Regulation of mTOR by Nutrients

Principal Investigator: GUAN, KUN-LIANG
Program: TSCRP
Proposal Number: TS080031
Award Number: W81XWH-09-1-0279
Funding Mechanism: Idea Development Award
Partnering Awards:
Award Amount: $675,002.00


Tuberous sclerosis complex (TSC) is an inherited genetic disease caused by mutations in either TSC1 or TSC2 gene. TSC is characterized by the development of benign hamartomas in many organs, including brain, kidney, heart, skin, and eyes. Mutations in TSC1 and TSC2 account for approximately 30% and 60% of TSC cases, respectively. TSC hamartomas are a mass of disorganized, but differentiated, cells originating from many different cell types. Clinical complications include seizures, mental retardation, and kidney dysfunction. Biochemical studies have established that TSC1 and TSC2 bind to each other and form a physical and functional complex. Rapid progresses in the last several years have established the TSC1/TSC2-Rheb-TORC1 pathway.

The TSC1/TSC2 complex has GTPase activating protein (GAP) activity towards the Rheb small GTPase, which is a direct activator of TORC1. It is well established that TORC1 activity is highly elevated in TSC mutant cells. TORC1 stimulates protein synthesis and is a central cell growth controller. Therefore, high TORC1 activity promotes unregulated cell growth and likely contributes to tumor formation in TSC patients. The elucidation of the TSC1/TSC2-Rheb-TORC1 pathway is very exciting because it provides an attractive drug target for TSC1. In fact, we were the first to propose that TSC1/TSC2 function to inhibit mTOR. Dr. Guan is the inventor of a United States patent that claims using rapamycin for TSC treatment. Rapamycin is a potent inhibitor of TORC1, and rapamycin analog is an FDA approved drug for immunosuppression and cancer. Recent clinical trials have demonstrated the therapeutic value of rapamycin for TSC and associated diseases.

Dysregulation of TORC1 is the major cellular consequence of TSC1 or TSC2 mutations and contributes to the pathogenesis of TSC disease. Therefore, understanding the regulation and function of TORC1 attracts major interest in TSC research. TORC1 is regulated by a wide range of signals, including growth factors, energy levels, and amino acids. The mechanisms for TORC1 regulation by growth factors and energy levels have been elucidated. In contrast, the mechanism of TORC1 activation by amino acids is largely unknown. Our preliminary studies have identified the Rag GTPases as key molecules in TORC1 activation in response to amino acid signals.

The major goal of this proposal is to understand how TORC1 is regulated. We will focus our efforts on biochemical mechanisms of Rag in mTOR regulation, especially in response to amino acid stimulation. Completion of this proposal will further our understanding of TORC1 regulation and may provide pivotal information for future TSC drug development.