Understanding How Wnt Influences Destruction Complex Activity and β-Catenin Dynamics

Abstract

Summary: Despite extensive research on the canonical Wnt signaling pathway, the mechanism by which this signal downregulates the activity of destruction complexes and inhibits β-catenin degradation remains controversial. In particular, recent attention has focused on two main competing mechanisms—inhibition of phosphorylation and inhibition of ubiquitination. Our combined experimental and theoretical analysis demonstrates that the disassembly of a fraction of the intracellular destruction complexes results in the partial inhibition of both β-catenin phosphorylation and ubiquitination. This inhibition is spatially patterned, consistent with the relocalization of some destruction complexes to the cellular membrane upon Wnt stimulation. Moreover, in contrast to the generally accepted view that the destruction complex is highly processive, our analysis supports a distributive model, in which β-catenin can dissociate from the complex between sequential phosphorylation events. Understanding the fundamental mechanism by which Wnt signaling is regulated provides a rational basis for tuning the pathway for scientific and therapeutic purposes. : Molecular Biology; Molecular Mechanism of Gene Regulation; Bioinformatics Subject Areas: Molecular Biology, Molecular Mechanism of Gene Regulation, Bioinformatics