Neil McDonald

Structural biology of the RET receptor tyrosine kinase

This PhD project involves the application of X-ray crystallography and biochemical methods to investigate the molecular function of the RET receptor tyrosine kinase and its established role in human thyroid cancer and Hirschsprungs disease.

RET is a membrane-spanning receptor with an intrinsic tyrosine kinase activity that is stimulated upon binding the glial cell-derived neurotrophic factor (GDNF). High levels of RET signalling via the Ras/MAPK and PI3-K/Akt pathways is one of the leading causes of neuroendocrine tumours. Gain-of-function mutations in RET are found in multiple endocrine neoplasias (MEN2A and MEN2B) and familial medullary thyroid carcinoma (FMTC). These mutations have distinct consequences for RET activation and have different requirements for activation loop phosphorylation. It remains unclear the precise mechanisms regulating RET tyrosine kinase catalytic activity and how such a mechanism(s) is affected by RET mutation.

Ongoing RET projects in the laboratory include the architecture of RET signalling complexes, regulatory mechanisms controlling RET activity and the chemical inhibition of oncogenic forms of the RET tyrosine kinase domain¹. This PhD project will present an opportunity to select and contribute to one of these ongoing research programs.

References

1. Knowles PP, Murray-Rust J, Kjaer S, Scott RP, Hanrahan S, Santoro M, Ibanez CF, McDonald NQ. Structure and chemical inhibition of the RET tyrosine kinase domain. Journal of Biological Chemistry 2006; 281: 33577-33587.