Modulation of beta-catenin phosphorylation/degradation by cyclin-dependent kinase 2.
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.
Park
Chun Shik
CS
Department of Life Science, Kwangju Institute of Science and Technology, 1 Oryong-dong, Puk-gu, Kwangju 500-712, Korea.
Kim
Sung Il
SI
Lee
Mi Su
MS
Youn
Cho-Ya
CY
Kim
Dae Joong
DJ
Jho
Eek-Hoon
EH
Song
Woo Keun
WK
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D042846:CDC2-CDC28 Kinases / Q000378:metabolism*; D002453:Cell Cycle; D002460:Cell Line; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation; D016193:G1 Phase; D005982:Glutathione Transferase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D013912:Threonine / Q000737:chemistry; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D009097:Multienzyme Complexes; D011994:Recombinant Proteins; D015534:Trans-Activators; D051176:beta Catenin; D013912:Threonine; D012694:Serine; D005982:Glutathione Transferase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex