 Faculty Profiles
TSC (tuberous sclerosis complex) -mTOR (mammalian target of rapamycin) signaling is an evolutionarily conserved pathway implicated in a wide array of cellular processes such as cell growth, proliferation, survival, and autophagy. mTOR forms two distinct functional complexes termed mTOR complex 1 and 2 (mTORC1 and mTORC2). mTORC1 activity is sensitive to inhibition by rapamycin and suppressed by TSC complex whereas mTORC2 activity is resistant to rapamycin.
The rapamycin-sensitive mTORC1 regulates the activity of the translational initiation machinery by modulating S6 kinase activity and eIF4E binding protein (4EBP1) phosphorylation, leading to increased protein synthesis and cell growth. On the other hand, mTORC2 activity is mainly regulated by growth factors such as insulin and IGF-1, and regulates the activation of Akt, a kinase involved in cell proliferation and survival.
Our studies on the regulation of mTOR signaling revealed that the tumor suppressor proteins TSC1 and TSC2 function as negative regulators of mTORC1 (NCB 2002 Inoki et al). TSC1 and TSC2 form a complex that contains GTPase (GAP) activity, resulting in the suppression of cell growth. Loss of function of either TSC1 or TSC2 causes Tuberous Sclerosis Complex (TSC), an inherited hamartoma syndrome. Tumor formation in the heart, lung, brain and kidney causes severe complications in TSC patients. A search for targets of the TSC complex resulted in the identification of the small G protein Rheb as an essential activator of mTORC1, providing a direct link to the GAP activity of TSC2 (Gene & Dev 2003 Inoki et al). Furthermore, we demonstrated that Akt phosphorylates and suppresses TSC2 activity (NCB 2002 Inoki et al). These findings revealed not only the function of tumor suppressor TSC proteins, but also a mechanism for mTORC1 activation by growth factors. These studies also suggested that rapamycin, an FDA approved immunosuppressant drug in organ transplantation, might be a potential treatment for TSC tumors. In fact, a preliminary clinical trial indicates that rapamycin has a potent anti-tumor effect in TSC patients.
The TORC1 complex is also regulated by nutrients such as glucose and amino acids, and activated by exposure of cells to high glucose, while inhibited under low glucose conditions. We elucidated the mechanism by which this occurs with the discovery that AMP-activated protein kinase (AMPK), an essential cellular energy sensor, phosphorylates and activates TSC2, resulting in the inhibition of mTORC1 activity (Cell 2003 Inoki et al). These findings revealed that the TSC complex plays a critical role in sensing intracellular energy levels via AMPK phosphorylation, in turn regulating protein synthesis and cell growth by modulating mTORC1 activity.
mTOR signaling is essential for organ development because ablation of the genes involved in this pathway leads to an embryonic lethality. However, hyper-activation of mTORC1 pathway may contribute to the development of cancer and cause metabolic diseases such as obesity and diabetes. Furthermore, the activity of mTORC1 pathway plays an important role in the longevity in a wide array of organisms.
Our group is investigating the roles of the TSC-mTOR signaling in various organs using conditional knockout mouse model to understand physiological and pathological roles of this pathway. Furthermore, our interests include the identification of new pathways which impinge on mTOR signaling pathway and the elucidation of molecular mechanism by which variety of nutrients regulate mTORC1 activity.
Ikenoue, T., Hong, S., and Inoki, K. (2009) Monitoring Mammalian Target of Rapamycin (mTOR) Activity. Methods Enzymol 452, 165-80.
Inoki, K and Guan, K.L. (2009). Tuberous sclerosis complex, implication from a rare genetic disease to common cancer treatment. Hum Mol Genet. 15, R94-R100.
Mori, H., Inoki, K., Münzberg, H., Opland, D., Faouzi, M., Villanueva, E.C., Ikenoue, T., Kwiatkowski, D., MacDougald, O.A., Myers, M.G.Jr., and Guan, K.L. (2009) Critical role for hypothalamic mTOR activity in energy balance. Cell Metabolism 9, 362-374.
Inoki, K. (2008). Role of TSC-mTOR pathway in diabetic nephropathy. Diabetes Res Clin Pract, 82, S59-62.
Inoki, K., Ouyang, H., Zhu, T., Lindvall, C., Wang, Y., Zhang, X., Yang, Q., Bennett, C., Harada, Y., Stankunas, K., Wang, CY., He, X., MacDougald, OA., You, M., Williams, BO., and Guan, K. L. (2006). TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126, 955-968.
Inoki, K., Corradetti, M. N., and Guan, K. L. (2005). Dysregulation of the TSC-mTOR pathway in human disease. Nat Genet 37, 19-24.
Corradetti, M. N., Inoki, K*., Bardeesy, N., DePinho, R. A., and Guan, K. L*. (2004). Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev 18, 1533-1538. (*co-corresponding)
Inoki, K., Li, Y., Xu, T., and Guan, K. L. (2003). Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 17, 1829-1834.
Inoki, K., Zhu, T., and Guan, K. L. (2003). TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577-590.
Inoki, K., Li, Y., Zhu, T., Wu, J., and Guan, K. L. (2002). TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4, 648-657.
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