The mechanistic target of rapamycin (mTOR) controls cell growth by integrating a wide range of signals, such as growth factors, nutrients, and stress. mTOR is a conserved protein kinase that forms two complexes, referred to as TORC1 and TORC2, with distinct subunit composition and physiological functions. The physiological function of TORC1 in promoting cell growth is well characterized and inhibitors that target the complex are used clinically to treat several diseases including cancer, transplant rejection, and restenosis. The mechanism of TORC1 regulation is a topic of intense interest in both basic cell biology and translational research. Growth factors and nutrients activate TORC1 to promote cell growth by stimulating anabolism and inhibiting catabolism. Previous studies have investigated TORC1 regulation by growth factors and nutrients. However, the molecular insights of inhibitory signals that regulate TORC1 are ambiguous. Both oxidative stress and hyperosmotic stress rapidly and potently inhibit TORC1. Our preliminary studies indicate that the nemo like kinase (NLK) plays a crucial role in TORC1 inhibition in response to hyperosmotic or oxidative stress. In addition to oxidative and hyperosmotic stress, we observed that protein kinase A (PKA) mediates an inhibitory effect to mTORC1 in response to the second messenger cyclic AMP (cAMP). The long-term goal of this project is to elucidate the molecular mechanisms of TORC1 regulation and the function of TORC1 in cell physiology and disease. In this proposal, we will determine the biological function and molecular mechanism of NLK in mediating the osmotic and oxidative stress to inhibit TORC1. Furthermore, we will investigate the mechanisms of mTORC1 inhibition by PKA and functional cross talk between cAMP and mTORC1.
The specific aims for this proposal are: 1. Determine the function of NLK in TORC1 regulation by osmotic and oxidative stress 2. Elucidate the biochemical basis of NLK in TORC1 inhibition by osmotic and oxidative stress 3. Investigate the molecular mechanisms and functional role of TORC1 inhibition by cAMP-PKA

Public Health Relevance

The target of rapamycin complex 1 (TORC1) is a master regulator that integrates multiple signals to modulate cell growth. The goal of this proposal is to elucidate the molecular mechanisms of TORC1 inhibition by osmotic and oxidative stress, and also cAMP signals. Completion of this project will not only advance our understanding of the fundamental biology of TORC1 in normal physiology and pathophysiology, but also provide valuable information for therapeutic intervention of the TORC1 signaling network.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM051586-24
Application #
9392172
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Maas, Stefan
Project Start
1994-08-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
24
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Zhang, Qian; Meng, Fansen; Chen, Shasha et al. (2017) Hippo signalling governs cytosolic nucleic acid sensing through YAP/TAZ-mediated TBK1 blockade. Nat Cell Biol 19:362-374
Gu, Yuchao; Albuquerque, Claudio P; Braas, Daniel et al. (2017) mTORC2 Regulates Amino Acid Metabolism in Cancer by Phosphorylation of the Cystine-Glutamate Antiporter xCT. Mol Cell 67:128-138.e7
Hong, Audrey W; Guan, Kun-Liang (2017) Non-radioactive LATS in vitro Kinase Assay. Bio Protoc 7:
Strnadel, Jan; Choi, Sunkyu; Fujimura, Ken et al. (2017) eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth. Cancer Res 77:1997-2007
Lin, Kimberly C; Moroishi, Toshiro; Meng, Zhipeng et al. (2017) Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation. Nat Cell Biol 19:996-1002
Lin, Kimberly C; Park, Hyun Woo; Guan, Kun-Liang (2017) Regulation of the Hippo Pathway Transcription Factor TEAD. Trends Biochem Sci 42:862-872
Ma, Xi; Zhang, Shen; He, Long et al. (2017) MTORC1-mediated NRBF2 phosphorylation functions as a switch for the class III PtdIns3K and autophagy. Autophagy 13:592-607
Hong, Audrey W; Meng, Zhipeng; Yuan, Hai-Xin et al. (2017) Osmotic stress-induced phosphorylation by NLK at Ser128 activates YAP. EMBO Rep 18:72-86
Fu, Vivian; Moroishi, Toshiro; Guan, Kun-Liang (2016) Glycoholics Anonymous: Cancer Sobers Up with mTORC1. Cancer Cell 29:432-434
Lin, Huai-Peng; Cheng, Zhou-Li; He, Ruo-Yu et al. (2016) Destabilization of Fatty Acid Synthase by Acetylation Inhibits De Novo Lipogenesis and Tumor Cell Growth. Cancer Res 76:6924-6936

Showing the most recent 10 out of 69 publications