The delineation of complex signaling pathways and networks is providing therapeutic targets and strategies for cancer and greatly enhancing our ability to predict and interpret clinical outcomes. The pathways involving the lipid kinase PI3K and the protein kinase mTOR are intimately linked in a cellular network, referred to here as the PI3K-TSC-mTOR network, that is comprised of numerous oncogenes and tumor suppressors. Dysregulation of this signaling network occurs in the majority of genetic tumor syndromes, such as tuberous sclerosis complex (TSC), neurofibromatosis, and Cowden disease, and all of the most common forms of cancer. Research under the original grant and continued in this renewal is revealing the molecular wiring of this signaling network in normal and tumor cells and providing novel insights into tumor development, progression, and therapeutic intervention. Progress: Research during the first 3.5 years of the original 4-year grant has yielded several new breakthroughs in our understanding of feedback regulation and other critical control points within the PI3K-TSC-mTOR network, and these have been reported and discussed in 14 publications during this time. Of particular significance for this renewal were discoveries regarding the two functionally distinct mTOR complexes (mTORC1 and 2), which provided some of the first insights into the regulatory mechanisms controlling mTORC2 activity. Current Direction:
The aims of the original grant were geared toward understanding signaling mechanisms and their effects in cell and tumor models of the TSC disease. While our intense interest in TSC continues, in this renewal we will also expand on these findings to understand the role of this signaling network in human malignancies. Given the nearly universal corruption of the PI3K-TSC-mTOR network in glioblastoma, Aim 3 is dedicated to defining the mechanisms leading to its misregulation and their consequences in these aggressive tumors. In contrast to our detailed understanding of mTORC1, we know very little regarding the regulatory mechanisms and functions of mTORC2. Therefore, building on our recent discoveries with mTORC2 and the increasing evidence that it plays a key role in promoting tumorigenesis, the aims of this renewal are focused on the mechanisms of mTORC2 regulation in normal cells and misregulation in tumors.
The specific aims use a variety of cell and mouse tumor models, as well as clinical samples, and involve several key collaborators.
Specific Aims : 1) To determine the mechanisms and consequences of our recent surprising finding that the TSC tumor suppressors, while inhibiting mTORC1, activate mTORC2. 2) To determine the molecular mechanisms leading to mTORC2 activation downstream of receptor tyrosine kinases. 3) To determine the role of mTORC2 activation and downstream signaling in glioblastoma.
This project will provide a detailed molecular understanding of the signaling network involving the tuberous sclerosis complex (TSC) tumor suppressors and the mammalian target of rapamycin (mTOR). These studies are critical to our understanding and treatment of the TSC disease, which is a genetic tumor syndrome, and a wide variety of human diseases in which defects in the control of mTOR have been implicated, including sporadic cancers, type-2 diabetes, and autism. Under this proposal, a particular emphasis will be put on the role of this signaling network in the development, progression, and treatment of glioblastoma.
|Ilagan, Erika; Manning, Brendan D (2016) Emerging role of mTOR in the response to cancer therapeutics. Trends Cancer 2:241-251|
|Zhang, Yinan; Manning, Brendan D (2015) mTORC1 signaling activates NRF1 to increase cellular proteasome levels. Cell Cycle 14:2011-7|
|Menon, Suchithra; Dibble, Christian C; Talbott, George et al. (2014) Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell 156:771-85|
|Zhang, Yinan; Nicholatos, Justin; Dreier, John R et al. (2014) Coordinated regulation of protein synthesis and degradation by mTORC1. Nature 513:440-3|
|Byles, Vanessa; Covarrubias, Anthony J; Ben-Sahra, Issam et al. (2013) The TSC-mTOR pathway regulates macrophage polarization. Nat Commun 4:2834|
|Dibble, Christian C; Manning, Brendan D (2013) Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat Cell Biol 15:555-64|
|Ricoult, Stéphane J H; Manning, Brendan D (2013) The multifaceted role of mTORC1 in the control of lipid metabolism. EMBO Rep 14:242-51|
|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|
|Howell, Jessica J; Ricoult, Stéphane J H; Ben-Sahra, Issam et al. (2013) A growing role for mTOR in promoting anabolic metabolism. Biochem Soc Trans 41:906-12|
|Kelsey, Ilana; Manning, Brendan D (2013) mTORC1 status dictates tumor response to targeted therapeutics. Sci Signal 6:pe31|
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