Regulation of signal transduction by the conserved protein kinase mTOR, the mammalian target of rapamycin Research in the Fingar Lab 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, evolutionarily conserved signaling complexes with differing sensitivities to acute rapamycin, a naturally-occurring mTOR inhibitory compound. The rapamycin-sensitive mTOR complex 1 (mTORC1), which contains mTOR, raptor, mLST8, and PRAS40, 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 rapamycin-insensitive mTOR complex 2 (mTORC2), which contains mTOR, rictor, mLST8, mSin, and PRR5/protor, 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 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; insulin-resistant 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.