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

Abstract

beta-Catenin functions as a downstream component of the Wnt/Wingless signal transduction pathway, and inappropriate control of cytosolic beta-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 beta-catenin. In vivo and in vitro kinase assays with cyclin-CDK2 demonstrate beta-catenin phosphorylation on residues Ser(33), Ser(37), Thr(41), and Ser(45). This phosphorylation promotes rapid degradation of cytosolic beta-catenin via the beta-TrCP-mediated proteasome pathway. Moreover, cyclin E-CDK2 contributes to rapid degradation of cytosolic beta-catenin levels during G(1) phase by regulating beta-catenin phosphorylation and subsequent degradation. In this way, CDK2 may "fine tune" beta-catenin levels over the course of the cell cycle.