Signalling Laboratory, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, UK.
York Biomedical Research Institute and Department of Biology, University of York, York, YO10 5DD, UK.
Nat Commun. 2020 Mar 13;11(1):1383. doi: 10.1038/s41467-020-15031-3.
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.
双蛋白激酶-转录因子 ERK5 是癌症和炎症的一个新兴药物靶点，已经开发出了小分子 ERK5 激酶抑制剂。然而，选择性 ERK5 激酶抑制剂无法重现 ERK5 基因缺失表型，这表明 ERK5 具有激酶非依赖性的功能。在这里，我们表明 ERK5 激酶抑制剂通过其独特的 C 端转录激活结构域（TAD）引起 ERK5 转录活性的反常激活。使用 ERK5 激酶抑制剂 Compound 26（ERK5-IN-1）作为范例，我们开发了 ERK5 的激酶活性、耐药性突变体。利用这些突变体，我们表明 ERK5 转录活性的诱导需要抑制剂与激酶结构域的直接结合。这反过来又促进了激酶结构域的构象变化，导致 ERK5 的核转位和基因转录的刺激。这表明，在评估 ERK5 的作用和抗 ERK5 治疗的有效性时，必须同时考虑 ERK5 激酶和 TAD。
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