Site-specific casein kinase 1ε-dependent phosphorylation of Dishevelled modulates β-catenin signaling

Laura K. Klimowski, Benjamin A. Garcia, Jeffrey Shabanowitz, Donald F. Hunt, David M. Virshup

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Careful regulation of the Wnt-B-catenin signaling pathway is critical to many aspects of development and cancer. Casein kinase Iε is a Wnt-activated positive regulator of this pathway. Members of the Dishevelled family have been identified as key substrates of casein kinase I (CKI). However, the specific sites phosphorylated in vivo by CKI and their relative importance in the physiologic regulation of these proteins in the canonical Wnt-β-catenin signaling pathway remain unclear. To address this question, recombinant mouse Dishevelled (mDvl-1) was phosphorylated by CKIin vitro and phosphorylation sites were identified by MS. CKI phosphorylation of mDvl-1 at two highly conserved residues, serines 139 and 142, was observed by MS and confirmed by phosphopeptide mapping of in vivo phosphorylated protein. Phosphorylation of these sites is dependent on casein kinase I epsilon activity in vivo. Phenotypic analysis of mutant mDvl-1 indicates that phosphorylation of these sites stimulates the Dvl-activated β-catenin-dependent Wnt signaling pathway in both cell culture and in Xenopus development. Casein kinase I epsilon is a Wnt-regulated kinase, and regulated phosphorylation of Dvl allows fine tuning of the Wnt-β-catenin signaling pathway.

Original languageEnglish
Pages (from-to)4594-4602
Number of pages9
JournalFEBS Journal
Volume273
Issue number20
DOIs
StatePublished - Oct 2006

Keywords

  • Casein kinase 1
  • Dishevelled
  • Phosphopeptides
  • Wnt
  • β-catenin

Fingerprint

Dive into the research topics of 'Site-specific casein kinase 1ε-dependent phosphorylation of Dishevelled modulates β-catenin signaling'. Together they form a unique fingerprint.

Cite this