MAP3K1 functionally interacts with Axin1 in the canonical Wnt signalling pathway.

Biological Chemistry
Ser Sue NgHans Clevers

Abstract

A central point of regulation in the Wnt/beta-catenin signalling pathway is the formation of the beta-catenin destruction complex. Axin1, an essential negative regulator of Wnt signalling, serves as a scaffold within this complex and is critical for rapid turnover of beta-catenin. To examine the mechanism by which Wnt signalling disables the destruction complex, we used an immunoprecipitation-coupled proteomics approach to identify novel endogenous binding partners of Axin1. We found mitogen-activated protein kinase kinase kinase 1 (MAP3K1) as an Axin1 interactor in Ls174T colorectal cancer (CRC) cells. Importantly, confirmation of this interaction in HEK293T cells indicated that the Axin1-MAP3K1 interaction is induced and modulated by Wnt stimulation. siRNA depletion of MAP3K1 specifically abrogated TCF/LEF-driven transcription and Wnt3A-driven endogenous gene expression in both HEK293T as well as DLD-1 CRC. Expression of ubiquitin ligase mutants of MAP3K1 abrogated TCF/LEF transcription, whereas kinase mutants had no effect in TCF-driven activity, highlighting the essential role of the MAP3K1 E3 ubiquitin ligase activity in regulation of the Wnt/beta-catenin pathway. These results suggest that MAP3K1, previously reported as a...Continue Reading

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Citations

Mar 5, 2010·Biological Chemistry·Fred Wittinghofer
Sep 11, 2012·Gastroenterology·Gui Jie FengTrevor C Dale
Nov 30, 2010·Drug Discovery Today·Folkert Verkaar, Guido J R Zaman
Dec 4, 2012·Developmental Biology·Chang JinYing Xia
Apr 2, 2015·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Mojtaba GolpichAbolhassan Ahmadiani
Oct 12, 2010·Cell Cycle·Daniele V F Tauriello, Madelon M Maurice
Oct 19, 2013·Human Molecular Genetics·Johnny LokeHarry Ostrer
Oct 21, 2011·Journal of Proteome Research·Maximiliane Hilger, Matthias Mann

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