A Tumor Suppressor Complex with GAP Activity for the Rag GTPases That Signal Amino Acid Sufficiency to mTORC1
available in PMC 2013 July 31.
| Main Authors: | , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
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American Association for the Advancement of Science
2014
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| Online Access: | http://hdl.handle.net/1721.1/85839 https://orcid.org/0000-0002-7043-5013 https://orcid.org/0000-0001-9388-1633 https://orcid.org/0000-0002-1446-7256 |
| _version_ | 1826198628750852096 |
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| author | Bar-Peled, Liron Chantranupong, Lynne Cherniack, Andrew D. Chen, Walter W. Ottina, Kathleen Grabiner, Brian C. Spear, Eric D. Carter, Scott L. Meyerson, Matthew L. Sabatini, David M. |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Bar-Peled, Liron Chantranupong, Lynne Cherniack, Andrew D. Chen, Walter W. Ottina, Kathleen Grabiner, Brian C. Spear, Eric D. Carter, Scott L. Meyerson, Matthew L. Sabatini, David M. |
| author_sort | Bar-Peled, Liron |
| collection | MIT |
| description | available in PMC 2013 July 31. |
| first_indexed | 2024-09-23T11:07:45Z |
| format | Article |
| id | mit-1721.1/85839 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:07:45Z |
| publishDate | 2014 |
| publisher | American Association for the Advancement of Science |
| record_format | dspace |
| spelling | mit-1721.1/858392022-09-27T17:18:33Z A Tumor Suppressor Complex with GAP Activity for the Rag GTPases That Signal Amino Acid Sufficiency to mTORC1 Bar-Peled, Liron Chantranupong, Lynne Cherniack, Andrew D. Chen, Walter W. Ottina, Kathleen Grabiner, Brian C. Spear, Eric D. Carter, Scott L. Meyerson, Matthew L. Sabatini, David M. Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Koch Institute for Integrative Cancer Research at MIT Bar-Peled, Liron Chantranupong, Lynne Chen, Walter W. Ottina, Kathleen Grabiner, Brian C. Sabatini, David M. available in PMC 2013 July 31. The mTOR complex 1 (mTORC1) pathway promotes cell growth in response to many cues, including amino acids, which act through the Rag guanosine triphosphatases (GTPases) to promote mTORC1 translocation to the lysosomal surface, its site of activation. Although progress has been made in identifying positive regulators of the Rags, it is unknown if negative factors also exist. Here, we identify GATOR as a complex that interacts with the Rags and is composed of two subcomplexes we call GATOR1 and -2. Inhibition of GATOR1 subunits (DEPDC5, Nprl2, and Nprl3) makes mTORC1 signaling resistant to amino acid deprivation. In contrast, inhibition of GATOR2 subunits (Mios, WDR24, WDR59, Seh1L, and Sec13) suppresses mTORC1 signaling, and epistasis analysis shows that GATOR2 negatively regulates DEPDC5. GATOR1 has GTPase-activating protein (GAP) activity for RagA and RagB, and its components are mutated in human cancer. In cancer cells with inactivating mutations in GATOR1, mTORC1 is hyperactive and insensitive to amino acid starvation, and such cells are hypersensitive to rapamycin, an mTORC1 inhibitor. Thus, we identify a key negative regulator of the Rag GTPases and reveal that, like other mTORC1 regulators, Rag function can be deregulated in cancer. National Institutes of Health (U.S.) (NIH CA103866) National Institutes of Health (U.S.) (NIH AI47389) United States. Dept. of Defense (W81XWH-07-0448) National Cancer Institute (U.S.) (NIH U24CA143867) David H. Koch Institute for Integrative Cancer Research at MIT (David H. Koch Graduate Fellowship Fund) National Science Foundation (U.S.) (Graduate Research Fellowship Program) Harvard University--MIT Division of Health Sciences and Technology (IDEA Program) American Cancer Society Howard Hughes Medical Institute (Investigator) 2014-03-20T13:45:13Z 2014-03-20T13:45:13Z 2013-05 2012-10 Article http://purl.org/eprint/type/JournalArticle 0036-8075 1095-9203 http://hdl.handle.net/1721.1/85839 Bar-Peled, L., L. Chantranupong, A. D. Cherniack, W. W. Chen, K. A. Ottina, B. C. Grabiner, E. D. Spear, S. L. Carter, M. Meyerson, and D. M. Sabatini. “A Tumor Suppressor Complex with GAP Activity for the Rag GTPases That Signal Amino Acid Sufficiency to mTORC1.” Science 340, no. 6136 (May 30, 2013): 1100-1106. https://orcid.org/0000-0002-7043-5013 https://orcid.org/0000-0001-9388-1633 https://orcid.org/0000-0002-1446-7256 en_US http://dx.doi.org/10.1126/science.1232044 Science Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Association for the Advancement of Science PMC |
| spellingShingle | Bar-Peled, Liron Chantranupong, Lynne Cherniack, Andrew D. Chen, Walter W. Ottina, Kathleen Grabiner, Brian C. Spear, Eric D. Carter, Scott L. Meyerson, Matthew L. Sabatini, David M. A Tumor Suppressor Complex with GAP Activity for the Rag GTPases That Signal Amino Acid Sufficiency to mTORC1 |
| title | A Tumor Suppressor Complex with GAP Activity for the Rag GTPases That Signal Amino Acid Sufficiency to mTORC1 |
| title_full | A Tumor Suppressor Complex with GAP Activity for the Rag GTPases That Signal Amino Acid Sufficiency to mTORC1 |
| title_fullStr | A Tumor Suppressor Complex with GAP Activity for the Rag GTPases That Signal Amino Acid Sufficiency to mTORC1 |
| title_full_unstemmed | A Tumor Suppressor Complex with GAP Activity for the Rag GTPases That Signal Amino Acid Sufficiency to mTORC1 |
| title_short | A Tumor Suppressor Complex with GAP Activity for the Rag GTPases That Signal Amino Acid Sufficiency to mTORC1 |
| title_sort | tumor suppressor complex with gap activity for the rag gtpases that signal amino acid sufficiency to mtorc1 |
| url | http://hdl.handle.net/1721.1/85839 https://orcid.org/0000-0002-7043-5013 https://orcid.org/0000-0001-9388-1633 https://orcid.org/0000-0002-1446-7256 |
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