Journal
ONCOGENE
Volume 27, Issue 25, Pages 3546-3555Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1211026
Keywords
Wnt signalling; beta-catenin; GSK-3 beta; colorectal cancer; nucleus
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beta-Catenin is the central signalling molecule of the canonical Wnt pathway, where it activates target genes in a complex with lymphoid enhancer factor/T-cell factor transcription factors in the nucleus. The regulation of beta-catenin activity is thought to occur via a cytoplasmatic multiprotein complex that includes the serine/threonine kinase glycogen synthase kinase-3 beta (GSK-3 beta) that phosphorylates beta-catenin, marking it for degradation by the proteasome. Here, we provide evidence showing that GSK-3 beta has a nuclear function in downregulating the activity of beta-catenin. Using colorectal cell lines that express a mutant form of beta-catenin, which cannot be phosphorylated by GSK-3 beta and ectopically expressed mutant beta-catenin protein, we show that nuclear GSK-3 beta functions in a mechanism that does not involve beta-catenin phosphorylation to reduce the levels of Wnt signalling. We show that GSK-3 beta enters the nucleus, forms a complex with beta-catenin and lowers the levels of beta-catenin/TCFdependent transcription in a mechanism that involves GSK-3 beta-Axin binding.
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