Structural characterisation of the co-inhibitory complex formed by the tumour suppressor PTEN and the metastatic factor PREX2

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 metastatic factor, PREX2, is an attractive alternative therapeutic target to combat cancer metastasis. However, a number of important structural, mechanistic, and functional knowledge gaps remain to be resolved. PREX2 forms a high-affinity complex with the tumour suppressor PTEN that results in the co-inhibition of the enzymatic activity of both proteins. PTEN is a key regulator of cell growth and proliferation by suppressing the PI3K-AKT-mTOR signalling pathway. Loss, or a reduction of PTEN activity by genomic disruption, reduction of expression, mutation, or changes in regulation can promote cancer cell growth and proliferation. Despite the importance of both PREX2 and PTEN in cancer progression, there are no structures available for either PREX2, or the PTEN:PREX2 complex. As such, there is little understanding of the molecular mechanisms underlying PTEN:PREX2 co-inhibition. This project will take an integrative biochemical, biophysical, and structural approach to determine the mechanism of PTEN:PREX2 co-inhibition, and investigate how this is dysregulated by cancer-associated somatic mutations. Together, these insights will form a platform from which to base future drug development programs targeting PREX2 activation in cancer. Students will have the opportunity to learn the cutting-edge techniques of single particle cryo-electron microscopy and X-ray crystallography.