title: Modulation of beta-catenin by cyclin-dependent kinase 6 in Wnt-stimulated cells.
abstract: Beta-catenin is implicated in quite different cellular processes, which require a fine-tuned regulation of its function. Here we demonstrate that cyclin-dependent kinase 6 (CDK6), in association with cyclin D1 (CCND1), directly binds to beta-catenin. We showed that CCND1-CDK6 phosphorylates beta-catenin on serine 45 (S45). This phosphorylation creates a priming site for glycogen synthase kinase 3beta (GSK3beta) and is both necessary and sufficient to initiate the beta-catenin phosphorylation-degradation cascade. Moreover, co-immunoprecipitation assays using Wnt3a-conditioned medium reveals that while Wnt stimulation leads to the dissociation of beta-catenin from axin and casein kinase Ialpha (CKIalpha), Wnt treatment promotes an increase in CCND1 level and the association of beta-catenin with CCND1-CDK6. Furthermore, Wnt3a-stimulated cytosolic beta-catenin levels were higher in CDK6 knockout mouse embryonic fibroblasts (CDK6-/- MEFs) compared to wild-type MEFs. Thus, the CCND1-CDK6 complex is like to negatively regulate Wnt signaling by mediating beta-catenin phosphorylation and its subsequent degradation in Wnt-stimulated cells.
authors.affiliation: Department of Life Science and Molecular Disease Research Center, Gwangju Institute of Science and Technology, 1 Oryong-dong, Buk-gu, Gwangju 500-712, Korea.
authors.forename: Chun Shik
authors.initials: CS
authors.lastname: Park
authors.forename: Mi Su
authors.initials: MS
authors.lastname: Lee
authors.forename: Hye-jin
authors.initials: HJ
authors.lastname: Oh
authors.forename: Kyu Yeong
authors.initials: KY
authors.lastname: Choi
authors.forename: Myeong Gu
authors.initials: MG
authors.lastname: Yeo
authors.forename: Jang-soo
authors.initials: JS
authors.lastname: Chun
authors.forename: Woo Keun
authors.initials: WK
authors.lastname: Song
mesh_terms: D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D051820:TCF Transcription Factors / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D010750:Phosphoproteins; D051820:TCF Transcription Factors; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1; D012694:Serine; D011494:Protein Kinases; D051361:Cyclin-Dependent Kinase 6