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Paradoxical activation of the protein kinase-transcription factor ERK5 by ERK5 kinase inhibitors
- Source :
- Nature Communications, Vol 11, Iss 1, Pp 1-16 (2020), Nature Communications
- Publication Year :
- 2020
- Publisher :
- Nature Publishing Group, 2020.
-
Abstract
- 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.<br />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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 11
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....b8580ed52562132fb3cdff6c6b5715a6