Understanding signal integration in eukaryotic cell growth (360G-Wellcome-206212_Z_17_Z)

The aim of the project would be to understand signal integration in the TOR (Target of Rapamycin) growth signaling pathway. TOR growth signaling is mediated by the kinase activity of TOR complex 1. This is contingent on concurrent activation of two sets of small GTPases, the Rags and Rheb, which recruit TORC1 to lysosomes and activate it there. Both GTPases are regulated by GTPase activating proteins, the GATOR complex(es) in the case of the Rag GTPases, and the TSC (tuberous sclerosis complex) in the case of Rheb. We would attempt to recombinantly express, purify and reconstitute these complexes, in order to interrogate their activity in response to known signals using biochemical and biophysical assays. We would also attempt to obtain their structures, using x-ray crystallography and electron cryo-microscopy, leading to a molecular understanding of their regulation. The results would be beneficial both academically, given the key position of TOR signaling in eukaryotic cell growth, and medically, as TOR is a known to be a key target in immuno-repression, cancer and tumour syndromes. Any new information on the regulation of the tuberous sclerosis complex would almost certainly be directly applicable to this, and related, hereditary condition(s).