Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism.
Wnt regulation of beta-catenin degradation is essential for development and carcinogenesis. beta-catenin degradation is initiated upon amino-terminal serine/threonine phosphorylation, which is believed to be performed by glycogen synthase kinase-3 (GSK-3) in complex with tumor suppressor proteins Axin and adnomatous polyposis coli (APC). Here we describe another Axin-associated kinase, whose phosphorylation of beta-catenin precedes and is required for subsequent GSK-3 phosphorylation of beta-catenin. This "priming" kinase is casein kinase Ialpha (CKIalpha). Depletion of CKIalpha inhibits beta-catenin phosphorylation and degradation and causes abnormal embryogenesis associated with excessive Wnt/beta-catenin signaling. Our study uncovers distinct roles and steps of beta-catenin phosphorylation, identifies CKIalpha as a component in Wnt/beta-catenin signaling, and has implications to pathogenesis/therapeutics of human cancers and diabetes.
Liu
Chunming
C
Division of Neuroscience, Children's Hospital, Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
Li
Yiming
Y
Semenov
Mikhail
M
Han
Chun
C
Baeg
Gyeong Hun
GH
Tan
Yi
Y
Zhang
Zhuohua
Z
Lin
Xinhua
X
He
Xi
X
D000595:Amino Acid Sequence; D000818:Animals; D051186:Armadillo Domain Proteins; D060466:Axin Protein; D019521:Body Patterning / Q000235:genetics; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D047388:Casein Kinases; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004330:Drosophila; D029721:Drosophila Proteins; D004789:Enzyme Activation / Q000502:physiology; D015870:Gene Expression / Q000502:physiology; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D019476:Insect Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D012097:Repressor Proteins; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D029867:Xenopus Proteins; D014982:Xenopus laevis; D029961:Zebrafish Proteins; D051176:beta Catenin
C495305:ARM protein, Drosophila; D051186:Armadillo Domain Proteins; D060466:Axin Protein; C495266:CTNNB1 protein, Xenopus; C495270:CTNNB1 protein, human; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D019476:Insect Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; C555454:axin1 protein, Xenopus; D051176:beta Catenin; D011494:Protein Kinases; D038341:Glycogen Synthase Kinases; D047388:Casein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3