Characterization of Neuronal Tau Protein as a Target of Extracellular Signal-regulated Kinase

• Published in: The Journal of biological chemistry Vol. 291; no. 14; pp. 7742 - 7753
• Main Authors: Qi, Haoling, Prabakaran, Sudhakaran, Cantrelle, François-Xavier, Chambraud, Béatrice, Gunawardena, Jeremy, Lippens, Guy, Landrieu, Isabelle
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2016; American Society for Biochemistry and Molecular Biology
• Subjects: Alzheimer disease; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amino Acid Motifs; Animals; Biochemistry; Biochemistry, Molecular Biology; extracellular signal-regulated kinase (ERK); Extracellular Signal-Regulated MAP Kinases - chemistry; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Humans; Life Sciences; Molecular Bases of Disease; nuclear magnetic resonance (NMR); Nuclear Magnetic Resonance, Biomolecular; Phosphorylation; protein phosphorylation; Protein Structure, Tertiary; protein-protein interaction; Rats; Tau protein (Tau); tau Proteins - chemistry; tau Proteins - genetics; tau Proteins - metabolism; protein-protein interaction; protein phosphorylation; Alzheimer disease; Tau protein (Tau); nuclear magnetic resonance (NMR); extracellular signal-regulated kinase (ERK); interaction Tau protein (Tau); protein phosphorylation protein-protein
• ISSN: 0021-9258; 1083-351X
• DOI: 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.