Nuclear GSK-3b inhibits the canonical Wnt signalling pathway in a b-catenin phosphorylation-independent manner

b-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 b-catenin activity is thought to occur via a cytoplasmatic multiprotein complex that includes the serine/threonine kinase glycogen synthase kinase-3b (GSK-3b) that phosphorylates b-catenin, marking it for degradation by the proteasome. Here, we provide evidence showing that GSK-3b has a nuclear function in downregulating the activity of b-catenin. Using colorectal cell lines that express a mutant form of b-catenin, which cannot be phosphorylated by GSK-3b and ectopically expressed mutant b-catenin protein, we show that nuclear GSK-3b functions in a mechanism that does not involve b-catenin phosphorylation to reduce the levels of Wnt signalling. We show that GSK-3b enters the nucleus, forms a complex with b-catenin and lowers the levels of b-catenin/TCF-dependent transcription in a mechanism that involves GSK-3b-Axin binding.Oncogene (2008) 27, 3546-3555; doi:10.1038/sj.onc.1211026; published online 28 January 2008