Exploring the RalA C-terminus for therapeutic intervention
Department name: Department of Biochemistry, Cambridge University. Oncology, AstraZeneca
Supervisors: Dr Helen Mott, Dr Sarah Ross and Dr Nichola Whalley
Activated Ras signals through 3 main downstream effector pathways, the MAPK pathway, the PI3K-AKT pathway and the lesser studied RalGDS/Ral pathway. The RalGDS/Ral pathway leads to activation of 2 small G proteins, RalA and RalB. Both Ral isoforms have been reported to enhance proliferation, anchorage independent growth, tumourgenicity, migration and metastasis. However, no therapies currently exist that target the Ral proteins and the regulation and the direct contribution of the Ral pathway to KRas mutant tumour phenotype still requires further understanding.
The sequences of RalA and RalB are 82% identical, with most differences occurring in the C-terminal ~25 residues. The extreme C-terminus of both Ral proteins is lipid modified and anchored into the bilayer. This project will involve the investigation of the RalA protein and its interaction with membranes using biochemical, biophysical and NMR based approaches in the Mott lab. Based on these studies RalA mutations will be generated and their effect on RalA function will be tested in cancer cell lines at the AstraZeneca labs in Cambridge.
We particularly welcome applicants who are interested in learning structural biology alongside functional assays and will relish the opportunity to experience research in both the academic and industrial setting. The techniques that the student will learn include: molecular biology, protein purification, NMR and fluorescence spectroscopy, CRISPR and mammalian tissue culture.
BBSRC funding is available for UK nationals and EU students who meet the residency requirements. Further information about eligibility for funding can be found on the BBSRC website:
H.R. Mott & D. Owen (2015) Structures of Ras superfamily effector complexes: What have we learnt in two decades? Crit Rev Biochem Mol Biol. 50 85-133.
S.Guin & D. Theodorescu (2015) The RAS-RAL axis in cancer: evidence for mutation specific selectivity in non-small cell lung cancer. Acta Pharmacologica Sinica. 36 291-297