Faculty

Professor of Pharmacology

Ph.D., Purdue University

Key Words: Phosphorylation, Signal Transduction, Tumor Suppresor, mTOR, TSC, Hippo.

Mutations in either TSC1 or TSC2 tumor suppressor gene cause the tuberous sclerosis complex (TSC) disease. The TSC1/TSC2 complex functions to inhibit the mammalian target of rapamycin (mTOR), which is a central cell growth controller.  mTOR integrates a wide range of signals, including growth factors, nutrients, and stress conditions.  Two distinct TOR complexes, TORC1 and TORC2, have been identified.  These two TOR complexes phosphorylate different substrates and have distinct physiological functions.  For example, TORC1 promotes translation and cell growth by phosphorylating ribosomal S6 kinase (S6K).  In contrast, TORC2 phosphorylates and activates AKT, a key kinase involved in cell growth and apoptosis. We are interested in the mechanism of mTOR regulation and the abnormality of this pathway in human diseases.

The second project in our laboratory focuses on the novel Hippo tumor suppressor pathway. Recent genetic studies in Drosophila have shown that the Hippo signaling pathway plays a key role in restricting organ size by controlling both cell proliferation and apoptosis.  Components of the Hippo pathway are highly conserved in mammalian cells.  Acting down stream of the Hippo pathway is the YAP oncogene, which encodes a transcription co-activator.  Our recent studies have shown that regulation of YAP by the Hippo pathway plays a critical role in cell contact inhibition.  The main focus of this project is to elucidate the physiological regulation of the Hippo pathway and to understand how dysregulation of the pathway contributes to tumorigenesis.

Selected Publications:

Inoki, K., Zhu, T., and Guan, K-L. (2003) TSC2 mediates cellular energy response to control cell growth and survival.  Cell 115, 577-590.

Corradetti, M., Inoki, K., Bardeesy, N., DePinho R., 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.

Inoki, K., Ouyang, H., Zhu, T., Lindvall, C., Wang, Y., Yang, Q., Bennett, C., Harada, Y., Stankunas, K., Wang, C., He, H., MacDougald, O., You, M., Williams, B., and Guan, K-L. (2006) TSC2 integrates Wnt and cellular energy signals through a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126, 955-68.

Yang, Q., Inoki, K., Ikenoue, T., and Guan, K-L. (2006) Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes & Dev. 20, 2833-47.

Zhao, B., Wei, X., et al and Guan, K-L. (2007) Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes & Dev., 21, 2762-74.

Lee, C.J, Inoki, K., and Guan, K-L. (2007) mTOR Pathway as a Target in Tissue Hypertrophy.  Annu. Rev. Pharmacol. Toxicol. (review) 47, 443-67.