The process of mass accumulation (cell growth) is an important regulator of cell, organ, and body size and can be deregulated in diverse diseases such as cancer and diabetes. Our lab is studying the mammalian TOR (mTOR) pathway, a signaling network that regulates growth in response to growth factors, stress, nutrients, and metabolism. The mTOR pathway is medically important, as it is the target of the FDA-approved immunosuppressant rapamycin that also prevents vessel restenosis after angioplasty and has potential as an anti-cancer agent. Moreover, recent work suggests that in the cancer-prone genetic syndrome tuberous sclerosis complex the mTOR pathway becomes hyperactive and deregulated. Over the last few years we have been studying the biochemistry of the mTOR pathway in human tissue culture cells and have discovered two distinct mTOR-containing protein complexes. The first contains mTOR and two novel proteins, raptor and GbL, and mediates the rapamycin-sensitive roles of mTOR (like S6K1 phosphorylation). The second complex also contains mTOR and GbetaL but, instead of raptor, another novel protein that we named rictor. Our proposed work focuses on understanding the biochemical, cellular and organismal functions of the rictor protein, the central component of the rapamycin-insensitive mTOR pathway. Although we know little about this pathway compared to the rapamycin-sensitive branch, our preliminary results suggest that rictor plays critical roles in the control of cell survival and proliferation by regulating the activity of known effectors of these processes. Our unexpected discovery that mTOR has rapamycin-insensitive functions suggests that direct inhibitors of the mTOR kinase activity will likely have different pharmacological effects and clinical applications than rapamycin. Therefore, our proposed work will lead to an important advance in our understanding of the molecular mechanisms that regulate cell growth and survival and that may be exploited to tackle diseases in which these processes are deregulated.
| Abu-Remaileh, Monther; Wyant, Gregory A; Kim, Choah et al. (2017) Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes. Science 358:807-813 |
| Ersching, Jonatan; Efeyan, Alejo; Mesin, Luka et al. (2017) Germinal Center Selection and Affinity Maturation Require Dynamic Regulation of mTORC1 Kinase. Immunity 46:1045-1058.e6 |
| Wolfson, Rachel L; Sabatini, David M (2017) The Dawn of the Age of Amino Acid Sensors for the mTORC1 Pathway. Cell Metab 26:301-309 |
| Caron, Alexandre; Mouchiroud, Mathilde; Gautier, Nicolas et al. (2017) Loss of hepatic DEPTOR alters the metabolic transition to fasting. Mol Metab 6:447-458 |
| Kalaitzidis, Demetrios; Lee, Dongjun; Efeyan, Alejo et al. (2017) Amino acid-insensitive mTORC1 regulation enables nutritional stress resilience in hematopoietic stem cells. J Clin Invest 127:1405-1413 |
| Okosun, Jessica; Wolfson, Rachel L; Wang, Jun et al. (2016) Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma. Nat Genet 48:183-8 |
| Muranen, Taru; Selfors, Laura M; Hwang, Julie et al. (2016) ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP. Cancer Res 76:7168-7180 |
| Chantranupong, Lynne; Scaria, Sonia M; Saxton, Robert A et al. (2016) The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway. Cell 165:153-164 |
| Saxton, Robert A; Knockenhauer, Kevin E; Wolfson, Rachel L et al. (2016) Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway. Science 351:53-8 |
| Saxton, Robert A; Chantranupong, Lynne; Knockenhauer, Kevin E et al. (2016) Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. Nature 536:229-33 |
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