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PMID: 18281465 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Trabid, a new positive regulator of Wnt-induced transcription with preference for binding and cleaving K63-linked ubiquitin chains.

Genes & development ·Vol. 22 ·No. 4 ·2008-02-15 ·Pages 528-42

Tran H, Hamada F, Schwarz-Romond T, Bienz M

Abstract

A key effector of the canonical Wnt pathway is beta-catenin, which binds to TCF/LEF factors to promote the transcription of Wnt target genes. In the absence of Wnt stimulation, beta-catenin is phosphorylated constitutively, and modified with K48-linked ubiquitin for subsequent proteasomal degradation. Here, we identify Trabid as a new positive regulator of Wnt signaling in mammalian and Drosophila cells. Trabid show a remarkable preference for binding to K63-linked ubiquitin chains with its three tandem NZF fingers (Npl4 zinc finger), and it cleaves these chains with its OTU (ovarian tumor) domain. These activities of Trabid are required for efficient TCF-mediated transcription in cells with high Wnt pathway activity, including colorectal cancer cell lines. We further show that Trabid can bind to and deubiquitylate the APC tumor suppressor protein, a negative regulator of Wnt-mediated transcription. Epistasis experiments indicate that Trabid acts below the stabilization of beta-catenin, and that it may affect the association or activity of the TCF-beta-catenin transcription complex. Our results indicate a role of K63-linked ubiquitin chains during Wnt-induced transcription.

MeSH Terms
Animals Blotting, Western Cells, Cultured Colorectal Neoplasms/genetics,metabolism Drosophila Proteins/genetics,metabolism Drosophila melanogaster Genes, APC Humans Immunoprecipitation Lymphoid Enhancer-Binding Factor 1 NF-kappa B/genetics,metabolism Nuclear Proteins/genetics,metabolism Plasmids Proto-Oncogene Proteins RNA, Messenger/genetics,metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction TCF Transcription Factors/genetics,metabolism Transcription, Genetic Two-Hybrid System Techniques Ubiquitin/metabolism Ubiquitin-Specific Proteases/genetics,metabolism Wnt Proteins/metabolism Wnt1 Protein beta Catenin/metabolism
Chemicals
Drosophila Proteins Lef1 protein, mouse Lymphoid Enhancer-Binding Factor 1 NF-kappa B Nuclear Proteins Proto-Oncogene Proteins RNA, Messenger TCF Transcription Factors Ubiquitin Wnt Proteins Wnt1 Protein beta Catenin wg protein, Drosophila Ubiquitin-Specific Proteases trbd protein, Drosophila
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Tran Hoanh
Medical Research Council Laboratory of Molecular Biology, Cambridge, CB2 2QH, United Kingdom.
Hamada Fumihiko
Schwarz-Romond Thomas
Bienz Mariann
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.463208
Published
2008-02-15
Pages
528-42
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC2238673
Subset
IM
Grants
Medical Research Council · MC_U105184273 · United Kingdom
Medical Research Council · MC_U105192713 · United Kingdom
External Links
PubMed source DOI: 10.1101/gad.463208 PMC Full Text View journal details
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