Molecular Analysis of the TSC Complex

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The TSC complex is a tumor suppressor that relay growth factor signaling to the mTORC1 (mechanistic target of rapamycin complex 1) kinase to control cell growth. Mutations in the complex subunits TSC1 and TSC2 cause tuberous sclerosis complex (TSC), a genetic disease characterized by benign tumors in multiple organs that lead to organ failure. The mechanistic understanding of TSC complex function is still limited. In this project, we will combine expertise in biochemistry and structural biology of regulators of small GTPases, and signal transduction and regulation of small GTPases in tumor cell biology to obtain comprehensive insight into the molecular function of the TSC complex. We want to obtain a detailed understanding of TSC complex assembly and function on a structural level. In addition, we will explore the molecular basis for the interaction of the TSC complex with phosphatidylinositol phosphates (PIPs) and role of PIP lipids in regulating TSC activity in different physiological settings. We will also characterize the effects of pathogenic patient variants on TSC complex structure, integrity and molecular function in TSC complex-dependent signaling pathways. We expect to not only gain novel insight into the mechanism of TSC complex function, but also the pathogenic processes that lead to the manifestation of tuberous sclerosis.