Casein kinase 1 γ couples Wnt receptor activation to cytoplasmic signal transduction

Abstract

Signalling by Wnt proteins (Wingless in Drosophila) has diverse roles during embryonic development and in adults, and is implicated in human diseases, including cancer. LDL-receptor-related proteins 5 and 6 (LRP5 and LRP6; Arrow in Drosophila) are key receptors required for transmission of Wnt/beta-catenin signalling in metazoa. Although the role of these receptors in Wnt signalling is well established, their coupling with the cytoplasmic signalling apparatus remains poorly defined. Using a protein modification screen for regulators of LRP6, we describe the identification of Xenopus Casein kinase 1 gamma (CK1gamma), a membrane-bound member of the CK1 family. Gain-of-function and loss-of-function experiments show that CK1gamma is both necessary and sufficient to transduce LRP6 signalling in vertebrates and Drosophila cells. In Xenopus embryos, CK1gamma is required during anterio-posterior patterning to promote posteriorizing Wnt/beta-catenin signalling. CK1gamma is associated with LRP6, which has multiple, modular CK1 phosphorylation sites. Wnt treatment induces the rapid CK1gamma-mediated phosphorylation of these sites within LRP6, which, in turn, promotes the recruitment of the scaffold protein Axin. Our results reveal an evolutionarily conserved mechanism that couples Wnt receptor activation to the cytoplasmic signal transduction apparatus.

Osteocytes, mechanosensing and Wnt signaling

“…Binding of Wnt to Lrp5 and frizzled, in addition to Dsh activation, also results in the phosphorylation of the cytoplasmic tail of Lrp5, likely mediated by Casein kinase 1γ (CK-1γ) (29), the binding of FRAT-1 to this tail and ultimately its association with axin. Axin binding to Lrp5 and the inhibition of GSK-3β results in the collapse of the degradation complex and the release of nonphosphorylated β-catenin into the cytoplasm where is can subsequently translocate into the nucleus to affect gene transcription.…”

Function and biological roles of the Dickkopf family of Wnt modulators

“…The cytoplasmic domain of Lrp5/6 contains five phosphorylated PPPSP motifs with flanking S/T clusters, which are targets for Casein kinase 1g phosphorylation. Upon Wnt-Fz interaction, Lrp6 becomes phosphorylated by Casein kinase 1g, which allows Axin to bind to Lrp6 (Davidson et al, 2005;Zeng et al, 2005).…”

Controlled levels of canonical Wnt signaling are required for neural crest migration

“…Upon binding of canonical Wnt ligands to their coreceptors Frizzleds (Fz) and low-density-lipoprotein-related protein5/6 (Lrp5/6) on the cell surface MacDonald and He, 2012) Lrp5/6 becomes dually phosphorylated by CK1 and GSK-3β and inactivates the destruction complex by recruitment of Axin to the plasma membrane (Davidson et al, 2005;Zeng et al, 2005). Additionally, Dsh is also recruited to the plasma membrane where it binds Fz receptors (Wong et al, 2003) and regulates phosphorylation of Lrp5/6 (Bilic et al, 2007).…”