Negative regulation of LRP6 function by casein kinase I epsilon phosphorylation.
ABSTRACT 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.
SourceAvailable from: PubMed Central
Article: Updating the Wnt pathways[Show abstract] [Hide abstract]
ABSTRACT: In the three decades since the discovery of the Wnt1 proto-oncogene in virus-induced mouse mammary tumors, our understanding of the signaling pathways that are regulated by the Wnt proteins has progressively expanded. Wnts are involved in an complex signaling network that governs multiple biological processes and cross-talk with multiple additional signaling cascades including the Notch, FGF, SHH, EGF and Hippo pathways. The Wnt signaling pathway also illustrates the link between abnormal regulation of the developmental processes and disease manifestation. Here we provide an overview of Wnt-regulated signaling cascades and highlight recent advances. We focus on new findings regarding the dedicated Wnt production and secretion pathway with potential therapeutic targets that might be beneficial for patients with Wnt-related diseases.Bioscience Reports 09/2014; 34(5). DOI:10.1042/BSR20140119 · 2.85 Impact Factor
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ABSTRACT: Casein kinase 1 (CK1) members play a critical and evolutionary conserved role in Wnt/β-catenin signaling. They phosphorylate several pathway components and exert a dual function, acting as both Wnt activators and Wnt inhibitors. Recent discoveries suggest that CK1 members act in a coordinated manner to regulate early responses to Wnt and notably that their enzymatic activity is regulated. Here, I provide a brief update of CK1 function and regulation in Wnt/β-catenin signaling.Current Opinion in Cell Biology 09/2014; 31C:46-55. DOI:10.1016/j.ceb.2014.08.003 · 8.74 Impact Factor