Paradoxical activation of the protein kinase-transcription factor ERK5 by ERK5 kinase inhibitors
| Autor: | Natalie J. Tatum, Megan A Cassidy, Pamela A. Lochhead, David Oxley, Julie A. Tucker, Victoria P Johnson, Andrew M. Kidger, Simon J. Cook, Martin E.M. Noble, Nathanael S. Gray, Jinhua Wang |
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| Přispěvatelé: | Lochhead, Pamela A [0000-0001-7498-0177], Tucker, Julie A [0000-0002-6119-676X], Tatum, Natalie J [0000-0003-3878-9265], Wang, Jinhua [0000-0002-1214-4103], Kidger, Andrew M [0000-0002-3808-0582], Johnson, Victoria P [0000-0002-1530-2322], Noble, Martin EM [0000-0002-3595-9807], Cook, Simon J [0000-0001-9087-1616], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Models Molecular Transcription Genetic Protein Conformation Science Protein domain General Physics and Astronomy Cellular imaging Biochemistry General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences 0302 clinical medicine Protein Domains Transcription (biology) Humans Protein kinase A lcsh:Science Transcription factor Protein Kinase Inhibitors Mitogen-Activated Protein Kinase 7 Cancer Regulation of gene expression Inflammation Multidisciplinary Kinase Chemistry HEK 293 cells General Chemistry 3. Good health Cell biology 030104 developmental biology HEK293 Cells Protein kinase domain Gene Expression Regulation 030220 oncology & carcinogenesis Enzyme mechanisms Mutation lcsh:Q Cell signalling HeLa Cells Transcription Factors |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-16 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | The dual protein kinase-transcription factor, ERK5, is an emerging drug target in cancer and inflammation, and small-molecule ERK5 kinase inhibitors have been developed. However, selective ERK5 kinase inhibitors fail to recapitulate ERK5 genetic ablation phenotypes, suggesting kinase-independent functions for ERK5. Here we show that ERK5 kinase inhibitors cause paradoxical activation of ERK5 transcriptional activity mediated through its unique C-terminal transcriptional activation domain (TAD). Using the ERK5 kinase inhibitor, Compound 26 (ERK5-IN-1), as a paradigm, we have developed kinase-active, drug-resistant mutants of ERK5. With these mutants, we show that induction of ERK5 transcriptional activity requires direct binding of the inhibitor to the kinase domain. This in turn promotes conformational changes in the kinase domain that result in nuclear translocation of ERK5 and stimulation of gene transcription. This shows that both the ERK5 kinase and TAD must be considered when assessing the role of ERK5 and the effectiveness of anti-ERK5 therapeutics. Selective ERK5 inhibitors target ERK5 kinase activity, but they do not phenocopy the effects of ERK5 genetic depletion. Here, the authors demonstrate that the direct interaction of these inhibitors to ERK5 kinase domain induces conformational changes that promote ERK5 nuclear translocation and transcriptional activities. |
| Databáze: | OpenAIRE |
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