The role of Ryk and Ror receptor tyrosine kinases in Wnt signal transduction

Abstract

Receptor tyrosine kinases of the Ryk and Ror families were initially classified as orphan receptors because their ligands were unknown. They are now known to contain functional extracellular Wnt-binding domains and are implicated in Wnt-signal transduction in multiple species. Although their signaling mechanisms still remain to be resolved in detail, both Ryk and Ror control important developmental processes in different tissues. However, whereas many other Wnt-signaling responses affect cell proliferation and differentiation, Ryk and Ror are mostly associated with controlling processes that rely on the polarized migration of cells. Here we discuss what is currently known about the involvement of this exciting class of receptors in development and disease.

Figure 1.

Schematic depicting the use of CRD and WIF domains in Wnt signal transduction. The mammalian genome encodes 19 different Wnts, which can mediate their signaling effects through 10 different FZDs that act in concert with the LRP5 and LRP6 coreceptors. The binding site for Wnt on Fzd is formed by the CRD. This motif is also used as the Wnt-binding site in members of the SFRP family of extracellular Wnt antagonists and in Ror1 and Ror2, both of which are members of the RTK family. A second Wnt-binding module, the so-called WIF domain, is used by extracellular Wnt antagonists of the WIF family, as well as by Ryk, another RTK family member. In spite of possessing functional Wnt-binding domains it remains unclear how Ror and Ryk receptors function in Wnt signal transduction. They have been proposed to function as stand-alone receptors, but also as coreceptors together with Fzd. In addition, they have been implicated in β-catenin-dependent and -independent signaling responses. At present, the molecular mechanisms used by these RTKs to transmit the Wnt-signal are ill understood. Only Ror2 has been shown to have a functional kinase domain, but both Ror1 and Ryk have been proposed to function as pseudokinases. See text for details.