Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism

Chunming Liu, Yiming Li, Mikhail Semenov, Chun Han, Gyeong Hun Baeg, Yi Tan, Zhuohua Zhang, Xinhua Lin, Xi He

Research output: Contribution to journalArticlepeer-review

1764 Scopus citations

Abstract

Wnt regulation of β-catenin degradation is essential for development and carcinogenesis. β-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 β-catenin precedes and is required for subsequent GSK-3 phosphorylation of β-catenin. This "priming" kinase is casein kinase Iα (CKIα). Depletion of CKIα inhibits β-catenin phosphorylation and degradation and causes abnormal embryogenesis associated with excessive Wnt/β-catenin signaling. Our study uncovers distinct roles and steps of β-catenin phosphorylation, identifies CKIα as a component in Wnt/β-catenin signaling, and has implications to pathogenesis/therapeutics of human cancers and diabetes.

Original languageEnglish
Pages (from-to)837-847
Number of pages11
JournalCell
Volume108
Issue number6
DOIs
StatePublished - Mar 22 2002

Bibliographical note

Funding Information:
We thank F. Constantini and J. Graff for reagents, L. Licklider for mass spectrum analysis, J. Kopinga, J. Monterecy, H.-Z. Liu, and D. Schmucker for fly embryo RNAi, L. Hu for advice on antibodies, J.-P. Saint-Jeannet for help, M. Greenberg and N. Perrimon for comments, and members of the He lab for discussion. G.-H.B. is a postdoctoral fellow in N. Perrimon's lab and supported by a National Institutes of Health grant to N. Perrimon. This work is partially supported by grants from NIH and Department of Defense to X.H., who is a Pew Scholar, Klingenstein Fellow, and Keck Foundation Distinguished Young Scholar.

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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