The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master regulator of growth. It integrates a diverse set of signals, including nutrient availability, energy levels, growth factors, and cellular stresses, to regulate ey homeostatic processes such as ribosome biogenesis, protein translation, and autophagy. Not surprisingly, this pathway is deregulated in common human diseases such as cancer, diabetes, and neurodegeneration. While the mechanisms governing the sensing of growth factors, energy levels, and cellular stresses are well characterized, nutrient sensing remains relatively poorly understood. Nutrients are absolutely required for kinase activity and utilize an independent mechanism from other inputs to regulate the mTORC1 pathway. Elucidation of the molecular mechanisms that control nutrient sensing is fundamental for the development of therapies that target the mTORC1 pathway with more efficacy, while minimizing side effects. We have used a proteomic approach to identify a new link between folliculin (FLCN), the tumor suppressor mutated in the familial cancer syndrome Birt-Hogg-Dube (BHD), and the nutrient sensing axis of the mTORC1 pathway. Despite its causative link to a human disease, the function of FLCN remains unclear. Preliminary evidence suggests that FLCN translocates to the lysosome in response to amino acid starvation to interact with the Rag GTPases and the Ragulator complex, key regulators of the mTORC1 nutrient response. The goal of this project is to characterize the functions of FLCN and FLCN interacting protein 1 and 2 (FNIPs) in the nutrient sensing mTORC1 pathway. We propose the following aims: 1) Characterize the FLCN interaction and localization with the Rags and Ragulator complex under different nutrient conditions. 2) Determine the effects of FLCN/FNIPs knockdown and overexpression on mTORC1 activity and localization under different nutrient conditions. 3) Investigate the mechanism through which FLCN/FNIPs modulate the activity of the Rag GTPases and the Ragulator complex. Through hypothesis driven and unbiased approaches, our proposed work will clarify how the tumor suppressor FLCN functions in the mTORC1 pathway commonly deregulated in human cancers. These insights will shed light on the pathogenesis of BHD and may lead to the rational development of novel therapies for cancer.

Public Health Relevance

The proposed work will provide insights into the mTORC1 pathway, an important signaling pathway for growth that malfunctions in common diseases such as cancer, diabetes, and neurodegeneration. The proposal examines the role of a gene whose mutation causes a tumor prone syndrome called Birt-Hogg-Dube in the mTORC1 pathway. The overarching goal for our research is to reveal the molecular mechanisms that control the mTORC1 pathway, which may enable the development of rationally targeted therapies for cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Damico, Mark W
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Harvard Medical School
Schools of Medicine
United States
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Wang, Shuyu; Tsun, Zhi-Yang; Wolfson, Rachel L et al. (2015) Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 347:188-94
Tsun, Zhi-Yang; Bar-Peled, Liron; Chantranupong, Lynne et al. (2013) The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol Cell 52:495-505