Jiang, Xiaomo, Kheifets, Olga, Zamponi, Raffaella, Yang, Yi and Cong, Feng (2015) Dishevelled promotes wnt receptor degradation through recruitment of znrf3/rnf43 e3ubiquitin ligases. Molecular Cell, 58 (3). pp. 522-533. ISSN 1097-4164

Abstract

Tumor suppressors ZNRF3 and RNF43 inhibit Wnt signaling through promoting degradation of Wnt coreceptors Frizzled (FZD) and LRP6, and this activity is counteracted by stem cell growth factor R-spondin. The mechanism by which ZNRF3 and RNF43 recognize Wnt receptors remains unclear. Here we uncover an unexpected role of Dishevelled (DVL), a positive Wnt regulator, in promoting Wnt receptor degradation. DVL knockout cells have significantly increased cell surface levels of FZD and LRP6. DVL is required for ZNRF3/RNF43-mediated ubiquitination and degradation of FZD. Physical interaction with DVL is essential for the Wnt inhibitory activity of ZNRF3/RNF43. Binding of FZD through the DEP domain of DVL is required for DVL-mediated downregulation of FZD. Fusion of the DEP domain to ZNRF3/RNF43 overcomes their DVL dependency to downregulate FZD. Our study reveals DVL as a dual function adaptor to recruit negative regulators ZNRF3/RNF43 to Wnt receptors to ensure proper control of pathway activity.

Item Type:	Article
Date Deposited:	14 Mar 2018 00:45
Last Modified:	25 Jan 2019 00:45
URI:	https://oak.novartis.com/id/eprint/23906