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USP9X Deubiquitylates DVL2 to Regulate WNT Pathway Specification

dc.contributor.authorNielsen, Casey P.
dc.contributor.authorJemigan, Kristin K.
dc.contributor.authorDiggins, Nicole L.
dc.contributor.authorWebb, Donna J.
dc.contributor.authorMacGurn, Jason A.
dc.description.abstractThe 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 noncanonical 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, regulate a ubiquitin rheostat on DVL2, a WNT signaling protein. Our findings indicate that USP9X-mediated deubiquitylation of DVL2 is required for canonical WNT activation, while increased DVL2 ubiquitylation is associated with localization to actin-rich projections and activation of the planar cell polarity (PCP) pathway. We propose that a WWP1-USP9X axis regulates a ubiquitin rheostat 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.en_US
dc.description.sponsorshipWe are very grateful to K. Rose for helpful advice regarding technical aspects and analysis of quantitative proteomic data. We are also grateful to E. Lee, K. Saito-Diaz, and V. Ng for reagents and technical advice. We also thank T. Graham, S.M. Ahmed, S. Lee, and N. Hepowit for critical reading of this manuscript and E. MacGurn for assistance with graphic design. This research was supported by NIH grant R00 GM101077 (to J.A.M.) and an NIH SPORE grant in GI Cancer (P50 CA095103).en_US
dc.publisherCell Reportsen_US
dc.rightsThis article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.
dc.titleUSP9X Deubiquitylates DVL2 to Regulate WNT Pathway Specificationen_US

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