The Sestrins Interact with GATOR2 to Negatively Regulate the Amino-Acid-Sensing Pathway Upstream of mTORC1
The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a major regulator of cell growth that responds to numerous environmental cues. A key input is amino acids, which act through the heterodimeric Rag GTPases (RagA or RagB bound to RagC or RagD) in order to promote the translocation of mT...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Elsevier
2015
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| Online Access: | http://hdl.handle.net/1721.1/96749 https://orcid.org/0000-0002-9535-7664 https://orcid.org/0000-0002-9376-3984 https://orcid.org/0000-0002-1446-7256 https://orcid.org/0000-0001-9388-1633 |
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| author | Chantranupong, Lynne Orozco, Jose M. Scaria, Sonia M. Bar-Peled, Liron Spooner, Eric Isasa, Marta Gygi, Steven P. Sabatini, David M. Wolfson, Rachel Laura Saxton, Robert Andrew Scaria, Sonia M. Sabatini, David |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Chantranupong, Lynne Orozco, Jose M. Scaria, Sonia M. Bar-Peled, Liron Spooner, Eric Isasa, Marta Gygi, Steven P. Sabatini, David M. Wolfson, Rachel Laura Saxton, Robert Andrew Scaria, Sonia M. Sabatini, David |
| author_sort | Chantranupong, Lynne |
| collection | MIT |
| description | The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a major regulator of cell growth that responds to numerous environmental cues. A key input is amino acids, which act through the heterodimeric Rag GTPases (RagA or RagB bound to RagC or RagD) in order to promote the translocation of mTORC1 to the lysosomal surface, its site of activation. GATOR2 is a complex of unknown function that positively regulates mTORC1 signaling by acting upstream of or in parallel to GATOR1, which is a GTPase-activating protein (GAP) for RagA or RagB and an inhibitor of the amino-acid-sensing pathway. Here, we find that the Sestrins, a family of poorly understood growth regulators (Sestrin1–Sestrin3), interact with GATOR2 in an amino-acid-sensitive fashion. Sestrin2-mediated inhibition of mTORC1 signaling requires GATOR1 and the Rag GTPases, and the Sestrins regulate the localization of mTORC1 in response to amino acids. Thus, we identify the Sestrins as GATOR2-interacting proteins that regulate the amino-acid-sensing branch of the mTORC1 pathway. |
| first_indexed | 2024-09-23T14:54:17Z |
| format | Article |
| id | mit-1721.1/96749 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T14:54:17Z |
| publishDate | 2015 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/967492022-09-29T11:20:41Z The Sestrins Interact with GATOR2 to Negatively Regulate the Amino-Acid-Sensing Pathway Upstream of mTORC1 Chantranupong, Lynne Orozco, Jose M. Scaria, Sonia M. Bar-Peled, Liron Spooner, Eric Isasa, Marta Gygi, Steven P. Sabatini, David M. Wolfson, Rachel Laura Saxton, Robert Andrew Scaria, Sonia M. Sabatini, David Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Koch Institute for Integrative Cancer Research at MIT Chantranupong, Lynne Wolfson, Rachel Laura Saxton, Robert Andrew Scaria, Sonia M. Sabatini, David M. The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a major regulator of cell growth that responds to numerous environmental cues. A key input is amino acids, which act through the heterodimeric Rag GTPases (RagA or RagB bound to RagC or RagD) in order to promote the translocation of mTORC1 to the lysosomal surface, its site of activation. GATOR2 is a complex of unknown function that positively regulates mTORC1 signaling by acting upstream of or in parallel to GATOR1, which is a GTPase-activating protein (GAP) for RagA or RagB and an inhibitor of the amino-acid-sensing pathway. Here, we find that the Sestrins, a family of poorly understood growth regulators (Sestrin1–Sestrin3), interact with GATOR2 in an amino-acid-sensitive fashion. Sestrin2-mediated inhibition of mTORC1 signaling requires GATOR1 and the Rag GTPases, and the Sestrins regulate the localization of mTORC1 in response to amino acids. Thus, we identify the Sestrins as GATOR2-interacting proteins that regulate the amino-acid-sensing branch of the mTORC1 pathway. National Institutes of Health (U.S.) (Grant R01 CA103866) National Institutes of Health (U.S.) (Grant AI47389) United States. Dept. of Defense (Grant W81XWH-07-0448) National Institutes of Health (U.S.) (Fellowship F31 CA180271) National Institutes of Health (U.S.) (Fellowship T32 GM007753) National Institutes of Health (U.S.) (Paul Gray UROP Fund 3143900) 2015-04-23T18:00:27Z 2015-04-23T18:00:27Z 2014-09 2014-09 Article http://purl.org/eprint/type/JournalArticle 22111247 http://hdl.handle.net/1721.1/96749 Chantranupong, Lynne, Rachel L. Wolfson, Jose M. Orozco, Robert A. Saxton, Sonia M. Scaria, Liron Bar-Peled, Eric Spooner, Marta Isasa, Steven P. Gygi, and David M. Sabatini. “The Sestrins Interact with GATOR2 to Negatively Regulate the Amino-Acid-Sensing Pathway Upstream of mTORC1.” Cell Reports 9, no. 1 (October 2014): 1–8. https://orcid.org/0000-0002-9535-7664 https://orcid.org/0000-0002-9376-3984 https://orcid.org/0000-0002-1446-7256 https://orcid.org/0000-0001-9388-1633 en_US http://dx.doi.org/10.1016/j.celrep.2014.09.014 Cell Reports Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License http://creativecommons.org/licenses/by-nc-nd/3.0/ application/pdf Elsevier Elsevier Open Access |
| spellingShingle | Chantranupong, Lynne Orozco, Jose M. Scaria, Sonia M. Bar-Peled, Liron Spooner, Eric Isasa, Marta Gygi, Steven P. Sabatini, David M. Wolfson, Rachel Laura Saxton, Robert Andrew Scaria, Sonia M. Sabatini, David The Sestrins Interact with GATOR2 to Negatively Regulate the Amino-Acid-Sensing Pathway Upstream of mTORC1 |
| title | The Sestrins Interact with GATOR2 to Negatively Regulate the Amino-Acid-Sensing Pathway Upstream of mTORC1 |
| title_full | The Sestrins Interact with GATOR2 to Negatively Regulate the Amino-Acid-Sensing Pathway Upstream of mTORC1 |
| title_fullStr | The Sestrins Interact with GATOR2 to Negatively Regulate the Amino-Acid-Sensing Pathway Upstream of mTORC1 |
| title_full_unstemmed | The Sestrins Interact with GATOR2 to Negatively Regulate the Amino-Acid-Sensing Pathway Upstream of mTORC1 |
| title_short | The Sestrins Interact with GATOR2 to Negatively Regulate the Amino-Acid-Sensing Pathway Upstream of mTORC1 |
| title_sort | sestrins interact with gator2 to negatively regulate the amino acid sensing pathway upstream of mtorc1 |
| url | http://hdl.handle.net/1721.1/96749 https://orcid.org/0000-0002-9535-7664 https://orcid.org/0000-0002-9376-3984 https://orcid.org/0000-0002-1446-7256 https://orcid.org/0000-0001-9388-1633 |
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