Characterization of Neuronal Tau Protein as a Target of Extracellular Signal-regulated Kinase
Journal of Biological Chemistry
American Society for Biochemistry and Molecular Biology Inc.
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Qi, H., Prabakaran, S., Cantrelle, F., Chambraud, B., Gunawardena, J., Lippens, G., & Landrieu, I. (2016). Characterization of Neuronal Tau Protein as a Target of Extracellular Signal-regulated Kinase. Journal of Biological Chemistry, 291 (14), 7742-7753. https://doi.org/10.1074/jbc.M115.700914
Tau neuronal protein has a central role in neurodegeneration and is implicated in Alzheimer disease development. Abnormal phosphorylation of Tau impairs its interaction with other proteins and is associated with its dysregulation in pathological conditions. Molecular mechanisms leading to hyperphosphorylation of Tau in pathological conditions are unknown. Here, we characterize phosphorylation of Tau by extracellular-regulated kinase (ERK2), a mitogen-activated kinase (MAPK) that responds to extracellular signals. Analysis of in vitro phosphorylated Tau by activated recombinant ERK2 with nuclear magnetic resonance spectroscopy (NMR) reveals phosphorylation of 15 Ser/Thr sites. In vitro phosphorylation of Tau using rat brain extract and subsequent NMR analysis identifies the same sites. Phosphorylation with rat brain extract is known to transform Tau into an Alzheimer disease-like state. Our results indicate that phosphorylation of Tau by ERK2 alone is sufficient to produce the same characteristics. We further investigate the mechanism of ERK2 phosphorylation of Tau. Kinases are known to recognize their protein substrates not only by their specificity for a targeted Ser or Thr phosphorylation site but also by binding to linear-peptide motifs called docking sites. We identify two main ERK2 docking sites in Tau sequence using NMR. Our results suggest that ERK2 dysregulation in Alzheimer disease could lead to abnormal phosphorylation of Tau resulting in the pathology of the disease.
Alzheimer disease, extracellular signal-regulated kinase (ERK), nuclear magnetic resonance (NMR), protein phosphorylation, protein-protein interaction, Tau protein (Tau)
This work was supported by TGE RMN THC (FR-3050, France) and FRABio (Lille University, CNRS, FR 3688) and also by a grant from the LabEx (Laboratory of Excellence), DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer's disease), and in part by the French government funding agency Agence Nationale de la Recherche TAF. This work was supported by National Institutes of Health Grant R01 GM081578 (to S. P. and J. G.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
External DOI: https://doi.org/10.1074/jbc.M115.700914
This record's URL: https://www.repository.cam.ac.uk/handle/1810/267174