Guan Lab
Research
Tuberous sclerosis complex
Tuberous sclerosis complex (TSC) is a relatively common autosomal dominant disorder characterized by the development of benign tumors termed as hamartomas in a variety of organs. Common clinical symptoms include seizures, mental retardation, autism, kidney failure, facial angiofibromas, and cardial rhabdomyomas. Mutations in either the TSC1 or TSC2 tumor suppressor genes are responsible for TSC disease. TSC1 and TSC2 proteins form a physical and functional complex. Recent studies from our laboratory demonstrate that TSC1/TSC2 function to inhibit the mammalian target of rapamycin (mTOR). The mTOR pathway is constitutively activated in cells with mutation of either TSC1 or TSC2. These observations provide the scientific basis for clinical trial of using rapamycin to treat TSC disease. TSC2 has GTPase activating protein (GAP) activity towards Rheb, which is a Ras family small GTPase and can activate mTOR. Therefore, TSC2 inhibits mTOR by inactivating Rheb. A major project in our laboratory is to investigate the molecular mechanisms how TSC1/TSC2 receive and integrate extracellular and intracellular signals to regulate the mTOR pathway and cell growth.
mTOR
TOR is a serine/threonine kinase that belongs to the phosphatidylinositol kinase related kinase family and is highly conserved from yeast to mammals. TOR functions as a central regulator of cell growth, and itself is regulated by a wide range of signals, including growth factors, nutrients, and stress conditions. Recent studies in eukaryotic cells have identified two distinct TOR complexes, TORC1 and TORC2. These two TOR complexes phosphorylate different substrates and have distinct physiological functions. For example, TORC1 phosphorylates the ribosomal S6 kinase (S6K), thereby regulating translation and cell growth. In contrast, TORC2 phosphorylates and activates AKT, a key kinase involved in cell growth and cell survival. TORC1 is sensitive to inhibition by rapamycin, while TORC2 is resistant to rapamycin. We are interested in how mTOR is regulated by upstream signals, such nutrients and cellular energy level. In addition, we are studying the mechanism of mTOR activation by the phosphatidyl inositol 3-kinase (PI3K) pathway.
