, Volume 62, Issue 5, pp 606-618

A second protein kinase CK1-mediated step negatively regulates Wnt signalling by disrupting the lymphocyte enhancer factor-1/β-catenin complex

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Abstract.

Deregulated activation of the canonical Wnt signalling pathway leads to stabilization of β-catenin and is critically involved in carcinogenesis by an inappropriate induction of lymphocyte enhancer factor (LEF-1)/β-catenindependent transcription of Wnt target genes. Phosphorylation of the pathway components β-catenin, Dishevelled, Axin and APC (adenomatous polyposis coli) by glycogen synthase kinase-3β, CK1 and CK2 is of central importance in the regulation of the β-catenin destruction complex. Here, we identify CK1 and CK2 as major kinases that directly bind to and phosphorylate LEF-1 inducing distinct, kinase-specific changes in the LEF-1/DNA complex. Moreover, CK1-dependent phosphorylation in contrast to CK2 disrupts the association of β-catenin and LEF-1 but does not impair DNA binding of LEF-1. Sequential phosphorylation assays revealed that for efficient disruption of the LEF-1/β-catenin complex, β-catenin also has to be phosphorylated. Consistent with these observations, CK1-dependent phosphorylation inhibits, whereas CK2 activates LEF-1/β-catenin transcriptional activity in reporter gene assays. These data are in line with a negative regulatory function of CK1 in the Wnt signalling pathway, where CK1 in addition to the β-catenin destruction complex at a second level acts as a negative regulator of the LEF-1/β-catenin transcription complex, thereby protecting cells from development of cancer.

Received 11 November 2004; received after revision 6 January 2005; accepted 10 January 2005