A genome-wide siRNA screen identifies a novel, 7 transmembrane protein that mediates amino acid signaling to mTORC1
Abstract/Contents
- Abstract
- Cells have an evolutionarily conserved mechanism to sense and integrate nutrient information for optimal growth and survival. The signaling network that is central to receiving nutritional inputs and translating them to effects on anabolic and catabolic activities of the cell consists of a large serine/threonine kinase known as mTOR. mTOR signaling is crucial for many important cellular processes such metabolism, growth, proliferation and differentiation. It is able to integrate diverse inputs including growth factors, cytokines, energy, oxygen and stress in addition to nutrients and regulate diverse outputs including translation, ribosome biogenesis, lipid biogenesis and autophagy. It is also an important therapeutic target and its inhibitor Rapamycin is currently being used or tested for a wide range of diseases including cancers and neurodegenerative diseases. Amino acids are arguably the most important regulators of mTOR and a long standing mystery in the field is the identity of the amino acid sensor and the mechanism of sensing. Using RNAi, we systematically screened through the human genome for candidate genes regulating amino acid signaling. We confirm that the mitochondria and the lysosomes are the two key sensing organelles, with amino acid metabolism and the RagGTPases being important for signal transduction. We identify a novel lysosomal 7 transmembrane protein that mediates signals upstream the RagGTPases and binds mTORC1-RagA in an amino-acid dependent manner. We also demonstrate that increasing levels of this protein enables cells to recruit mTOR to lysosomes and activate its kinase activity in the absence of amino acids. We show that GPR137B, mTORC1 and RagA form an amino acid sensitive, high-affinity binding complex at the lysosome. We propose a model of sensing where the 7-transmembrane protein, which we renamed to MORTOR, forms a tight complex with mTORC1-RagA in the presence of amino acids, resulting in the persistent lysosomal recruitment and activation of mTORC1. In addition to identifying novel regulators, this systematic study has also generated testable hypotheses about systems level properties of mTORC1 signaling, thus providing the foundation to understand mTOR signaling as a network. The discovery of the novel 7 transmembrane protein and its GPCR-like characteristics also has the potential to lead to new classes of therapeutics and targets for this important pathway.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2013 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Gan, Lin |
|---|---|
| Associated with | Stanford University, Department of Chemical and Systems Biology. |
| Primary advisor | Meyer, Tobias |
| Thesis advisor | Meyer, Tobias |
| Thesis advisor | Brunet, Anne, 1972- |
| Thesis advisor | Ferrell, James Ellsworth |
| Advisor | Brunet, Anne, 1972- |
| Advisor | Ferrell, James Ellsworth |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Lin Gan. |
|---|---|
| Note | Submitted to the Department of Chemical and Systems Biology. |
| Thesis | Ph.D. Stanford University 2013 |
| Location | electronic resource |
Access conditions
- Copyright
- © 2013 by Lin Gan
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