The mammalian target of rapamycin (mTOR) is a central cell growth regulator that integrates a wide range of growth stimulating and inhibitory signals. mTOR inhibitors are FDA approved drugs for immunosuppression in organ transplantation and cancer treatment. The mTOR kinase forms two complexes, TORC1 and TORC2, with distinct subunit composition and physiological functions. In response to growth factors and nutrients, TORC1 promotes cell growth by stimulating translation. Overwhelming evidence has also demonstrated a key role of TORC1 in inhibiting autophagy. However, the molecular mechanism of TORC1 in autophagy regulation is unknown. The AMP activated protein kinase (AMPK) is a key cellular energy sensor and functions to maintain cellular energy homeostasis. AMPK has been implicated in autophagy induction, yet little is known about the mechanism of AMPK in regulating the autophagy machinery. Our preliminary studies indicate that TORC1 and AMPK can regulate key components of the autophagy machinery by direct phosphorylation. The long-term goal of this project is to elucidate the molecular mechanisms of TORC1 and AMPK in induction of autophagy in response to nutrient signals.
The specific aims for this proposal are: 1 To elucidate the functional significance of ULK1 phosphorylation by TORC1 in autophagy 2 To determine the mechanism of AMPK in regulating ULK1 activation and function in autophagy 3 To investigate the mechanism of AMPK in VPS34 regulation during autophagy

Public Health Relevance

Autophagy is a regulated catabolic process in which the cell degrades its own components through fusion with lysosomes;it is an adaptive starvation response to generate nutrients for maintaining essential cellular functions. Autophagy also plays important roles in removing toxic protein aggregates, damaged organelles, and infected pathogens;dysregulation of autophagy has been implicated in many diseases, including cancer and neurodegeneration. The goal of this proposal is to gain knowledge of autophagy regulation, particularly to understand the mechanisms of mTOR and AMPK, both are key nutrient signaling molecules, in autophagy regulation;the completion of this project will not only advance our understanding the fundamental biology of autophagy but also provide important information for therapeutic interventions of human diseases such as cancer and neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01GM051586-21
Application #
8641697
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Maas, Stefan
Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Russell, Ryan C; Tian, Ye; Yuan, Haixin et al. (2013) ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat Cell Biol 15:741-50
Kim, Joungmok; Kim, Young Chul; Fang, Chong et al. (2013) Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy. Cell 152:290-303
Kim, Joungmok; Guan, Kun-Liang (2013) AMPK connects energy stress to PIK3C3/VPS34 regulation. Autophagy 9:1110-1
Li, Li; Guan, Kun-Liang (2013) Microtubule-associated protein/microtubule affinity-regulating kinase 4 (MARK4) is a negative regulator of the mammalian target of rapamycin complex 1 (mTORC1). J Biol Chem 288:703-8
Zhang, Tengfei; Wang, Shiwen; Lin, Yan et al. (2012) Acetylation negatively regulates glycogen phosphorylase by recruiting protein phosphatase 1. Cell Metab 15:75-87
Inoki, Ken; Kim, Joungmok; Guan, Kun-Liang (2012) AMPK and mTOR in cellular energy homeostasis and drug targets. Annu Rev Pharmacol Toxicol 52:381-400
Kang, Y J; Lu, M-K; Guan, K-L (2011) The TSC1 and TSC2 tumor suppressors are required for proper ER stress response and protect cells from ER stress-induced apoptosis. Cell Death Differ 18:133-44
Russell, Ryan C; Fang, Chong; Guan, Kun-Liang (2011) An emerging role for TOR signaling in mammalian tissue and stem cell physiology. Development 138:3343-56
Xie, Xiaoduo; Zhang, Denghong; Zhao, Bin et al. (2011) IkappaB kinase epsilon and TANK-binding kinase 1 activate AKT by direct phosphorylation. Proc Natl Acad Sci U S A 108:6474-9
Xie, Xiaoduo; Guan, Kun-Liang (2011) The ribosome and TORC2: collaborators for cell growth. Cell 144:640-2

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