Dataset Information

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

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.

SUBMITTER: Lochhead PA

PROVIDER: S-EPMC7069993 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Lochhead Pamela A PA Tucker Julie A JA Tatum Natalie J NJ Wang Jinhua J Oxley David D Kidger Andrew M AM Johnson Victoria P VP Cassidy Megan A MA Gray Nathanael S NS Noble Martin E M MEM Cook Simon J SJ

Nature communications 20200313 1

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). ...[more]

PMID: 32170057

Similar Datasets

Project description:Background:Skin denervation that develops in patients with diabetes mellitus as a neuropathic manifestation is known as diabetic peripheral neuropathy (DPN). Skin denervation is parallel to neuronal injuries that alter intracellular signaling. To date, the correlation between nerve injury and the activation of intracellular responses to neuropathic manifestations has not been elucidated; specifically, whether activating transcription factor 3 (ATF3) is responsible for neuronal injury and a critical molecule that modulates the activation of intracellular protein kinase C epsilon (p-PKC?) and pain development in DPN is a crucial question. Methods:To address, ATF3 knockout (atf3 -/- group, C57/B6 genetic background) and wild-type mice (atf3+/+ group) received a single dose of streptozotocin (200 mg/kg) to generate a mouse model of DPN. Results:Both atf3+/+ and atf3 -/- mice exhibited hyperglycemia and the same pathology of skin denervation at posttreatment month 2, but only atf3+/+ mice developed thermal hyperalgesia (P<0.001) and mechanical allodynia (P=0.002). The atf3+/+ group, but not the atf3 -/- group, had preferential ATF3 upregulation on p-PKC?(+) neurons with a ratio of 37.7%±6.1% in p-PKC?(+):ATF3(+) neurons (P<0.001). In addition, B-cell lymphoma-extra large (Bcl-XL), an antiapoptotic Bcl2 family protein, exhibited parallel patterns to p-PKC? (ie, Bcl-XL upregulation was reversed in atf3 -/- mice). These two molecules were colocalized and increased by approximately two-fold in the atf3+/+ group compared with the atf3 -/- group (30.0%±3.4% vs 13.7% ± 6.2%, P=0.003). Furthermore, linear analysis results showed that the densities of p-PKC? and Bcl-XL had a reverse linear relationship with the degrees of thermal hyperalgesia and mechanical allodynia. Conclusion:Collectively, this report suggested that ATF3 is a critical upstream molecule that modulates p-PKC? and Bcl-XL expression, which consequently mediated the development of neuropathic manifestation in DPN.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets