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Nat Commun. 2020 Mar 13;11(1):1383. doi: 10.1038/s41467-020-15031-3.

Paradoxical activation of the protein kinase-transcription factor ERK5 by ERK5 kinase inhibitors.

Author information

1
Signalling Laboratory, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK. pamela.lochhead@babraham.ac.uk.
2
York Biomedical Research Institute and Department of Biology, University of York, York, YO10 5DD, UK.
3
CRUK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Newcastle University, Newcastle, NE2 4HH, UK.
4
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
5
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115, USA.
6
Signalling Laboratory, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
7
Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London, SW3 6JB, UK.
8
Signalling Laboratory, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK. simon.cook@babraham.ac.uk.

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.

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