Modulation of beta-catenin by cyclin-dependent kinase 6 in Wnt-stimulated cells.
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.
Park
Chun Shik
CS
Department of Life Science and Molecular Disease Research Center, Gwangju Institute of Science and Technology, 1 Oryong-dong, Buk-gu, Gwangju 500-712, Korea.
Lee
Mi Su
MS
Oh
Hye-jin
HJ
Choi
Kyu Yeong
KY
Yeo
Myeong Gu
MG
Chun
Jang-soo
JS
Song
Woo Keun
WK
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*
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