Regulation of TS1/TSC2 Stability and Rheb GTP Level by Herc1

摘要

Over the past decade, considerable progress has been made in understanding the molecular genetics of Tuberous Sclerosis (TSC), highlighted by the identification of the two tumor suppressor genes tsc1 and tsc2. Mutations in either tsc1 or tsc2 cause the disease TSC. A surge of recent research from several labs has shown that TSC1/2 antagonizes the mTOR (mammalian target of rapamycin) signaling network, which plays a central role in the regulation of cell growth in response to growth factors, cellular energy, and nutrient levels. In TSC1 or TSC2 mutant cells, the mTOR signaling pathway, as determined by the phosphorylation of S6K (ribosomal S6 kinase) and 4EBP1 (eukaryote initiation factor 4E binding protein), is highly elevated. Recent studies have also shown that TSC2 functions as a GTPase activating protein (GAP) to stimulate GTP hydrolysis of Rheb (a Ras family GTPase), therefore, inactivating Rheb. Both genetic and biochemical studies support that Rheb is a key direct downstream target of TSC2 and plays an essential role to mediate the physiological functions of TSC1/TSC2. The main objective of this project is to investigate the function of Herc in the regulation of TSC1/TSC2 stability and Rheb GTP level.