Alternative titles; symbols
HGNC Approved Gene Symbol: RYK
Cytogenetic location: 3q22.2 Genomic coordinates (GRCh38): 3:134,157,133-134,250,859 (from NCBI)
Hovens et al. (1992) isolated RYK, a novel member of the family of growth factor receptor protein tyrosine kinases. Comparison of mouse and human RYK cDNA sequences demonstrated a very high degree of sequence identity, suggesting an important and conserved role for this molecule (Stacker et al., 1993).
Katso et al. (1999) demonstrated that the signaling properties of RYK are divergent from those of other classic receptor tyrosine kinases.
Lu et al. (2004) reported that mammalian RYK, unlike the Drosophila RYK homolog Derailed, functions as a coreceptor along with Frizzled (603408) for Wnt ligands (see WNT3A; 606359). They found that RYK binds to Dishevelled (601365), through which it activates the canonical Wnt pathway, providing a link between Wnt and Dishevelled. Transgenic mice expressing RYK small interfering RNA exhibited defects in axon guidance, and RYK was required for neurite outgrowth induced by Wnt3a and in the activation of T-cell factor (see 189908) induced by Wnt1 (164820). Lu et al. (2004) concluded that RYK plays a crucial role in Wnt-mediated signaling.
Schmitt et al. (2006) found that Wnt3 (165330) is expressed in a medial-lateral decreasing gradient in chick optic tectum and mouse superior colliculus. Retinal ganglion cell axons from different dorsal-ventral positions showed graded and biphasic response to Wnt3 in a concentration-dependent manner. Wnt3 repulsion is mediated by Ryk, expressed in a ventral-to-dorsal decreasing gradient, whereas attraction of dorsal axons at lower Wnt3 concentrations is mediated by Frizzled(s) (see 603408). Overexpression of Wnt3 in the lateral tectum repelled the termination zones of dorsal retinal ganglion cell axons in vivo. Expression of a dominant-negative Ryk in dorsal retinal ganglion cell axons caused a medial shift of the termination zones, promoting medially directed interstitial branches and eliminating laterally directed branches. Therefore, Schmitt et al. (2006) concluded that a classic morphogen, Wnt3, acting as an axon guidance molecule, plays a role in retinotectal mapping along the medial-lateral axis, counterbalancing the medial-directed EphrinB1-EphB (see 300035) activity.
By Western blot analysis, Majumder et al. (2021) showed that levels of GRB2 (108355) and NOX4 (605261) were elevated in tissues from mouse models for Alzheimer disease (AD; see 104300) and type 2 diabetes (T2D; 125853), as well as in tissues from AD and T2D patients. Knockdown analysis in SHSY-5Y and HepG2 cells revealed that miRNA1271 targeted and restricted expression of ALK (105590) and RYK, which elevated expression of GRB2 and NOX4. Moreover, PAX4 (167413), a transcription factor for both GRB2 and NOX4, was overexpressed during ALK and RYK knockdown due to reduced expression of the PAX4 suppressor ARX (300382) via beta-catenin (see 116806) signaling. In addition, expression of various cytoskeletal proteins was downregulated in liver tissue of T2D patients and in ALK/RYK knockdown cells, but overexpression of GRB2 reversed the cytoskeletal degradation through interaction with NOX4.
By genetic linkage analysis with recombinant inbred strains of mice, Gough et al. (1995) identified 2 distinct mouse Ryk loci (Ryk1 and Ryk2) and showed that they mapped to chromosomes 9 and 12, respectively. A similar arrangement of RYK-related loci had been determined in the human: in situ hybridization placed human RYK1 on 3q22 and RYK2 on 17q. It was thought that the chromosome 3 locus was the one from which the human RYK mRNA (Hovens et al., 1992; Stacker et al., 1993) was derived, since the 3-prime untranslated region of the human RYK cDNA detected only this locus. Gough et al. (1995) were uncertain as to whether the Ryk2 gene in the mouse (and presumably in man) codes a functional protein or represents a pseudogene.
