TOR was discovered as the largest of Rapamycin; the latter is a potent and clinically important immunosuppressive and potential antiproliferative drug. All of rapamycins pharmacologic actions appear to he due to its ability to inhibit TOR function. TOR is a giant protein kinase in the PIK family, whose catalytic domain is closely related to the Ataxia Teleangiectasia gene product (ATM). TOR was first identified in S. Cerevisiae where it controls cell growth and proliferation in response to nutrient signals. When high quality N-and fermentable C-sources are available, TOR promotes growth. When nutrients are limiting (or in the presence of rapamycin) the fall in TOR activity inhibits overall mRNA translation (thereby arresting growth), activates autophagy as well as proteosomal degradation of specific proteins, and alters gene transcription by activation of the N- and C- catabolite repression responses and by inhibition of ribosome biogenesis. These responses are controlled by TOR kinase activity, which signals through two primary effector limbs; through TOR-catalyzed phosphorylation, which alters target function or marks targets for degradation, and through the modulation of protein phosphatase activity, achieved by TOR-catalyzed phosphorylation of the phosphatase regulatory protein Tap42. In multicellular organisms, TOR control of cell growth is shared with the IR/IGF1R tyrosine kinases. We and others have shown that mTOR controls the function of a subset of the downstream targets of the Type 1A PI-3 kinases, especially the p70 S6 kinase and the eIF-4E inhibitor proteins, PHASI/4E-BP. Thus, rapamycin or withdrawal of amino acids produces dephosphorylation of p70 S6K and 4E-BP, which become unresponsive to insulin and P1-3 kinase. Concomitantly, the translation of several subsets of rnRNA critical to growth are inhibited. Although we showed that mTOR can phosphorylate and activate the p70 S6 kinase in vitro, our data indicate that mTOR regulation of p70 S6K in vivo occurs indirectly, through the regulation of phosphatase activity. Moreover, the molecular basis for the regulation of mTOR activity by nutrients and tyrosine kinases is unknown. We propose to study the mechanism of mTOR regulation and signaling by a combination of genetics and biochemistry. We have identified loss-of-function mutants in C. elegans TOR; these arrest as undersized larvae. We are carrying out a screen for suppressor mutants, seeking the elements downstream of CeTOR most critical to its function in development. A second effort involves direct biochemical experiments addressing the mechanism by which mTOR regulates protein phosphatase activity. Finally, we will characterize in vitro the basis for the radically different TOR kinase activity toward p70 S6K and 4E BP, and seek to identify the molecular basis for mTOR regulation in vivo.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Blair, Donald G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Papageorgiou, Angela; Rapley, Joseph; Mesirov, Jill P et al. (2015) A genome-wide siRNA screen in mammalian cells for regulators of S6 phosphorylation. PLoS One 10:e0116096
Oshiro, Noriko; Rapley, Joseph; Avruch, Joseph (2014) Amino acids activate mammalian target of rapamycin (mTOR) complex 1 without changing Rag GTPase guanyl nucleotide charging. J Biol Chem 289:2658-74
Dai, Ning; Christiansen, Jan; Nielsen, Finn C et al. (2013) mTOR complex 2 phosphorylates IMP1 cotranslationally to promote IGF2 production and the proliferation of mouse embryonic fibroblasts. Genes Dev 27:301-12
Papageorgiou, Angela; Avruch, Joseph (2012) A genome-wide RNAi screen for polypeptides that alter rpS6 phosphorylation. Methods Mol Biol 821:187-214
Rapley, Joseph; Oshiro, Noriko; Ortiz-Vega, Sara et al. (2011) The mechanism of insulin-stimulated 4E-BP protein binding to mammalian target of rapamycin (mTOR) complex 1 and its contribution to mTOR complex 1 signaling. J Biol Chem 286:38043-53
Dai, Ning; Rapley, Joseph; Angel, Matthew et al. (2011) mTOR phosphorylates IMP2 to promote IGF2 mRNA translation by internal ribosomal entry. Genes Dev 25:1159-72
Wexler, Tamara L; Durst, Ronen; McCarty, David et al. (2010) Growth hormone status predicts left ventricular mass in patients after cure of acromegaly. Growth Horm IGF Res 20:333-7
Avruch, Joseph; Long, Xiaomeng; Lin, Yenshou et al. (2009) Activation of mTORC1 in two steps: Rheb-GTP activation of catalytic function and increased binding of substrates to raptor. Biochem Soc Trans 37:223-6
Avruch, Joseph; Long, Xiaomeng; Ortiz-Vega, Sara et al. (2009) Amino acid regulation of TOR complex 1. Am J Physiol Endocrinol Metab 296:E592-602
Oshiro, Noriko; Takahashi, Rinako; Yoshino, Ken-ichi et al. (2007) The proline-rich Akt substrate of 40 kDa (PRAS40) is a physiological substrate of mammalian target of rapamycin complex 1. J Biol Chem 282:20329-39

Showing the most recent 10 out of 27 publications