Journal article
USP47 deubiquitylates Groucho/TLE to promote Wnt-?-catenin signaling
Science signaling, Vol.16(771), 8372
02/07/2023
DOI: 10.1126/scisignal.abn8372
PMCID: PMC10038201
PMID: 36749823
Abstract
The Wnt-beta-catenin signal transduction pathway is essential for embryonic development and adult tissue ho-meostasis. Wnt signaling converts TCF from a transcriptional repressor to an activator in a process facilitated by the E3 ligase XIAP. XIAP-mediated monoubiquitylation of the transcriptional corepressor Groucho (also known as TLE) decreases its affinity for TCF, thereby allowing the transcriptional coactivator beta-catenin to dis -place it on TCF. Through a genome-scale screen in cultured Drosophila melanogaster cells, we identified the deubiquitylase USP47 as a positive regulator of Wnt signaling. We found that USP47 was required for Wnt sig-naling during Drosophila and Xenopus laevis development, as well as in human cells, indicating evolutionary conservation. In human cells, knockdown of USP47 inhibited Wnt reporter activity, and USP47 acted down-stream of the (3-catenin destruction complex. USP47 interacted with TLE3 and XIAP but did not alter their amounts; however, knockdown of USP47 enhanced XIAP-mediated ubiquitylation of TLE3. USP47 inhibited ubiquitylation of TLE3 by XIAP in vitro in a dose-dependent manner, suggesting that USP47 is the deubiquity-lase that counteracts the E3 ligase activity of XIAP on TLE. Our data suggest a mechanism by which regulated ubiquitylation and deubiquitylation of TLE enhance the ability of (3-catenin to cycle on and off TCF, thereby helping to ensure that the expression of Wnt target genes continues only as long as the upstream signal is present.
Details
- Title: Subtitle
- USP47 deubiquitylates Groucho/TLE to promote Wnt-?-catenin signaling
- Creators
- Sara Kassel - Vanderbilt UniversityAlison J. Hanson - Vanderbilt UniversityHassina Benchabane - Dartmouth Coll, Dept Mol & Syst Biol, Geisel Sch Med, Hanover, NH 03755 USAKenyi Saito-Diaz - Vanderbilt UniversityCarly R. Cabel - University of ArizonaLily Goldsmith - Vanderbilt UniversityMuhammad Taha - Dartmouth Coll, Dept Mol & Syst Biol, Geisel Sch Med, Hanover, NH 03755 USAAksheta Kanuganti - Dartmouth Coll, Dept Mol & Syst Biol, Geisel Sch Med, Hanover, NH 03755 USAVictoria H. Ng - Vanderbilt UniversityGeorge Xu - Vanderbilt UniversityFei Ye - Vanderbilt UniversityJulia Picker - Dartmouth Coll, Dept Mol & Syst Biol, Geisel Sch Med, Hanover, NH 03755 USAFillip Port - Heidelberg Univ, German Canc Res Ctr DKFZ, Div Signaling & Funct Genom, Med Fac Mannheim, Neuenheimer Feld 580, D-69120 Heidelberg, GermanyMichael Boutros - Heidelberg Univ, German Canc Res Ctr DKFZ, Div Signaling & Funct Genom, Med Fac Mannheim, Neuenheimer Feld 580, D-69120 Heidelberg, GermanyVivian L. Weiss - Vanderbilt UniversityDavid J. Robbins - Georgetown UniversityCurtis A. Thorne - University of ArizonaYashi Ahmed - Dartmouth Coll, Dept Mol & Syst Biol, Geisel Sch Med, Hanover, NH 03755 USAEthan Lee - Vanderbilt University
- Resource Type
- Journal article
- Publication Details
- Science signaling, Vol.16(771), 8372
- DOI
- 10.1126/scisignal.abn8372
- PMID
- 36749823
- PMCID
- PMC10038201
- NLM abbreviation
- Sci Signal
- ISSN
- 1945-0877
- eISSN
- 1937-9145
- Publisher
- Amer Assoc Advancement Science
- Number of pages
- 10
- Grant note
- T32CA009213; 5T32GM008554; T32CA00959228; 5F30ES016504; R35GM136233; R35GM122516; R01CA219189; R01CA244188; DK103126; R35GM147128; K08 CA240901-01A1; R01CA272875 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 133934-CSDG-19-216-01-TBG; RSG-22-084-01-MM / American Cancer Society Lombardi Comprehensive Cancer Center SFB1324 / Deutsche Forschungsgemeinschaft (DFG, German Research Foundation); German Research Foundation (DFG)
- Language
- English
- Date published
- 02/07/2023
- Academic Unit
- Psychiatry
- Record Identifier
- 9984823120702771
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