Halford et al. (2000) generated mice deficient in Ryk by targeted disruption. Ryk -/- mice were represented in mendelian proportions up to birth, but virtually none survived to weaning. Ryk -/- mice typically died on the day of birth, whereas a few survivors became increasingly cachexic and died before 8 days. Two Ryk-deficient mice survived to adulthood, but were severely growth retarded and exhibited microcephaly, bilateral microphthalmia, and an unusual gait involving dragging of the hindlimbs. The brains from Ryk -/- mice were grossly normal. Whereas Ryk +/- mice were indistinguishable from wildtype littermates, all Ryk -/- neonates showed a shortened snout and a completely cleft secondary palate. All Ryk -/- mice had disproportionately shorter limbs, with hindlimbs splayed laterally. The cranial vault was smaller and more rounded and the mandible was reduced in size. The long bones were reduced in length by 18 to 25%, but were of normal or slightly greater than normal width. Halford et al. (2000) performed beta-galactosidase histochemistry on sections of the developing facial complex to reveal Ryk promoter activity. They observed intense staining of the tongue at 12.5 to 13.5 days postcoitum, particularly the subepidermal mesenchyme, and weaker staining of palatal shelf mesenchyme. Examination of coronal sections through the midpalate region of wildtype and Ryk -/- embryos showed indistinguishable downward growth of the vertical palatal shelves at 13.5 days postcoitum. However, by 14.5 days postcoitum, the tongue obstructed physical elevation of 1 of the 2 palatal shelves in Ryk -/- embryos. In vitro experiments by Halford et al. (2000) demonstrated coprecipitation of EPHB2 (600997), EPHB3 (601839), and EPHA7 (602190) with epitope-tagged Ryk from cotransfected 293T cells. Ryk was tyrosyl-phosphorylated when coexpressed with EPHB2 or EPHB3, but not EPHA7. The phosphorylation of Ryk was found to be critically dependent on the kinase activity of EPHB3.
Gough, N. M., Rakar, S., Hovens, C. M., Wilks, A. Localization of two mouse genes encoding the protein tyrosine kinase receptor-related protein RYK. Mammalian Genome 6: 255-256, 1995. [PubMed: 7613029] [Full Text: https://doi.org/10.1007/BF00352411]
Halford, M. M., Armes, J., Buchert, M., Meskenaite, V., Grail, D., Hibbs, M. L., Wilks, A. F., Farlie, P. G., Newgreen, D. F., Hovens, C. M., Stacker, S. A. Ryk-deficient mice exhibit craniofacial defects associated with perturbed Eph receptor crosstalk. Nature Genet. 25: 414-418, 2000. [PubMed: 10932185] [Full Text: https://doi.org/10.1038/78099]
Hovens, C. M., Stacker, S. A., Andres, A.-C., Harpur, A. G., Wilks, A. F. RYK, a receptor tyrosine kinase-related molecule with unusual kinase domain motifs. Proc. Nat. Acad. Sci. 89: 11818-11822, 1992. [PubMed: 1334548] [Full Text: https://doi.org/10.1073/pnas.89.24.11818]
Katso, R. M., Russell, R. B., Ganesan, T. S. Functional analysis of H-Ryk, an atypical member of the receptor tyrosine kinase family. Molec. Cell. Biol. 19: 6427-6440, 1999. [PubMed: 10454588] [Full Text: https://doi.org/10.1128/MCB.19.9.6427]
Lu, W., Yamamoto, V., Ortega, B., Baltimore, D. Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth. Cell 119: 97-108, 2004. [PubMed: 15454084] [Full Text: https://doi.org/10.1016/j.cell.2004.09.019]
Majumder, P., Chanda, K., Das, D., Singh, B. K., Chakrabarti, P., Jana, N. R., Mukhopadhyay, D. A nexus of miR-1271, PAX4 and ALK/RYK influences the cytoskeletal architectures in Alzheimer's disease and type 2 diabetes. Biochem. J. 478: 3297-3317, 2021. [PubMed: 34409981] [Full Text: https://doi.org/10.1042/BCJ20210175]
Schmitt, A. M., Shi, J., Wolf, A. M., Lu, C.-C., King, L. A., Zou, Y. Wnt-Ryk signalling mediates medial-lateral retinotectal topographic mapping. Nature 439: 31-37, 2006. [PubMed: 16280981] [Full Text: https://doi.org/10.1038/nature04334]
Stacker, S. A., Hovens, C. M., Vitali, A., Pritchard, M. A., Baker, E., Sutherland, G. R., Wilks, A. F. Molecular cloning and chromosomal localisation of the human homologue of a receptor related to tyrosine kinases (RYK). Oncogene 8: 1347-1356, 1993. [PubMed: 8386829]