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In Vitro Analysis of E3 Ubiquitin Ligase Function
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In Vitro Analysis of E3 Ubiquitin Ligase Function

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Disinhibition of the HECT E3 ubiquitin ligase WWP2 by polymerized Dishevelled

Thomas Mund1, Michael Graeb1, Juliusz Mieszczanek1

  • 1MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.

Open Biology
|December 25, 2015
PubMed

Insights

Dishevelled (Dvl) activates the WWP2 ubiquitin ligase within signalosomes, leading to Notch signaling downregulation. This mechanism links Wnt and Notch pathways, impacting cell fate transitions.

Area of Science:

  • Cellular signaling pathways
  • Molecular biology
  • Developmental biology

Background:

  • Dishevelled (Dvl) is a key regulator in Wnt signal transduction, influencing both gene transcription and cell polarity.
  • Dvl levels are controlled by ubiquitylation, involving ubiquitin ligases like NEDD4 family members that interact with Dvl's PPxY motif.
  • Dvl forms dynamic signalosomes in response to Wnt signals or high concentrations.

Purpose of the Study:

  • To investigate the interaction between Dvl2 and the ubiquitin ligase WWP2.
  • To elucidate the mechanism by which Dvl2 regulates WWP2 activity.
  • To understand the role of Dvl-activated WWP2 in Wnt-Notch signaling crosstalk.

Main Methods:

  • Biochemical assays to study Dvl2-WWP2 binding and WWP2 activity.
  • Analysis of Dvl2 polymerization and its effect on WWP2.
  • Assessment of Notch signaling components as substrates for Dvl-activated WWP2.

Main Results:

  • Dvl2 binds to WWP2 and relieves its autoinhibition, activating its ligase activity.
  • WWP2 activation by Dvl2 depends on Dvl2's PPxY motif, DEP domain, and critically, its polymerization into signalosomes.
  • Dvl-activated WWP2 targets Notch intracellular domains, reducing their transcriptional activity.
  • This crosstalk mechanism is conserved in Drosophila, where Suppressor-of-deltex (Drosophila WWP2) is activated by Dishevelled to downregulate Notch signaling.

Conclusions:

  • Dvl-mediated activation of WWP2 within signalosomes provides a molecular link between Wnt and Notch signaling pathways.
  • This regulation is crucial for attenuating Notch signaling during the transition from proliferative to post-mitotic states.
  • The findings reveal a conserved mechanism controlling cell fate decisions through pathway crosstalk.
Keywords:
DEP domainDishevelled polymerizationNEDD4 family HECT E3 ubiquitin ligasesNotchWnt

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