Abstract

The long-term goals of this project are to elucidate the function and regulation of protein phosphorylation in the control of cell growth, differentiation, survival, and metabolism in response to various growth factors, such as EGF and insulin. Phosphatidylinositol-3 kinase (PI3K) is a critical component in the growth factor signaling pathway and plays an important role in cell growth and survival. A key downstream effector of PI3K is the AKT/PKB protein kinase. AKT activation requires the phosphorylation of two key residues, T308 by PDK1 and S473 by PDK2. The identity of PDK2 has remained elusive until the recent identification of TORC2 (TOR complex 2) as a candidate PDK2. Recent studies have established that TORC2 plays a key role in the phosphorylation of AKT S473 and is stimulated by the PI3K pathway. Dysregulation of the PI3K pathway is associated with many human diseases, such as cancers and hypertrophic disorders. We have identified Sin1 as a novel TORC2 component required for complex formation and kinase activity. The major goal of this proposal is to investigate the molecular mechanism of TORC2 regulation by insulin and PI3K.
The specific aims of the proposal are: 1. To determine the functional significance of Sin1 phosphorylation in regulation of TORC2 2. To determine the regulation of Sin1 protein levels by Rictor and mTOR 3. To investigate the mechanisms of TORC2 activation by insulin and PI3K

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM051586-16
Application #
7590401
Study Section
Cellular Signaling and Dynamics Study Section (CSD)
Project Start
1994-08-01
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
16
Fiscal Year
2009
Total Cost
$368,483
Indirect Cost

  Institution

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

  Publications

Liu, Meng-Xi; Jin, Lei; Sun, Si-Jia et al. (2018) Metabolic reprogramming by PCK1 promotes TCA cataplerosis, oxidative stress and apoptosis in liver cancer cells and suppresses hepatocellular carcinoma. Oncogene 37:1637-1653
Chen, Lei-Lei; Lin, Huai-Peng; Zhou, Wen-Jie et al. (2018) SNIP1 Recruits TET2 to Regulate c-MYC Target Genes and Cellular DNA Damage Response. Cell Rep 25:1485-1500.e4
Han, Han; Qi, Ruxi; Zhou, Jeff Jiajing et al. (2018) Regulation of the Hippo Pathway by Phosphatidic Acid-Mediated Lipid-Protein Interaction. Mol Cell 72:328-340.e8
Meng, Zhipeng; Qiu, Yunjiang; Lin, Kimberly C et al. (2018) RAP2 mediates mechanoresponses of the Hippo pathway. Nature 560:655-660
Ma, Shenghong; Guan, Kun-Liang (2018) Polycystic kidney disease: a Hippo connection. Genes Dev 32:737-739
Ye, Dan; Guan, Kun-Liang; Xiong, Yue (2018) Metabolism, Activity, and Targeting of D- and L-2-Hydroxyglutarates. Trends Cancer 4:151-165
Plouffe, Steven W; Lin, Kimberly C; Moore 3rd, Jerrell L et al. (2018) The Hippo pathway effector proteins YAP and TAZ have both distinct and overlapping functions in the cell. J Biol Chem 293:11230-11240
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
Lin, Kimberly C; Park, Hyun Woo; Guan, Kun-Liang (2017) Regulation of the Hippo Pathway Transcription Factor TEAD. Trends Biochem Sci 42:862-872

Showing the most recent 10 out of 76 publications