Cthrc1 Selectively Activates the Planar Cell Polarity Pathway of Wnt Signaling by Stabilizing the Wnt-Receptor Complex

Abstract

Vertebrate Wnt proteins activate several distinct pathways. Intrinsic differences among Wnt ligands and Frizzled (Fzd) receptors, and the availability of pathway-specific coreceptors, LRP5/6, and Ror2, affect pathway selection. Here, we show that a secreted glycoprotein, Cthrc1, is involved in selective activation of the planar cell polarity (PCP) pathway by Wnt proteins. Although Cthrc1 null mutant mice appeared normal, the introduction of a heterozygous mutation of a PCP gene, Vangl2, resulted in abnormalities characteristic of PCP mutants. In HEK293T cells, Cthrc1 activated the PCP pathway but suppressed the canonical pathway. Cell-surface-anchored Cthrc1 bound to Wnt proteins, Fzd proteins, and Ror2 and enhanced the interaction of Wnt proteins and Fzd/Ror2 by forming the Cthrc1-Wnt-Fzd/Ror2 complex. Consistent with this, Ror2 mutant mice also showed PCP-related abnormalities in the inner ear. These results suggest that Cthrc1 is a Wnt cofactor protein that selectively activates the Wnt/PCP pathway by stabilizing ligand-receptor interaction.

When pathways collide: collaboration and connivance among signalling proteins in development

“…Aside from the presence or absence of Ryk and Ror2, other factors can bias Wnt5a to act through a canonical or non-canonical response. For example, a secreted collagen protein, Cthrc1, can potentiate the Wnt-Ror2-Fz interaction, enhancing PCP signaling of Wnt5a 55 . Conversely, there are also non-Wnt ligands for the Frizzled receptors, such as Norrin 56 , that can activate the canonical pathway.…”

Ror2 Receptor Mediates Wnt11 Ligand Signaling and Affects Convergence and Extension Movements in Zebrafish

“…The immunoprecipitates or whole-cell lysates were separated by SDS-PAGE and blotted onto PVDF membranes. The primary antibodies were as follows: anti-His and anti-FLAG M2 (24).…”

Autonomous regulation of osteosarcoma cell invasiveness by Wnt5a/Ror2 signaling

“…Ror2 has been shown to act as a receptor or co-receptor for Wnt5a (Oishi et al, 2003;Mikels and Nusse, 2006;Nishita et al, 2006). In fact, both Ror2-and Wnt5a-mutant mice showed similar skeletal, cardiovascular, genital and inner ear abnormalities that are caused at least partly by disrupted planar cell polarity and convergent extension movements during development (Qian et al, 2007;Yamamoto et al, 2008). It has been shown that Ror2 mediates Wnt5a signaling by activating the Wnt/JNK pathway and inhibiting the b-catenin-TCF pathway (Oishi et al, 2003;Mikels and Nusse, 2006).…”