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Modeling Paracrine Noncanonical Wnt Signaling In Vitro
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Dishevelled phase separation promotes Wnt signalosome assembly and destruction complex disassembly

Kexin Kang1, Qiaoni Shi1, Xu Wang2

  • 1The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.

The Journal of Cell Biology
|November 7, 2022
PubMed

Insights

Dishevelled 2 (Dvl2) protein undergoes liquid-liquid phase separation (LLPS), a crucial mechanism controlling Wnt/β-catenin signaling. Dvl2 LLPS regulates signalosome assembly and disrupts the β-catenin destruction complex.

Area of Science:

  • Cell biology
  • Molecular signaling
  • Biochemistry

Background:

  • Wnt/β-catenin signaling is vital for development and disease.
  • Precise control of signaling amplitude relies on two key protein complexes: the Wnt receptor signalosome and the β-catenin destruction complex.
  • The coordination between these complexes is not well understood.

Purpose of the Study:

  • To investigate the role of Dishevelled 2 (Dvl2) in Wnt/β-catenin signaling.
  • To elucidate the mechanism by which Dvl2 influences the assembly and function of the Wnt receptor signalosome and the β-catenin destruction complex.
  • To explore the involvement of liquid-liquid phase separation (LLPS) in this process.

Main Methods:

  • Investigated Dvl2's ability to undergo LLPS.
  • Examined the role of Dvl2's intrinsically disordered region in LLPS.
  • Studied the interaction of Dvl2 with signalosome components like Fzd5.
  • Analyzed the recruitment dynamics of Dvl2 and Axin1 to the cell membrane.
  • Assessed the impact of Dvl2 on Axin1 LLPS and the destruction complex.

Main Results:

  • Demonstrated that Dvl2 undergoes LLPS, mediated by its intrinsically disordered region and facilitated by Fzd5.
  • Showed that Dvl2 rapidly recruits to the membrane, initiating signalosome assembly, followed by slower Axin1 recruitment.
  • Revealed that Dvl2 attenuates Axin1 LLPS, thereby disrupting the β-catenin destruction complex.
  • Observed that Axin partitions into the signalosome at lower concentrations with higher mobility compared to the destruction complex.

Conclusions:

  • Dvl2-mediated LLPS is essential for controlling Wnt receptor signalosome assembly.
  • Dvl2 LLPS plays a critical role in disrupting the phase-separated β-catenin destruction complex.
  • These findings provide new insights into the regulation of Wnt/β-catenin signaling through phase separation.

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