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bioRxiv · 10.1101/289595

Regulation of DVL2 ubiquitylation by USP9X biases participation in canonical or non-canonical WNT signalling

Nielsen, C. P.·Jernigan, K. K.·MacGurn, J. A.
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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.

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Nielsen, C. P., Jernigan, K. K., MacGurn, J. A.. 2018-03-27. Regulation of DVL2 ubiquitylation by USP9X biases participation in canonical or non-canonical WNT signalling. https://doi.org/10.1101/289595

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