Large-Scale Discovery of ERK2 Substrates Identifies ERK-Mediated Transcriptional Regulation by ETV3
The mitogen-activated protein kinase (MAPK) extracellular signal–regulated kinase 2 (ERK2) is ubiquitously expressed in mammalian tissues and is involved in a wide range of biological processes. Although MAPKs have been intensely studied, identification of their substrates remains challenging. We ha...
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| Format: | Article |
| Language: | en_US |
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American Association for the Advancement of Science (AAAS)
2014
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| Online Access: | http://hdl.handle.net/1721.1/88730 https://orcid.org/0000-0002-1545-1651 https://orcid.org/0000-0001-9249-8181 |
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| author | Carlson, Scott M. Chouinard, Candace R. Labadorf, Adam Lam, Carol J. Schmelzle, Katrin Fraenkel, Ernest White, Forest M. |
| author2 | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory |
| author_facet | Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Carlson, Scott M. Chouinard, Candace R. Labadorf, Adam Lam, Carol J. Schmelzle, Katrin Fraenkel, Ernest White, Forest M. |
| author_sort | Carlson, Scott M. |
| collection | MIT |
| description | The mitogen-activated protein kinase (MAPK) extracellular signal–regulated kinase 2 (ERK2) is ubiquitously expressed in mammalian tissues and is involved in a wide range of biological processes. Although MAPKs have been intensely studied, identification of their substrates remains challenging. We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5′-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. The 80 substrates are associated with diverse cellular processes, including regulation of transcription and translation, mRNA processing, and regulation of the activity of the Rho family guanosine triphosphatases. We found that one of the newly identified substrates, ETV3 (a member of the E twenty-six family of transcriptional regulators), was extensively phosphorylated on sites within canonical and noncanonical ERK motifs. Phosphorylation of ETV3 regulated transcription by preventing its binding to DNA at promoters for several thousand genes, including some involved in negative feedback regulation of itself and of upstream signals. |
| first_indexed | 2024-09-23T12:07:36Z |
| format | Article |
| id | mit-1721.1/88730 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T12:07:36Z |
| publishDate | 2014 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/887302022-10-01T08:20:36Z Large-Scale Discovery of ERK2 Substrates Identifies ERK-Mediated Transcriptional Regulation by ETV3 Carlson, Scott M. Chouinard, Candace R. Labadorf, Adam Lam, Carol J. Schmelzle, Katrin Fraenkel, Ernest White, Forest M. Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory Massachusetts Institute of Technology. Department of Biological Engineering Koch Institute for Integrative Cancer Research at MIT Carlson, Scott M. Chouinard, Candace R. Labadorf, Adam Lam, Carol J. Schmelzle, Katrin Fraenkel, Ernest White, Forest M. The mitogen-activated protein kinase (MAPK) extracellular signal–regulated kinase 2 (ERK2) is ubiquitously expressed in mammalian tissues and is involved in a wide range of biological processes. Although MAPKs have been intensely studied, identification of their substrates remains challenging. We have optimized a chemical genetic system using analog-sensitive ERK2, a form of ERK2 engineered to use an analog of adenosine 5′-triphosphate (ATP), to tag and isolate ERK2 substrates in vitro. This approach identified 80 proteins phosphorylated by ERK2, 13 of which are known ERK2 substrates. The 80 substrates are associated with diverse cellular processes, including regulation of transcription and translation, mRNA processing, and regulation of the activity of the Rho family guanosine triphosphatases. We found that one of the newly identified substrates, ETV3 (a member of the E twenty-six family of transcriptional regulators), was extensively phosphorylated on sites within canonical and noncanonical ERK motifs. Phosphorylation of ETV3 regulated transcription by preventing its binding to DNA at promoters for several thousand genes, including some involved in negative feedback regulation of itself and of upstream signals. Massachusetts Institute of Technology (Eugene Bell Career Development Chair) David H. Koch Institute for Integrative Cancer Research at MIT (Graduate Fellowship) Massachusetts Institute of Technology (Whitaker Health Science Fellowship) National Science Foundation (U.S.) (Graduate Research Fellowship) Pfizer Inc. National Institutes of Health (U.S.) (grant ES002109) National Institutes of Health (U.S.) (grant R01DK42816) National Institutes of Health (U.S.) (grant R01CA118705) National Institutes of Health (U.S.) (grant U54CA112967) 2014-08-15T17:38:17Z 2014-08-15T17:38:17Z 2011-10 Article http://purl.org/eprint/type/JournalArticle 1945-0877 1937-9145 http://hdl.handle.net/1721.1/88730 Carlson, S. M., C. R. Chouinard, A. Labadorf, C. J. Lam, K. Schmelzle, E. Fraenkel, and F. M. White. “Large-Scale Discovery of ERK2 Substrates Identifies ERK-Mediated Transcriptional Regulation by ETV3.” Science Signaling 4, no. 196 (October 25, 2011): rs11–rs11. https://orcid.org/0000-0002-1545-1651 https://orcid.org/0000-0001-9249-8181 en_US http://dx.doi.org/10.1126/scisignal.2002010 Science Signaling Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | Carlson, Scott M. Chouinard, Candace R. Labadorf, Adam Lam, Carol J. Schmelzle, Katrin Fraenkel, Ernest White, Forest M. Large-Scale Discovery of ERK2 Substrates Identifies ERK-Mediated Transcriptional Regulation by ETV3 |
| title | Large-Scale Discovery of ERK2 Substrates Identifies ERK-Mediated Transcriptional Regulation by ETV3 |
| title_full | Large-Scale Discovery of ERK2 Substrates Identifies ERK-Mediated Transcriptional Regulation by ETV3 |
| title_fullStr | Large-Scale Discovery of ERK2 Substrates Identifies ERK-Mediated Transcriptional Regulation by ETV3 |
| title_full_unstemmed | Large-Scale Discovery of ERK2 Substrates Identifies ERK-Mediated Transcriptional Regulation by ETV3 |
| title_short | Large-Scale Discovery of ERK2 Substrates Identifies ERK-Mediated Transcriptional Regulation by ETV3 |
| title_sort | large scale discovery of erk2 substrates identifies erk mediated transcriptional regulation by etv3 |
| url | http://hdl.handle.net/1721.1/88730 https://orcid.org/0000-0002-1545-1651 https://orcid.org/0000-0001-9249-8181 |
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