Signaling by the mTOR protein kinase complex 1 (mTORC1) plays a major role in proper differentiation and development, and in regulating normal cellular homeostasis. When improperly regulated this signaling systems has been linked to a variety of diseases associated with altered metabolism such as aging, diabetes, obesity, immune disorders, neurodegeneration, diseased muscle physiology, benign tumor syndromes and malignant cancers. The overall goals of the previous funding period were to begin to define at a molecular and biochemical level how mTOR signaling controls cell growth through the regulation of protein synthesis, to initiate efforts to define the signaling landscape (the mTORC1 phospho-proteome) and biological processes regulated downstream of mTORC1, and to develop high-throughput, RNAi-based screens to extensively evaluate how mTORC1 is regulated by growth factors, oncogenes, tumor suppressors, nutrients, stress and cellular energy status. Our continuing success on all fronts has provided the foundation for the current proposal. From our innovative approaches and proposed research, we will illuminate previously unknown roles of C3G and various GEFs in mTORC1 activation (aim #1);define how and why AAs regulate the Ran gradient and the nuclear entry of Rags and/or mTORC1 (aim #2);and identify new molecular details of how mTORC1 regulates mRNA biogenesis (aim #3). Through these aims, we will identify and characterize new upstream regulators and downstream effectors of mTORC1, further explaining how improper regulation of mTORC1 contributes to a variety of human diseases. Furthermore, our research will result in the identification of new biomarkers and potential therapeutic targets needed for detection and intervention in human diseases resulting from improper mTOR signaling.

Public Health Relevance

With the vast amount of new data we have generated regarding the signaling landscape surrounding the mTORC1 protein kinase, we have placed ourselves in the unique position to uncover and understand at a biochemical and molecular level new regulatory processes, new biomarkers and new potential targets for drug discovery, that are needed for personalized therapeutic intervention in the many diseases, such as cancer, diabetes, and neurodegenerative disorders, linked to improper mTORC1 signaling.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM051405-17
Application #
8243194
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Marino, Pamela
Project Start
1995-09-01
Project End
2016-01-31
Budget Start
2012-03-01
Budget End
2013-01-31
Support Year
17
Fiscal Year
2012
Total Cost
$616,204
Indirect Cost
$249,472
Name
Harvard University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Dunlop, Elaine A; Seifan, Sara; Claessens, Tijs et al. (2014) FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation. Autophagy 10:1749-60
Li, Chenggang; Lee, Po-Shun; Sun, Yang et al. (2014) Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells. J Exp Med 211:15-28
Csibi, Alfredo; Lee, Gina; Yoon, Sang-Oh et al. (2014) The mTORC1/S6K1 pathway regulates glutamine metabolism through the eIF4B-dependent control of c-Myc translation. Curr Biol 24:2274-80
Li, Jing; Kim, Sang Gyun; Blenis, John (2014) Rapamycin: one drug, many effects. Cell Metab 19:373-9
Sun, Y; Gu, X; Zhang, E et al. (2014) Estradiol promotes pentose phosphate pathway addiction and cell survival via reactivation of Akt in mTORC1 hyperactive cells. Cell Death Dis 5:e1231
Liu, Meilian; Bai, Juli; He, Sijia et al. (2014) Grb10 promotes lipolysis and thermogenesis by phosphorylation-dependent feedback inhibition of mTORC1. Cell Metab 19:967-80
Csibi, Alfred; Fendt, Sarah-Maria; Li, Chenggang et al. (2013) The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 153:840-54
Kim, Sang Gyun; Hoffman, Gregory R; Poulogiannis, George et al. (2013) Metabolic stress controls mTORC1 lysosomal localization and dimerization by regulating the TTT-RUVBL1/2 complex. Mol Cell 49:172-85
Kim, Sang Gyun; Buel, Gwen R; Blenis, John (2013) Nutrient regulation of the mTOR complex 1 signaling pathway. Mol Cells 35:463-73
Liu, Pengda; Gan, Wenjian; Inuzuka, Hiroyuki et al. (2013) Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signalling to suppress tumorigenesis. Nat Cell Biol 15:1340-50

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