The majority of cancer deaths are attributed to metastases rather than the primary tumour. Therefore, the development of new therapeutics targeting metastasis is of fundamental importance. Rho GTPases drive cell growth, proliferation and metastatic pathways, however, historically, inhibition of the catalytic activity of GTPases, such as Ras and Rac1 has proved notoriously difficult. Due to its position as a key upstream activator of several GTPases, the novel oncogene, P-Rex1, is an attractive alternative therapeutic target to combat cancer metastasis. P-Rex1 overexpression and mutation is correlated with tumourigenesis in breast and prostate cancers and P-Rex1 knockdown inhibits cell migration and invasion in melanoma, prostate, and ovarian cancers. We have recently solved the X-ray crystal structure of the P-Rex1 catalytic domain in complex with Rac1, revealing the molecular mechanism of Rac1 activation by P-Rex1. However, a number of important structural, mechanistic, and functional knowledge gaps remain to be resolved. P-Rex1 is tightly regulated enabling strict spatial and temporal control of its cellular activity. For example, P-Rex1 requires synergistic activation at the plasma membrane by both PIP3 and G, which are dependent on receptor tyrosine kinase and G protein-coupled receptor signalling. P-Rex1 is also maintained in an autoinhibited conformation under basal conditions. The molecular basis of both the synergistic activation and autoinhibtion of P-Rex1 remains unclear. Finally, the role of somatic cancer-associated P-Rex1 mutations in driving metastasis are yet to be investigated. Here, we will undertake an integrative biochemical, biophysical, and structural approach to determine the mechanism of P-Rex1 regulation, and investigate how this is dysregulated to promote cancer metastasis in breast cancer cell lines. Together, these insights will form a platform from which to base future drug development programs targeting P-Rex1 activation in cancer. Students will have the opportunity to learn the cutting-edge techniques of single particle cryo-electron microscopy and X-ray crystallography during the project.
Cancer, electron microscopy, metastasis, structural biology, X-ray crystallography, Department of Biochemistry & Molecular Biology
Biomedicine Discovery Institute (School of Biomedical Sciences) » Biochemistry and Molecular Biology
Masters by research
Biomedicine Discovery Institute