Off-track takes Frizzled off the canonical path.

Like many other signalling pathways, the Wnt pathway is seen as part of a network that integrates extracellular information mediated by a variety of cell surface proteins to produce cell context-specific outputs. The identification of Frizzled as Wnt receptors (Bhanot et al, 1996) provided the essential link between extracellular Wnts and the intracellular components of Wnt signal transduction. Recent observations, however, indicate a rather complex interplay of this ‘core’ receptor element with an increasing number of co-receptors. In this issue of The EMBO Journal, Tolwinski and Borchers (Peradziryi et al, 2011) describe PTK7/Off-track as a novel co-receptor element that might govern specificity in cellular Wnt responses. The b-catenin/TCF pathway is often described as canonical because it mediates the core activities of Wnts in cell specification and tumourigenesis. This distinction is necessary because Frizzled receptors had previously been shown to participate in planar cell polarity (PCP), a process whereby cells acquire polarity within the plane of epithelia (Strutt, 2008). PCP is the best characterised of various alternative Wnt signalling pathways that have collectively been termed non-canonical. Over the years, vertebrate Wnts have been classified into canonical and non-canonical Wnts. For example, vertebrate Wnt3a is an archetypical canonical Wnt while vertebrate Wnt5a has been implicated in PCP signalling. This distinction can be useful but is almost certainly an oversimplification, as the effect of various Wnts is strongly dependent on the nature of the Frizzled receptors present (van Amerongen and Nusse, 2009). It is worth mentioning that, in Drosophila, no Wnt has so far been shown to be required for PCP signalling. One feature that has often been noted is that activation of the two pathways is somewhat exclusive. How PCP and canonical signalling affect each other and what the relative contribution of various Frizzled and Wnts to either pathway is are questions currently under active investigation. Despite their central importance, Frizzled proteins are far from being the only receptors that modulate or control Wnt signalling. Indeed, members of the LRP (LDL-related protein) family are essential co-receptors for canonical signalling. For example, Arrow, the sole Drosophila LRP, is absolutely required for Wingless signal transduction (Wehrli et al, 2000). A current view is that LRP family members form a tripartite complex with Wnt and Frizzled. As arrow mutations do not cause a PCP phenotype in flies, and vertebrate LRPs do not modulate PCP signalling, this class of co-receptors is seen as strictly canonical. Another class of single-pass transmembrane proteins, including ROR1 and ROR2, also act as Wnt coreceptors although their effect on canonical signalling is inhibitory (Green et al, 2008). Initially, ROR receptors were thought to act by merely sequestering Wnt receptors. However, a recent paper suggests that, in addition to suppressing canonical signalling, these receptors could actively promote PCP signalling in a Frizzled-dependent manner (Grumolato et al, 2010). One simple model is that the ROR2/Fz/Wnt complex could trigger PCP signalling while the LRP/Fz/Wnt complex would activate canonical signalling. Individual Wnts would favour the formation of one or the other type of complex thus explaining why some Wnts tend to activate PCP while others activate canonical signalling. Tolwinski, Borchers and colleagues describe another transmembrane receptor that inhibits canonical signalling and could act in the PCP pathway (Peradziryi et al, 2011). This protein, which is known as protein tyrosine kinase-7 (PTK7) in vertebrates and Off-track (Otk) in Drosophila, has been shown previously to be deregulated in cancers and to be