Dataset Information

Understanding How Wnt Influences Destruction Complex Activity and ?-Catenin Dynamics.

ABSTRACT: Despite extensive research on the canonical Wnt signaling pathway, the mechanism by which this signal downregulates the activity of destruction complexes and inhibits ?-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 ?-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 ?-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.

SUBMITTER: Mukherjee A

PROVIDER: S-EPMC6137275 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Mukherjee Abhirup A Dhar Neha N Stathos Mark M Schaffer David V DV Kane Ravi S RS

iScience 20180717

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 resul ...[more]

PMID: 30240607

Similar Datasets

Project description:Wnt signaling provides a paradigm for cell-cell signals that regulate embryonic development and stem cell homeostasis and are inappropriately activated in cancers. The tumor suppressors APC and Axin form the core of the multiprotein destruction complex, which targets the Wnt-effector beta-catenin for phosphorylation, ubiquitination and destruction. Based on earlier work, we hypothesize that the destruction complex is a supramolecular entity that self-assembles by Axin and APC polymerization, and that regulating assembly and stability of the destruction complex underlie its function. We tested this hypothesis in Drosophila embryos, a premier model of Wnt signaling. Combining biochemistry, genetic tools to manipulate Axin and APC2 levels, advanced imaging and molecule counting, we defined destruction complex assembly, stoichiometry, and localization in vivo, and its downregulation in response to Wnt signaling. Our findings challenge and revise current models of destruction complex function. Endogenous Axin and APC2 proteins and their antagonist Dishevelled accumulate at roughly similar levels, suggesting competition for binding may be critical. By expressing Axin:GFP at near endogenous levels we found that in the absence of Wnt signals, Axin and APC2 co-assemble into large cytoplasmic complexes containing tens to hundreds of Axin proteins. Wnt signals trigger recruitment of these to the membrane, while cytoplasmic Axin levels increase, suggesting altered assembly/disassembly. Glycogen synthase kinase3 regulates destruction complex recruitment to the membrane and release of Armadillo/beta-catenin from the destruction complex. Manipulating Axin or APC2 levels had no effect on destruction complex activity when Wnt signals were absent, but, surprisingly, had opposite effects on the destruction complex when Wnt signals were present. Elevating Axin made the complex more resistant to inactivation, while elevating APC2 levels enhanced inactivation. Our data suggest both absolute levels and the ratio of these two core components affect destruction complex function, supporting models in which competition among Axin partners determines destruction complex activity.

Dataset Information

Understanding How Wnt Influences Destruction Complex Activity and ?-Catenin Dynamics.

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets