Casein kinase I phosphorylates and destabilizes the β-catenin degradation complex

Zhong Hua Gao, Joni M. Seeling, Virginia Hill, April Yochum, David M. Virshup

Research output: Contribution to journalArticlepeer-review

179 Scopus citations

Abstract

Wnt signaling plays a key role in cell proliferation and development. Recently, casein kinase I (CKI) and protein phosphatase 2A (PP2A) have emerged as positive and negative regulators of the Wnt pathway, respectively. However, it is not clear how these two enzymes with opposing functions regulate Wnt signaling. Here we show that both CKIδ and CKIε interacted directly with DvI-1, and that CKI phosphorylated multiple components of the Wnt-regulated β-catenin degradation complex in vitro, including DvI-1, adenomatous polyposis coli (APC), axin, and β-catenin. Comparison of peptide maps from in vivo and in vitro phosphorylated β-catenin and axin suggests that CKI phosphorylates these proteins in vivo as well. CKI abrogated β-catenin degradation in Xenopus egg extracts. Notably, CKI decreased, whereas inhibition of CKI increased, the association of PP2A with the β-catenin degradation complex in vitro. Additionally, inhibition of CKI in vivo stabilized the β-catenin degradation complex, suggesting that CKI actively destabilizes the complex in vivo. The ability of CKI to induce secondary body axes in Xenopus embryos was reduced by the B56 regulatory subunit of PP2A, and kinase-dead CKIε acted synergistically with B56 in inhibiting Wnt signaling. The data suggest that CKI phosphorylates and destabilizes the β-catenin degradation complex, likely through the dissociation of PP2A, providing a mechanism by which CKI stabilizes β-catenin and propagates the Wnt signal.

Original languageEnglish (US)
Pages (from-to)1182-1187
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number3
DOIs
StatePublished - Feb 5 2002

All Science Journal Classification (ASJC) codes

  • General

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