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Site-specific casein kinase 1epsilon-dependent phosphorylation of Dishevelled modulates beta-catenin signaling

Laura K Klimowski1, Benjamin A Garcia, Jeffrey Shabanowitz

  • 1Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, 84103, USA.

The FEBS Journal
|September 13, 2006
PubMed

Insights

Casein kinase I epsilon (CKIε) phosphorylation of Dishevelled (Dvl) at serines 139 and 142 activates Wnt-beta-catenin signaling. This discovery reveals how CKIε fine-tunes this crucial pathway in development and cancer.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Developmental Biology

Background:

  • The Wnt-beta-catenin signaling pathway is vital for development and cancer.
  • Casein kinase I epsilon (CKIε) is a known Wnt-activated regulator, and Dishevelled (Dvl) proteins are key substrates.
  • The precise phosphorylation sites on Dvl by CKI and their physiological significance remain largely unknown.

Purpose of the Study:

  • To identify and characterize the in vivo phosphorylation sites of Dishevelled (Dvl) by Casein kinase I (CKI).
  • To determine the functional importance of these phosphorylation sites in regulating the Wnt-beta-catenin signaling pathway.
  • To elucidate the role of CKIε in the Wnt-beta-catenin pathway through Dvl phosphorylation.

Main Methods:

  • In vitro phosphorylation of recombinant mouse Dishevelled (mDvl-1) by CKI.
  • Mass spectrometry (MS) to identify phosphorylation sites.
  • Phosphopeptide mapping of in vivo phosphorylated protein.
  • Phenotypic analysis of mutant mDvl-1 in cell culture and Xenopus development.

Main Results:

  • CKI phosphorylates mDvl-1 at conserved serines 139 and 142.
  • These phosphorylation events are dependent on Casein kinase I epsilon (CKIε) activity in vivo.
  • Phosphorylation of Dvl at these sites enhances beta-catenin-dependent Wnt signaling in cellular and developmental contexts.

Conclusions:

  • CKIε directly phosphorylates Dvl at serines 139 and 142, stimulating Wnt-beta-catenin signaling.
  • Regulated Dvl phosphorylation by CKIε provides a mechanism for fine-tuning the Wnt-beta-catenin pathway.
  • This finding has implications for understanding both normal development and cancer progression.

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