Proteomics

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Huwe1-mediated ubiquitylation of Dvl defines a novel negative feedback loop in the Wnt signaling pathway

ABSTRACT: Wnt signaling plays a central role in development, adult tissue homeostasis and cancer. Several steps in the canonical Wnt/b-catenin signaling cascade are regulated by ubiquitylation, a protein modification that influences the stability, subcellular localization or protein-protein interactions of target proteins. To identify novel regulators of the Wnt/b-catenin pathway, we performed RNAi screens in C. elegans and human tissue culture cells and identified the HECT domain containing ubiquitin ligase eel-1/Huwe1 as a negative regulator of Wnt signaling. Huwe1 functions cell autonomously in signal-receiving cells and genetically acts upstream of b-catenin. Mechanistically, Huwe1 binds to and ubiquitylates the cytoplasmic Wnt pathway component Dishevelled (Dvl) in a Wnt3a and CK1e dependent manner. Huwe1 mediated ubiquitylation does not target Dvl for degradation. Instead, we found that Huwe1 decreases Dvl signaling by inhibiting Dvl multimerization. We conclude that Huwe1 is part of an evolutionarily conserved negative feedback loop in the Wnt/b-catenin pathway

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): T Cell, Cell Culture

SUBMITTER: Katerina Sedova  

LAB HEAD: Zbynek Zdrahal

PROVIDER: PXD000781 | Pride | 2014-05-28

REPOSITORIES: Pride

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Huwe1-mediated ubiquitylation of dishevelled defines a negative feedback loop in the Wnt signaling pathway.

de Groot Reinoud E A RE   Ganji Ranjani S RS   Bernatik Ondrej O   Lloyd-Lewis Bethan B   Seipel Katja K   Šedová Kateřina K   Zdráhal Zbyněk Z   Dhople Vishnu M VM   Dale Trevor C TC   Korswagen Hendrik C HC   Bryja Vitezslav V  

Science signaling 20140318 317

Wnt signaling plays a central role in development, adult tissue homeostasis, and cancer. Several steps in the canonical Wnt/β-catenin signaling cascade are regulated by ubiquitylation, a protein modification that influences the stability, subcellular localization, or interactions of target proteins. To identify regulators of the Wnt/β-catenin pathway, we performed an RNA interference screen in Caenorhabditis elegans and identified the HECT domain-containing ubiquitin ligase EEL-1 as an inhibitor  ...[more]