The importance of the PI3Kinase-Akt-Tsd/Tsc2-mTOR signaling pathway in the regulation of both cell size and cell growth has become apparent in recent years. The seminal observations that initiated this explosive increase in our understanding were made in Drosophila 4 years ago. Although much progress has been made in mammalian systems on this pathway as well, Drosophila continues to offer major advantages and insights due to the ease of genetic manipulation, and relatively low costs. In addition, recently the technological approach of whole genome RNAi screens in Drosophila has provided the opportunity for pathway analysis that cannot be approached in mammalian systems. This approach is robust and reliable, and is the primary tool we will use to explore critical questions on Tsc1/Tsc2-Tor-S6K signaling in four specific aims.
In Aim 1 and Aim 2, two small scale - hypothesis driven - RNAi screen will be performed to identify a crucial missing links in this pathway: The GEF(s) for Rheb and kinases/phosphatases affecting AMPK_ phosphorylation and activity.
In Aim 3, we will identify core components involved in Akt phosphorylation and its regulation by a feedback mechanism. We will distinguish those that affect both S6K and Akt,and those that affect Akt only.
In Aim 4, a comprehensive genome-wide RNAi screen will be performed to identify regulators acting downstream of Tsc1/Tsc2 on S6K phosphorylation. Findings will be explored and confirmed through biochemical and genetic analyses in vivo in the fly,and also translated to mammalian systems in concert with the other projects of this PPG. The improved understanding of the wiring of this signaling pathway will provide both fundamental insight and the opportunity for therapeutic intervention.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
Lewis Jr, Tommy L; Kwon, Seok-Kyu; Lee, Annie et al. (2018) MFF-dependent mitochondrial fission regulates presynaptic release and axon branching by limiting axonal mitochondria size. Nat Commun 9:5008
Eichner, Lillian J; Brun, Sonja N; Herzig, Sébastien et al. (2018) Genetic Analysis Reveals AMPK Is Required to Support Tumor Growth in Murine Kras-Dependent Lung Cancer Models. Cell Metab :
Deng, Jiehui; Wang, Eric S; Jenkins, Russell W et al. (2018) CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation. Cancer Discov 8:216-233
Herzig, Sébastien; Shaw, Reuben J (2018) AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 19:121-135
Du, Heng; Dreier, John R; Zarei, Mahsa et al. (2018) A novel mouse model of hemangiopericytoma due to loss of Tsc2. Hum Mol Genet 27:4169-4175
McBrayer, Samuel K; Mayers, Jared R; DiNatale, Gabriel J et al. (2018) Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma. Cell 175:101-116.e25
Kamareddine, Layla; Wong, Adam C N; Vanhove, Audrey S et al. (2018) Activation of Vibrio cholerae quorum sensing promotes survival of an arthropod host. Nat Microbiol 3:243-252
Wu, Shulin; Ye, Jianheng; Wang, Zongwei et al. (2018) Expression of aromatase in tumor related stroma is associated with human bladder cancer progression. Cancer Biol Ther 19:175-180
Ye, Jianheng; Zhang, Yanqiong; Cai, Zhiduan et al. (2018) Increased expression of immediate early response gene 3 protein promotes aggressive progression and predicts poor prognosis in human bladder cancer. BMC Urol 18:82
Cañadas, Israel; Thummalapalli, Rohit; Kim, Jong Wook et al. (2018) Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses. Nat Med 24:1143-1150

Showing the most recent 10 out of 289 publications