Fig. 3. Central role of GSK-3 in the Wnt/ß-catenin pathway. In unstimulated cells, CKI phosphorylates ß-catenin on S45, priming it for subsequent phosphorylation by GSK-3 (S41, S37, S33), which targets ß-catenin for ubiquitylation and proteasomal degradation. The ankyrin repeat protein, Diversin (Div), may help recruit CKI to the destruction complex. Wnt stimulation activates the receptor Frizzled, which then signals through Dishevelled (Dvl), using an unclear mechanism, to inactivate ß-catenin phosphorylation. Unphosphorylated ß-catenin accumulates and then translocates to the nucleus where it transactivates genes regulated by TCF/LEF transcription factors. The GSK-3-binding protein (GBP/FRAT) may be involved in transmission of a Wnt signal by regulating binding of GSK-3 to the scaffold protein, axin.

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