Regulation and function of signal transduction by mTOR complexes
My laboratory focuses on signal transduction by the evolutionarily conserved mammalian target of rapamycin (mTOR) protein kinase. mTOR integrates signals from diverse cellular stimuli to control cellular physiology. mTOR associates with partner proteins to form functionally distinct, signaling complexes with differing sensitivities to rapamycin, a naturally-occurring inhibitor. The rapamycin-sensitive mTOR complex 1 (mTORC1) promotes cellular biosynthetic processes such as protein synthesis, cell growth, cell proliferation, and cell metabolism only during growth factor, amino acid, and energy sufficiency. Thus, mTORC1 functions as an environmental sensor. The more recently identified and thus less well-characterized rapamycin-insensitive mTOR complex 2 (mTORC2) responds to growth factors to modulate the organization of the actin cytoskeleton. Currently, rapamycin is employed clinically as an immunosuppressive agent to reduce kidney transplant rejection and as a cardiology drug to inhibit coronary artery restenosis following angioplasty. Additionally, rapamycin analogs (rapalogs) and second-generation mTOR catalytic inhibitors hold promise as novel anti-neoplastic compounds. The clinical efficacy of rapamycin, as well as the emerging idea that aberrant mTOR signaling contributes to several prevalent human diseases (e.g. cancer; diabetes; cardiovascular diseases), underscores the importance of elucidating all aspects of mTOR biology.
Diverse environmental stimuli regulate mTORC1 and mTORC2 signaling. Although many mTORC1 regulatory molecules have been identified, the molecular mechanisms by which cellular signals directly modulate mTOR activity in either TORC1 or TORC2 are not known. As phosphorylation controls the activity of many proteins in the TORC1 pathway, we hypothesized that phosphorylation of mTOR itself or its partners in response to cellular signals may regulate mTOR signaling and biological function. Thus, a major focus of the lab has been to employ tandem mass spectrometry to identify novel sites of phosphorylation on mTOR and its partners and to elucidate their regulation and function in mTOR complex signal transduction. Thus, our studies investigate the individual and combined roles of site-specific mTOR complex phosphorylation in regulation of mTOR complex function at the cellular level using immortalized cells in culture and a variety of molecular, biochemical, and cellular techniques. In the future, we hope to generate animal models in order to understand the role of mTOR complex phosphorylation in control of organismal physiology.
1. Fingar DC, Salama S, Tsou C, Harlow E and Blenis J. Mammalian cell size is controlled by mTOR and its downstream targets S6K1 and 4EBP1/eIF4E. (2002) Genes and Dev 16: 1472-1487. PMCID: PMC186342
2. Fingar DC, Tee AR, Richardson CJ, Cheatham L, Tsou C, and Blenis J. (2004) mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eurkaryotic translation initiation factor 4E. Mol Cell Biol 24(1): 200-216. PMCID: PMC303352
3. Fingar DC and Blenis J. (2004) Review: Target of rapamycin (TOR): An integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression. Oncogene 23: 3151-3171.
4. Acosta-Jaquez, HA, Keller, JA, Foster, KG, Soliman, GA, Ballif, BA, and Fingar, DC. (2009) Site-specific mTOR phosphorylation promotes mTORC1-mediated biochemical signaling and cell growth 2009). Mol Cell Biol 29(15): 4308-4324.
5. *Foster, KG, *Acosta-Jaquez, HA, Romeo, Yves, Ekim, B, Soliman, GA, Carriere, A, Roux, PP, Ballif, BA, and Fingar, DC. (2009) Regulation of mTOR complex 1 (mTORC1) by raptor S863 and multi-site phosphorylation. J Biol Chem 285 (1): 80-94. *Equal contribution.
6. Soliman, GA, *Acosta-Jaquez, HA, Elaine A. Dunlop, Ekim, B, Maj, N, Tee, AR and Fingar, DC. mTOR S2481 autophosphorylation monitors mTORC-specific catalytic activity and clarifies rapamycin mechanism of action (2009). J Biol Chem 285 (11): 7866-79. *Equal contribution.
7. Foster, KG and Fingar, DC. (2010) Review: mTOR- Conducting the cellular signaling symphony. J Biol Chem 285 (19): 14071-14077.
8. Soliman, GA, Acosta Jaquez, HA, and Fingar, DC (2010). mTORC1 inhibition via rapamycin promotes triacylglycerol lipolysis to release free fatty acids in 3T3-L1 adipocytes. Lipids, 45 (12): 1089-1100.
9. Carriere, A, Romeo, Y, Acosta-Jaquez, HA, Moreau, J, Bonneil, E, Thibault, P, Fingar, DC, and Roux, P. ERK1/2 phosphorylate raptor to promote Ras-dependent activation of mTOR complex 1 (mTORC1). J Biol Chem. In press Nov. 11, 2010.
10. Ekim, E, Magnuson, BA, Acosta Jaquez, HA, Keller, JA Feener, EP, and Fingar, DC. mTOR kinase domain phosphorylation promotes mTORC1 signaling, cell growth, and cell cycle progression. Submitted.