Discovery of a gatekeeper residue in the C-terminal tail of the extracellular signal-regulated protein kinase 5 (ERK5)

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Adam J. Pearson
  • Paul Fullwood
  • Gabriela Toro Tapia
  • Ian Prise
  • Michael P. Smith
  • Qiuping Xu
  • Allan Jordan
  • Emanuele Giurisato

Abstract

The extracellular signal-regulated protein kinase 5 (ERK5) is a non-redundant mitogen-activated protein kinase (MAPK) that exhibits a unique C-terminal extension which comprises distinct structural and functional properties. Here, we sought to elucidate the significance of phosphoacceptor sites in the C-terminal transactivation domain of ERK5. We have found that Thr732 acted as a functional gatekeeper residue controlling C-terminal-mediated nuclear translocation and transcriptional enhancement. Consistently, using a non-bias quantitative mass spectrometry approach, we demonstrated that phosphorylation at Thr732 conferred selectivity for binding interactions of ERK5 with proteins related to chromatin and RNA biology, whereas a number of metabolic regulators were associated with full-length wild type ERK5. Additionally, our proteomic analysis revealed that phosphorylation of the Ser730-Glu-Thr732-Pro motif could occur independently of dual phosphorylation at Thr218-Glu-Tyr220 in the activation loop. Collectively, our results firmly establish the significance of C-terminal phosphorylation in regulating ERK5 function. The post-translational modification of ERK5 on its C-terminal tail might be of particular relevance in cancer cells where ERK5 has be found to be hyperphosphoryated.

Bibliographical metadata

Original languageEnglish
Article number929
JournalInternational Journal of Molecular Sciences
Volume21
Issue number3
DOIs
Publication statusPublished - 1 Feb 2020