Receptor Kinases & Phosphatases

RYK

The receptor related to tyrosine kinases (Ryk) is a member of the cell surface receptor tyrosine kinase (RTK) family, which, in general, function to regulate cellular growth and differentiation. Ryk is unlike most RTK members in that it contains an inactive protein tyrosine kinase domain and appears to rely on association with other RTK members to generate signal transduction.

Introduction

Ryk was discovered by LICR investigators in the early 1990’s. Data have suggested that a Drosophila melanogaster (fruit-fly) homolog (equivalent) of Ryk binds a member of the Wnt family of proteins. The Wnt proteins regulate cell-cell interactions during embryogenesis, and have also been implicated in cancer. These studies point to Ryk as a key nexus in the growth factor receptor and Wnt signaling pathways.

Gene Discovery & Characterization

The mouse Ryk receptor was first cloned by LICR investigators from the Melbourne Branch using techniques developed at the Branch for amplifying specifically RTK sequences(1). The team then used the mouse sequence to isolate the human Ryk gene and elucidate its chromosomal location(2). Much of the initial characterization of the Ryk receptor included the elucidation of the genomic organization of mouse and human Ryk and identification of gene promoters(3). The subsequent cloning of Ryk equivalents in several other species indicates that Ryk, being conserved in evolution, has an important role in cell function.

Ryk Receptor Function

Ryk is an ‘orphan’ growth factor receptor, meaning that the identity of the ligand that binds and activates the receptor is not known (although LICR investigators from the Stockholm Branch have shown that not all receptors, at least in the case of the nuclear receptor, Nurr1, are activated by ligand binding).

Ryk’s role in signal transduction has remained unclear for some time, because it has an inactive tyrosine kinase ‘domain’ (protein subunit). In other RTKs, this domain activates downstream molecules by ‘phosphorylation’ (the addition of a phosphate group); the physical mechanism of signal transduction. A breakthrough in understanding of Ryk’s function came when investigators at the LICR Melbourne Branch generated Ryk-deficient mice. The mice had major defects in craniofacial development and palate formation, and died soon after birth indicating that Ryk plays an indispensable role in the development of mammalian tissues. The Melbourne Branch studies indicate that Ryk may be involved in signal transduction through its association with members of the Eph receptor subfamily of RTKs. The LICR team has shown that Ryk is activated by binding to some Eph receptors, and it is likely that some of the diverse signal transduction by the Eph family may be due to Ryk’s association with different Eph receptors(4).

Ryk and Cancer

RTKs constitute a broad family of receptors frequently deregulated in cancer, with over-expression (‘over-production’), leading to aberrant signaling, often observed. Ryk is expressed on many cell types in cancer, including epithelial cells and connective tissue stroma and vessels. Indeed, one study has shown that over-expression of human Ryk in epithelial ovarian cancer is strongly correlated to overall survival and progression free survival. The Eph receptors are also frequently expressed in a range of human cancers, and seem to play a key role in tumor cell migration, invasion and metastasis. Thus it is possible that Ryk also contributes to cancer growth and spread by facilitating the oncogenic activity of Eph receptors(5).

RYK as a Therapeutic Target

LICR investigators at the Melbourne Branch have generated antibodies that bind to the extracellular region of the Ryk receptor. The aim now is to generate antibodies that bind to Ryk and potentially block its interaction with other receptors. Other receptor modulators being considered as potential therapeutics are ‘ligand-traps’, which bind to ligands for Ryk (when identified) and the Eph receptors to prevent their activation. As more information is gained about the activation and function of Ryk, LICR continues to further explore the potential targeting of this pathway to inhibit the growth and spread of cancer.

References

  1. Hovens C.M., Stacker S.A., Andres A.C., Harpur A.G., Ziemiecki A., and Wilks A.F. RYK, a receptor tyrosine kinase-related molecule with unusual kinase domain motifs. Proc.Natl.Acad.Sci.U.S.A (1992) 89(24):11818-11822.
  2. Stacker S.A., Hovens C.M., Vitali A., Pritchard M.A., Baker E., Sutherland G.R., and Wilks A.F. Molecular cloning and chromosomal localisation of the human homologue of a receptor related to tyrosine kinases (RYK). Oncogene (1993) 8(5):1347-1356.
  3. Halford M.M., Oates A.C., Hibbs M.L., Wilks A.F., and Stacker S.A. Genomic structure and expression of the mouse growth factor receptor related to tyrosine kinases (Ryk). J.Biol.Chem. (1999) 274(11):7379-7390.
  4. 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., and Stacker S.A. Ryk-deficient mice exhibit craniofacial defects associated with perturbed Eph receptor crosstalk. Nat.Genet. (2000) 25(4):414-418.
  5. Halford M.M. and Stacker S.A. Revelations of the RYK receptor. Bioessays (2001) 23(1):34-45.

Centers Involved in this Research