Deubiquitination of Dishevelled by Usp14 is required for Wnt signaling.

ABSTRACT: Dishevelled (Dvl) is a key regulator of Wnt signaling both in the canonical and non-canonical pathways. Here we report the identification of a regulatory domain of ubiquitination (RDU) in the C-terminus of Dvl. Mutations in the RDU resulted in accumulation of polyubiquitinated forms of Dvl, which were mainly K63 linked. Small interfering RNA-based screening identified Usp14 as a mediator of Dvl deubiquitination. Genetic and chemical suppression of Usp14 activity caused an increase in Dvl polyubiquitination and significantly impaired downstream Wnt signaling. These data suggest that Usp14 functions as a positive regulator of the Wnt signaling pathway. Consistently, tissue microarray analysis of colon cancer revealed a strong correlation between the levels of Usp14 and ?-catenin, which suggests an oncogenic role for Usp14 via enhancement of Wnt/?-catenin signaling.

SUBMITTER: Jung H 

PROVIDER: S-EPMC3759127 | biostudies-other | 2013 Aug

REPOSITORIES: biostudies-other