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Updated: Jan 21, 2026

Measuring Enzymatic Activity of Neurodevelopmental Disorder-Associated Deubiquitylating Enzymes via an In Vitro Ubiquitin Chain Cleavage Assay
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Measuring Enzymatic Activity of Neurodevelopmental Disorder-Associated Deubiquitylating Enzymes via an In Vitro Ubiquitin Chain Cleavage Assay

Published on: September 27, 2024

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USP9X Deubiquitylates DVL2 to Regulate WNT Pathway Specification

Casey P Nielsen1, Kristin K Jernigan1, Nicole L Diggins2

  • 1Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37240, USA.

Cell Reports
|July 25, 2019
PubMed

Insights

USP9X and WWP1 control DVL2 ubiquitylation, directing WNT signaling. USP9X promotes canonical WNT, while ubiquitylation activates the WNT-planar cell polarity pathway, impacting cancer therapeutics.

Area of Science:

  • Cellular biology
  • Molecular signaling
  • Biochemistry

Background:

  • The WNT signaling network regulates complex cellular processes through distinct pathways.
  • Distinguishing between canonical and noncanonical WNT pathways is crucial but challenging due to shared signaling components.

Purpose of the Study:

  • To investigate the roles of USP9X and WWP1 in regulating DVL2 ubiquitylation.
  • To elucidate how DVL2 ubiquitylation status determines its involvement in canonical WNT versus WNT-planar cell polarity (PCP) pathways.

Main Methods:

  • Investigated the deubiquitylase USP9X and E3 ligase WWP1 activity on DVL2.
  • Analyzed DVL2 ubiquitylation levels and localization under different WNT pathway activations.

Main Results:

  • USP9X deubiquitylation of DVL2 is essential for canonical WNT pathway activation.
  • Increased ubiquitylation of DVL2 correlates with its localization to actin-rich regions and activation of the WNT-PCP pathway.
  • A WWP1-USP9X axis regulates DVL2 ubiquitylation, acting as a switch between WNT pathways.

Conclusions:

  • A novel regulatory mechanism involving a ubiquitin rheostat on DVL2 specifies WNT pathway choice.
  • Targeting USP9X offers potential therapeutic strategies for WNT-pathway-driven human cancers.
Keywords:
DUB-E3 interactionsE3 ubiquitin ligasesUSP9XWNT signalingWNT-PCP signalingWWP1deubiquitylasesnon-canonical WNT signalingubiquitin rheostat

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