|
|
|
|
| LEADER |
03368 am a22004813u 4500 |
| 001 |
85839 |
| 042 |
|
|
|a dc
|
| 100 |
1 |
0 |
|a Bar-Peled, Liron
|e author
|
| 100 |
1 |
0 |
|a Massachusetts Institute of Technology. Department of Biology
|e contributor
|
| 100 |
1 |
0 |
|a Whitehead Institute for Biomedical Research
|e contributor
|
| 100 |
1 |
0 |
|a Koch Institute for Integrative Cancer Research at MIT
|e contributor
|
| 100 |
1 |
0 |
|a Bar-Peled, Liron
|e contributor
|
| 100 |
1 |
0 |
|a Chantranupong, Lynne
|e contributor
|
| 100 |
1 |
0 |
|a Chen, Walter W.
|e contributor
|
| 100 |
1 |
0 |
|a Ottina, Kathleen
|e contributor
|
| 100 |
1 |
0 |
|a Grabiner, Brian C.
|e contributor
|
| 100 |
1 |
0 |
|a Sabatini, David M.
|e contributor
|
| 700 |
1 |
0 |
|a Chantranupong, Lynne
|e author
|
| 700 |
1 |
0 |
|a Cherniack, Andrew D.
|e author
|
| 700 |
1 |
0 |
|a Chen, Walter W.
|e author
|
| 700 |
1 |
0 |
|a Ottina, Kathleen
|e author
|
| 700 |
1 |
0 |
|a Grabiner, Brian C.
|e author
|
| 700 |
1 |
0 |
|a Spear, Eric D.
|e author
|
| 700 |
1 |
0 |
|a Carter, Scott L.
|e author
|
| 700 |
1 |
0 |
|a Meyerson, Matthew L.
|e author
|
| 700 |
1 |
0 |
|a Sabatini, David M.
|e author
|
| 245 |
0 |
0 |
|a A Tumor Suppressor Complex with GAP Activity for the Rag GTPases That Signal Amino Acid Sufficiency to mTORC1
|
| 260 |
|
|
|b American Association for the Advancement of Science,
|c 2014-03-20T13:45:13Z.
|
| 856 |
|
|
|z Get fulltext
|u http://hdl.handle.net/1721.1/85839
|
| 520 |
|
|
|a available in PMC 2013 July 31.
|
| 520 |
|
|
|a 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.
|
| 520 |
|
|
|a National Institutes of Health (U.S.) (NIH CA103866)
|
| 520 |
|
|
|a National Institutes of Health (U.S.) (NIH AI47389)
|
| 520 |
|
|
|a United States. Dept. of Defense (W81XWH-07-0448)
|
| 520 |
|
|
|a National Cancer Institute (U.S.) (NIH U24CA143867)
|
| 520 |
|
|
|a David H. Koch Institute for Integrative Cancer Research at MIT (David H. Koch Graduate Fellowship Fund)
|
| 520 |
|
|
|a National Science Foundation (U.S.) (Graduate Research Fellowship Program)
|
| 520 |
|
|
|a Harvard University--MIT Division of Health Sciences and Technology (IDEA Program)
|
| 520 |
|
|
|a American Cancer Society
|
| 520 |
|
|
|a Howard Hughes Medical Institute (Investigator)
|
| 546 |
|
|
|a en_US
|
| 655 |
7 |
|
|a Article
|
| 773 |
|
|
|t Science
|
