by Dishevelled signalosomes could be important during the transition of cells from the proliferative to the post-mitotic state.
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Mund
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Graeb
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Juliusz
authors.initials: J
authors.lastname: Mieszczanek
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.
authors.forename: Melissa
authors.initials: M
authors.lastname: Gammons
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK hp@mrc-lmb.cam.ac.uk.
authors.forename: Hugh R B
authors.initials: HR
authors.lastname: Pelham
authors.affiliation: MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK mb2@mrc-lmb.cam.ac.uk.
authors.forename: Mariann
authors.initials: M
authors.lastname: Bienz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002460:Cell Line; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D006801:Humans; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000606578:DVL1 protein, human; C000606581:DVL2 protein, human; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D010750:Phosphoproteins; D051153:Wnt Proteins; C000606588:dsh protein, Drosophila; C465283:WWP2 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: DEP domain; Dishevelled polymerization; NEDD4 family HECT E3 ubiquitin ligases; Notch; Wnt