Discovery of a Gatekeeper Residue in the C-Terminal Tail of the Extracellular Signal-Regulated Protein Kinase 5 (ERK5)

International Journal of Molecular Sciences

卷:21

Emanuele Giurisato¹  Qiuping Xu¹  Cathy Tournier¹  AdamJ. Pearson¹  Ian Prise²  Gabriela Toro Tapia³  Paul Fullwood³  Chiara Francavilla³  AlanJ. Whitmarsh³  MichaelP. Smith³  Allan Jordan⁴ 

[1] Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PT, UK;

[2] Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PT, UK;

[3] Division of Molecular and Cellular Function, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PT, UK;

[4] Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Manchester M13 9PT, UK;

关键词: erk5;    mapk;    phosphorylation;    proteomics;    mass spectrometry;    transcription;   

DOI  :  10.3390/ijms21030929

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown