USP9X deubiquitylates DVL2 to regulate WNT pathway specification

Abstract

The WNT signaling network is comprised of multiple receptors that relay various input signals via distinct transduction pathways to execute multiple complex and context-specific output processes. Integrity of the WNT signaling network relies on proper specification between canonical and non-canonical pathways, which presents a regulatory challenge given that several signal transducing elements are shared between pathways. Here, we report that USP9X, a deubiquitylase, and WWP1, an E3 ubiquitin ligase, interact physically to regulate a ubiquitin switch on DVL2, a WNT signaling protein. Our findings indicate that USP9X-mediated deubiquitylation of DVL2 is required for canonical WNT activation, while DVL2 ubiquitylation promotes its localization to actin-rich projections and increased cellular motility. We propose that a WWP1-USP9X axis regulates a ubiquitin switch on DVL2 that specifies its participation in either canonical WNT or WNT-PCP pathways. These findings have important implications for therapeutic targeting of USP9X in human cancer.