Wnt pathway activation by ADP-ribosylation

Area of Science:

• Cell Biology
• Developmental Biology
• Molecular Oncology

Background:

• Wnt/β-catenin signalling is vital for metazoan development and implicated in cancer.
• Wnt stimulation triggers Axin scaffold protein relocation from a destruction complex to a signalosome.
• Tankyrase (Tnks) targets Axin for degradation, influencing Wnt pathway activity.

Purpose of the Study:

• To investigate the early effects of Wnt stimulation on Axin.
• To elucidate the role of Tankyrase (Tnks) in regulating Axin's transition during Wnt signalling.
• To understand how ADP-ribosylation impacts Axin function and Wnt signalosome assembly.

Main Methods:

• Analysis of early Wnt effects on Axin in Drosophila and human cells.
• Quantification of ADP-ribosylated Axin levels following Wnt stimulation.
• Assessment of Axin's interaction with the Wnt co-receptor LRP6.

Main Results:

• ADP-ribosylated Axin levels increase immediately upon Wnt stimulation.
• ADP-ribosylation enhances Axin's interaction with LRP6, facilitating signalosome assembly.
• Tnks-dependent ADP-ribosylation promotes Axin reprogramming post-Wnt stimulation.

Conclusions:

• Tnks regulates Axin's dynamic transition during Wnt signalling through ADP-ribosylation.
• ADP-ribosylation is essential for both Axin stability and signalosome formation.
• Inhibiting Tnks disrupts Wnt signalling by impairing signalosome assembly, not just increasing destruction complex activity.