The TSC/Rheb/mTOR signaling pathway plays important roles in protein synthesis, growth and cell cycle progression in response to nutrients, energy and growth factors such as insulin and insulin like growth factor. Overactivation of this signaling pathway is detected in a variety of human cancers and rapamycin, an inhibitor of mTOR, is being evaluated in clinical trials. Our recent work demonstrated that a single amino acid change can confer constitutive activation. More recently, we have made an important discovery that activating mutants of mTOR can be identified in human cancer genome database. In this application, we will focus on these mTOR mutants and ask first whether these mutants exhibit transforming activities. We will then carry out experiments aimed at gaining insight into the mechanism of activation of mTOR by the mutations. Finally, we will use fission yeast as a system amenable to genetic analysis to gain further insight into the mechanism of activation of the TOR signaling.

Public Health Relevance

The mTOR signaling plays critical roles in growth and proliferation of mammalian cells. Deregulation of this signaling pathway causes cancer and genetic disorders. We will identify and characterize mutations in mTOR that confer constitutive activation.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Spalholz, Barbara A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Coffman, Kimberly; Yang, Bing; Lu, Jie et al. (2014) Characterization of the Raptor/4E-BP1 interaction by chemical cross-linking coupled with mass spectrometry analysis. J Biol Chem 289:4723-34
Heard, Jeffrey J; Fong, Valerie; Bathaie, S Zahra et al. (2014) Recent progress in the study of the Rheb family GTPases. Cell Signal 26:1950-7
Zimonjic, Drazen B; Chan, Lai N; Tripathi, Veenu et al. (2013) In vitro and in vivo effects of geranylgeranyltransferase I inhibitor P61A6 on non-small cell lung cancer cells. BMC Cancer 13:198
Chan, Lai N; Fiji, Hannah D G; Watanabe, Masaru et al. (2011) Identification and characterization of mechanism of action of P61-E7, a novel phosphine catalysis-based inhibitor of geranylgeranyltransferase-I. PLoS One 6:e26135
Hardt, Molly; Chantaravisoot, Naphat; Tamanoi, Fuyuhiko (2011) Activating mutations of TOR (target of rapamycin). Genes Cells 16:141-51
Hanker, A B; Mitin, N; Wilder, R S et al. (2010) Differential requirement of CAAX-mediated posttranslational processing for Rheb localization and signaling. Oncogene 29:380-91
Jiang, Huaidong; Song, Changyong; Chen, Chien-Chun et al. (2010) Quantitative 3D imaging of whole, unstained cells by using X-ray diffraction microscopy. Proc Natl Acad Sci U S A 107:11234-9
Lu, Jie; Liong, Monty; Li, Zongxi et al. (2010) Biocompatibility, biodistribution, and drug-delivery efficiency of mesoporous silica nanoparticles for cancer therapy in animals. Small 6:1794-805
Nakashima, Akio; Sato, Tatsuhiro; Tamanoi, Fuyuhiko (2010) Fission yeast TORC1 regulates phosphorylation of ribosomal S6 proteins in response to nutrients and its activity is inhibited by rapamycin. J Cell Sci 123:777-86
Sato, T; Nakashima, A; Guo, L et al. (2010) Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer. Oncogene 29:2746-52

Showing the most recent 10 out of 80 publications