Specificity of WNT-receptor interactions

Abstract

The highly conserved Wnt signaling proteins play critical roles in guiding pattern formation, cell fate decision, and morphogenetic movement during animal development. They bind to the Frizzled family of seven-pass transmembrane proteins and initiate at least three different intracellular signaling pathways, resulting in regulation of gene expression and/or changes in cell behavior. A single transmembrane protein from the low-density-lipoprotein family functions as a co-receptor in the canonical/beta-catenin pathway. The specificity of Wnt signaling depends in part on the affinities between various Wnt-Frizzled pairs. A Wnt-dependent receptor dimerization or clustering step has been hypothesized as the step that initiates the canonical signaling cascade in cells.

International Union of Basic and Clinical Pharmacology. LXXX. The Class Frizzled Receptors

“…With the limited number of FZDs and WNTs in D. melanogaster, it was also possible to investigate WNT-FZD interaction profiles (Hsieh et al, 1999b;Wu and Nusse, 2002), but the specificity of interaction between WNTs and FZDs in vertebrates remains largely unmapped and obscure (Hsieh, 2004;Kikuchi et al, 2009). As detailed in section VIII, HH does not bind SMO but rather the regulatory transmembrane-spanning protein PTCH; thus, it would be misleading to discuss HH and SMO as a ligandreceptor pair.…”

“…The most obvious way to achieve specificity in a signaling system composed of 10 FZDs and 19 mammalian WNTs would be a specific ligand-receptor interaction profile (Hsieh, 2004). Some degree of specificity was shown for the D. melanogaster FZDs and WNTs (Hsieh et al, 1999b;Wu and Nusse, 2002), whereas WNT-FZD interaction profiles and binding affinities of the mammalian proteins have not yet been completely mapped (Hsieh, 2004;Kikuchi et al, 2009). In addition, recruitment of certain coreceptors is important (Mikels and Nusse, 2006;van Amerongen et al, 2008;Kikuchi et al, 2009).…”

Signal transduction cascades and hepatitis B and C related hepatocellular carcinoma

“…These specific interactions depend, in part, on the relative affinities of a particular FZD receptor for the Wnt ligands. 45,46 The canonical pathway is activated only when Wnt ligands are associated with both FZD and its co-receptor members of the single transmembrane low density lipoprotein receptor related family (LRP5 or LRP6). 47,48 The ␤-catenin protein is the key signaling molecule in the canonical Wnt/FZD pathway (Fig.…”

Wnt-5a induces Dishevelled phosphorylation and dopaminergic differentiation via a CK1-dependent mechanism

“…To date, the underlying molecular mechanism of action of Wnt-5a and the signalling pathways activated in DN as well as in other mammalian cells is still largely unknown (Veeman et al, 2003). Several molecular players have been implicated, including the Wnt receptors of the Frizzled family and the downstream signalling phosphoprotein Dishevelled (Dvl) (Gonzalez-Sancho et al, 2004;Hsieh, 2004;Wallingford and Habas, 2005;Wharton, Jr, 2003).…”