Modulation of β-Catenin Phosphorylation/Degradation by Cyclin-dependent Kinase 2

β-Catenin functions as a downstream component of the Wnt/Wingless signal transduction pathway, and inappropriate control of cytosolic β-catenin is a crucial step in the genesis of several human cancers. Here we demonstrate that cyclin-dependent kinase 2 (CDK2) in association with cyclin A or cyclin E directly binds to β-catenin. In vivo and in vitro kinase assays with cyclin-CDK2 demonstrate β-catenin phosphorylation on residues Ser³³, Ser³⁷, Thr⁴¹, and Ser⁴⁵. This phosphorylation promotes rapid degradation of cytosolic β-catenin via the β-TrCP-mediated proteasome pathway. Moreover, cyclin E-CDK2 contributes to rapid degradation of cytosolic β-catenin levels during G₁ phase by regulating β-catenin phosphorylation and subsequent degradation. In this way, CDK2 may "fine tune" β-catenin levels over the course of the cell cycle.