mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin
The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) protein kinase promotes growth and is the target of rapamycin, a clinically useful drug that also prolongs life span in model organisms. A persistent mystery is why the phosphorylation of many bona fide mTORC1 substrates is resistant to r...
| Main Authors: | , , , , , , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
American Association for the Advancement of Science (AAAS)
2014
|
| Online Access: | http://hdl.handle.net/1721.1/85630 https://orcid.org/0000-0002-9547-3251 https://orcid.org/0000-0002-1446-7256 |
| _version_ | 1826194164635664384 |
|---|---|
| author | Cervantes, Christopher L. Lim, Daniel Cham-Chin Kang, Seong A. Pacold, Michael E. Lou, Hua Jane Ottina, Kathleen Gray, Nathanael S. Turk, Benjamin E. Yaffe, Michael B Sabatini, David |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Cervantes, Christopher L. Lim, Daniel Cham-Chin Kang, Seong A. Pacold, Michael E. Lou, Hua Jane Ottina, Kathleen Gray, Nathanael S. Turk, Benjamin E. Yaffe, Michael B Sabatini, David |
| author_sort | Cervantes, Christopher L. |
| collection | MIT |
| description | The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) protein kinase promotes growth and is the target of rapamycin, a clinically useful drug that also prolongs life span in model organisms. A persistent mystery is why the phosphorylation of many bona fide mTORC1 substrates is resistant to rapamycin. We find that the in vitro kinase activity of mTORC1 toward peptides encompassing established phosphorylation sites varies widely and correlates strongly with the resistance of the sites to rapamycin, as well as to nutrient and growth factor starvation within cells. Slight modifications of the sites were sufficient to alter mTORC1 activity toward them in vitro and to cause concomitant changes within cells in their sensitivity to rapamycin and starvation. Thus, the intrinsic capacity of a phosphorylation site to serve as an mTORC1 substrate, a property we call substrate quality, is a major determinant of its sensitivity to modulators of the pathway. Our results reveal a mechanism through which mTORC1 effectors can respond differentially to the same signals. |
| first_indexed | 2024-09-23T09:51:55Z |
| format | Article |
| id | mit-1721.1/85630 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:51:55Z |
| publishDate | 2014 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/856302022-09-26T14:09:05Z mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin Cervantes, Christopher L. Lim, Daniel Cham-Chin Kang, Seong A. Pacold, Michael E. Lou, Hua Jane Ottina, Kathleen Gray, Nathanael S. Turk, Benjamin E. Yaffe, Michael B Sabatini, David Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Koch Institute for Integrative Cancer Research at MIT Cervantes, Christopher L. Lim, Daniel Cham-Chin Yaffe, Michael B. Sabatini, David M. The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) protein kinase promotes growth and is the target of rapamycin, a clinically useful drug that also prolongs life span in model organisms. A persistent mystery is why the phosphorylation of many bona fide mTORC1 substrates is resistant to rapamycin. We find that the in vitro kinase activity of mTORC1 toward peptides encompassing established phosphorylation sites varies widely and correlates strongly with the resistance of the sites to rapamycin, as well as to nutrient and growth factor starvation within cells. Slight modifications of the sites were sufficient to alter mTORC1 activity toward them in vitro and to cause concomitant changes within cells in their sensitivity to rapamycin and starvation. Thus, the intrinsic capacity of a phosphorylation site to serve as an mTORC1 substrate, a property we call substrate quality, is a major determinant of its sensitivity to modulators of the pathway. Our results reveal a mechanism through which mTORC1 effectors can respond differentially to the same signals. National Institutes of Health (U.S.) (Grant CA103866) National Institutes of Health (U.S.) (Grant AI047389) National Institutes of Health (U.S.) (Grant ES015339) National Institutes of Health (U.S.) (Grant GM59281) National Institutes of Health (U.S.) (Grant CA112967) United States. Dept. of Defense (Grant W81XWH-07-0448) W. M. Keck Foundation LAM Foundation 2014-03-14T16:47:11Z 2014-03-14T16:47:11Z 2013-07 2013-02 Article http://purl.org/eprint/type/JournalArticle 0036-8075 1095-9203 http://hdl.handle.net/1721.1/85630 Kang, S. A., M. E. Pacold, C. L. Cervantes, D. Lim, H. J. Lou, K. Ottina, N. S. Gray, B. E. Turk, M. B. Yaffe, and D. M. Sabatini. “mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin.” Science 341, no. 6144 (July 25, 2013): 1236566-1236566. https://orcid.org/0000-0002-9547-3251 https://orcid.org/0000-0002-1446-7256 en_US http://dx.doi.org/10.1126/science.1236566 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 (AAAS) PMC |
| spellingShingle | Cervantes, Christopher L. Lim, Daniel Cham-Chin Kang, Seong A. Pacold, Michael E. Lou, Hua Jane Ottina, Kathleen Gray, Nathanael S. Turk, Benjamin E. Yaffe, Michael B Sabatini, David mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin |
| title | mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin |
| title_full | mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin |
| title_fullStr | mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin |
| title_full_unstemmed | mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin |
| title_short | mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin |
| title_sort | mtorc1 phosphorylation sites encode their sensitivity to starvation and rapamycin |
| url | http://hdl.handle.net/1721.1/85630 https://orcid.org/0000-0002-9547-3251 https://orcid.org/0000-0002-1446-7256 |
| work_keys_str_mv | AT cervanteschristopherl mtorc1phosphorylationsitesencodetheirsensitivitytostarvationandrapamycin AT limdanielchamchin mtorc1phosphorylationsitesencodetheirsensitivitytostarvationandrapamycin AT kangseonga mtorc1phosphorylationsitesencodetheirsensitivitytostarvationandrapamycin AT pacoldmichaele mtorc1phosphorylationsitesencodetheirsensitivitytostarvationandrapamycin AT louhuajane mtorc1phosphorylationsitesencodetheirsensitivitytostarvationandrapamycin AT ottinakathleen mtorc1phosphorylationsitesencodetheirsensitivitytostarvationandrapamycin AT graynathanaels mtorc1phosphorylationsitesencodetheirsensitivitytostarvationandrapamycin AT turkbenjamine mtorc1phosphorylationsitesencodetheirsensitivitytostarvationandrapamycin AT yaffemichaelb mtorc1phosphorylationsitesencodetheirsensitivitytostarvationandrapamycin AT sabatinidavid mtorc1phosphorylationsitesencodetheirsensitivitytostarvationandrapamycin |