Negative regulation of LRP6 function by casein kinase I epsilon phosphorylation.
Wnt signaling acts in part through the low density lipoprotein receptor-related transmembrane proteins LRP5 and LRP6 to regulate embryonic development and stem cell proliferation. Up-regulated signaling is associated with many forms of cancer. Casein kinase I epsilon (CKIepsilon) is a known component of the Wnt-beta-catenin signaling pathway. We find that CKIepsilon binds to LRP5 and LRP6 in vitro and in vivo and identify three CKIepsilon-specific phosphorylation sites in LRP6. Two of the identified phosphorylation sites, Ser1420 and Ser1430, influence Wnt signaling in vivo, since LRP6 with mutation of these sites is a more potent activator of both beta-catenin accumulation and Lef-1 reporter activity. Whereas Wnt3a regulates CKIepsilon kinase activity, LRP6 does not, placing CKIepsilon upstream of LRP6. Mutation of LRP6 Ser1420 and Ser1430 to alanine strengthens its interaction with axin, suggesting a mechanism by which CKIepsilon may negatively regulate Wnt signaling. The role of CKIepsilon is therefore more complex than was previously appreciated. Generation of active CKIepsilon may induce a negative feedback loop by phosphorylation of sites on LRP5/6 that modulate axin binding and hence beta-catenin degradation.
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- beta Catenin
- Wnt3A Protein
- Wnt3 Protein
- Wnt Proteins
- Signal Transduction
- Sequence Homology, Amino Acid
- Phosphorylation
- Molecular Sequence Data
- Lymphoid Enhancer-Binding Factor 1
- Low Density Lipoprotein Receptor-Related Protein-6
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- beta Catenin
- Wnt3A Protein
- Wnt3 Protein
- Wnt Proteins
- Signal Transduction
- Sequence Homology, Amino Acid
- Phosphorylation
- Molecular Sequence Data
- Lymphoid Enhancer-Binding Factor 1
- Low Density Lipoprotein Receptor-Related Protein-6