Comprehensive substrate specificity profiling of the human Nek kinome reveals unexpected signaling outputs
© van de Kooij et al. Human NimA-related kinases (Neks) have multiple mitotic and non-mitotic functions, but few substrates are known. We systematically determined the phosphorylation-site motifs for the entire Nek kinase family, except for Nek11. While all Nek kinases strongly select for hydrophobi...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications, Ltd
2020
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| Online Access: | https://hdl.handle.net/1721.1/125507 |
| _version_ | 1826202413663518720 |
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| author | Van de Kooij, Bert Creixell Morera, Pau Van Vlimmeren, Anne Elise Joughin, Brian Alan Yaffe, Michael B |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Van de Kooij, Bert Creixell Morera, Pau Van Vlimmeren, Anne Elise Joughin, Brian Alan Yaffe, Michael B |
| author_sort | Van de Kooij, Bert |
| collection | MIT |
| description | © van de Kooij et al. Human NimA-related kinases (Neks) have multiple mitotic and non-mitotic functions, but few substrates are known. We systematically determined the phosphorylation-site motifs for the entire Nek kinase family, except for Nek11. While all Nek kinases strongly select for hydrophobic residues in the -3 position, the family separates into four distinct groups based on specificity for a serine versus threonine phospho-acceptor, and preference for basic or acidic residues in other positions. Unlike Nek1-Nek9, Nek10 is a dual-specificity kinase that efficiently phosphorylates itself and peptide substrates on serine and tyrosine, and its activity is enhanced by tyrosine auto-phosphorylation. Nek10 dual-specificity depends on residues in the HRD+2 and APE- 4 positions that are uncommon in either serine/threonine or tyrosine kinases. Finally, we show that the phosphorylation-site motifs for the mitotic kinases Nek6, Nek7 and Nek9 are essentially identical to that of their upstream activator Plk1, suggesting that Nek6/7/9 function as phosphomotif amplifiers of Plk1 signaling. |
| first_indexed | 2024-09-23T12:07:04Z |
| format | Article |
| id | mit-1721.1/125507 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T12:07:04Z |
| publishDate | 2020 |
| publisher | eLife Sciences Publications, Ltd |
| record_format | dspace |
| spelling | mit-1721.1/1255072022-10-01T08:18:54Z Comprehensive substrate specificity profiling of the human Nek kinome reveals unexpected signaling outputs Van de Kooij, Bert Creixell Morera, Pau Van Vlimmeren, Anne Elise Joughin, Brian Alan Yaffe, Michael B Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Biological Engineering Koch Institute for Integrative Cancer Research at MIT © van de Kooij et al. Human NimA-related kinases (Neks) have multiple mitotic and non-mitotic functions, but few substrates are known. We systematically determined the phosphorylation-site motifs for the entire Nek kinase family, except for Nek11. While all Nek kinases strongly select for hydrophobic residues in the -3 position, the family separates into four distinct groups based on specificity for a serine versus threonine phospho-acceptor, and preference for basic or acidic residues in other positions. Unlike Nek1-Nek9, Nek10 is a dual-specificity kinase that efficiently phosphorylates itself and peptide substrates on serine and tyrosine, and its activity is enhanced by tyrosine auto-phosphorylation. Nek10 dual-specificity depends on residues in the HRD+2 and APE- 4 positions that are uncommon in either serine/threonine or tyrosine kinases. Finally, we show that the phosphorylation-site motifs for the mitotic kinases Nek6, Nek7 and Nek9 are essentially identical to that of their upstream activator Plk1, suggesting that Nek6/7/9 function as phosphomotif amplifiers of Plk1 signaling. Dutch Cancer Society (Grant BUIT 2015-7546) National Cancer Institute (U.S.) (Grant K99CA226396) National Institutes of Health (U.S.) (Grant 01-GM104047) National Institutes of Health (U.S.) (Grant 01-ES015339) National Institutes of Health (U.S.) (Grant R35-ES028374) National Cancer Institute (U.S.) (Grant P30-CA14051) National Institute of Environmental Health Sciences (Grant P30-ES002109) 2020-05-27T17:03:25Z 2020-05-27T17:03:25Z 2019-05 2020-01-15T15:55:01Z Article http://purl.org/eprint/type/JournalArticle 1534-4983 https://hdl.handle.net/1721.1/125507 Van de Kooij, Bert et al. “Comprehensive substrate specificity profiling of the human Nek kinome reveals unexpected signaling outputs.” eLife 8 (2019): e44635 © 2019 The Author(s) en https://dx.doi.org/10.7554/ELIFE.44635 eLife Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf eLife Sciences Publications, Ltd eLife |
| spellingShingle | Van de Kooij, Bert Creixell Morera, Pau Van Vlimmeren, Anne Elise Joughin, Brian Alan Yaffe, Michael B Comprehensive substrate specificity profiling of the human Nek kinome reveals unexpected signaling outputs |
| title | Comprehensive substrate specificity profiling of the human Nek kinome reveals unexpected signaling outputs |
| title_full | Comprehensive substrate specificity profiling of the human Nek kinome reveals unexpected signaling outputs |
| title_fullStr | Comprehensive substrate specificity profiling of the human Nek kinome reveals unexpected signaling outputs |
| title_full_unstemmed | Comprehensive substrate specificity profiling of the human Nek kinome reveals unexpected signaling outputs |
| title_short | Comprehensive substrate specificity profiling of the human Nek kinome reveals unexpected signaling outputs |
| title_sort | comprehensive substrate specificity profiling of the human nek kinome reveals unexpected signaling outputs |
| url | https://hdl.handle.net/1721.1/125507 |
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