Tyrosine 394 Is Phosphorylated in Alzheimer's Paired Helical Filament Tau and in Fetal Tau with c-Abl as the Candidate Tyrosine Kinase
Copyright policy )Tyrosine 394 Is Phosphorylated in Alzheimer's Paired Helical Filament Tau and in Fetal Tau with c-Abl as the Candidate Tyrosine Kinase
Tau is a major microtubule-associated protein of axons and is also the principal component of the paired helical filaments (PHFs) that comprise the neurofibrillary tangles found in Alzheimer's disease and other tauopathies. Besides phosphorylation of tau on serine and threonine residues in both normal tau and tau from neurofibrillary tangles, Tyr-18 was reported to be a site of phosphorylation by the Src-family kinase Fyn. We examined whether tyrosine residues other than Tyr-18 are phosphorylated in tau and whether other tyrosine kinases might phosphorylate tau. Using mass spectrometry, we positively identified phosphorylated Tyr-394 in PHF-tau from an Alzheimer brain and in human fetal brain tau. When wild-type human tau was transfected into fibroblasts or neuroblastoma cells, treatment with pervanadate caused tau to become phosphorylated on tyrosine by endogenous kinases. By replacing each of the five tyrosines in tau with phenylalanine, we identified Tyr-394 as the major site of tyrosine phosphorylation in tau. Tyrosine phosphorylation of tau was inhibited by PP2 (4-amino-5-(4-chlorophenyl-7-(t-butyl)pyrazolo[3,4-d]pyrimidine), which is known to inhibit Src-family kinases and c-Abl. Cotransfection of tau and kinases showed that Tyr-18 was the major site for Fyn phosphorylation, but Tyr-394 was the main residue for Abl.In vitro, Abl phosphorylated tau directly. Abl could be coprecipitated with tau and was present in pretangle neurons in brain sections from Alzheimer cases. These results show that phosphorylation of tau on Tyr-394 is a physiological event that is potentially part of a signal relay and suggest that Abl could have a pathogenic role in Alzheimer's disease.
- University of Queensland Australia
- King's College London United Kingdom
- University of California, San Francisco United States
- University of Queensland Australia
- Université Libre de Bruxelles Belgium
Fetal Proteins, tau Proteins -- chemistry, Paired helical filaments, Post-Translational -- drug effects, Mass Spectrometry, Tyrosine phosphorylation, In-vitro, Cricetinae, Neuroblastoma: pathology, Neurofibrillary Tangles: chemistry, Chlorocebus aethiops, 80 and over, Fetal Proteins -- metabolism, Fetal Proteins: metabolism, Site-Directed, genetics, tau, mass spectrometry, Nerve Tissue Proteins: physiology, Aged, 80 and over, Tumor, src-Family Kinases -- metabolism, Brain, Sciences bio-médicales et agricoles, Alzheimer's disease, 730104 Nervous system and disorders, Proto-Oncogene Proteins c-fyn -- physiology, COS Cells, Post-Translational: drug effects, Female, Vanadates -- pharmacology, Alzheimer Disease: metabolism, 570, Neuroblastoma -- pathology, Glycogen-synthase Kinase-3-beta, Neurofibrillary Tangles -- chemistry, 571, Neurons: metabolism, 572, Abl, Molecular Sequence Data, 610, Alzheimer Disease -- metabolism, Nerve Tissue Proteins, Src Family Kinases, CHO Cells, Transfection, Transgenic Mice, Cell Line, Cercopithecus aethiops, Central-nervous-system, Phosphorylation: drug effects, F-actin, C1, Cricetulus, Activated Protein-kinases, Alzheimer Disease, Phosphotyrosine: metabolism, Cell Line, Tumor, Animals, Humans, Neurons -- metabolism, Brain: embryology, Amino Acid Sequence, Protein Processing, Proto-Oncogene Proteins c-abl: physiology, 270201 Gene Expression, Aged, Brain Chemistry, tau Proteins -- metabolism, Proto-Oncogene Proteins c-fyn: physiology, tau Proteins -- genetics, 270107 Cell Neurochemistry, Phosphorylation -- drug effects, tau Proteins: chemistry, Nerve Tissue Proteins -- physiology, tyrosine phosphorylation, Phosphotyrosine -- metabolism, 270106 Cell Development (incl. Cell Division and Apoptosis), Amino Acid Substitution, Mutagenesis, src-Family Kinases: metabolism, Mutagenesis, Site-Directed, Vanadates: pharmacology, paired helical filaments, Tau, N-terminal Kinase, metabolism, Brain -- embryology, Proto-Oncogene Proteins c-abl -- physiology
Fetal Proteins, tau Proteins -- chemistry, Paired helical filaments, Post-Translational -- drug effects, Mass Spectrometry, Tyrosine phosphorylation, In-vitro, Cricetinae, Neuroblastoma: pathology, Neurofibrillary Tangles: chemistry, Chlorocebus aethiops, 80 and over, Fetal Proteins -- metabolism, Fetal Proteins: metabolism, Site-Directed, genetics, tau, mass spectrometry, Nerve Tissue Proteins: physiology, Aged, 80 and over, Tumor, src-Family Kinases -- metabolism, Brain, Sciences bio-médicales et agricoles, Alzheimer's disease, 730104 Nervous system and disorders, Proto-Oncogene Proteins c-fyn -- physiology, COS Cells, Post-Translational: drug effects, Female, Vanadates -- pharmacology, Alzheimer Disease: metabolism, 570, Neuroblastoma -- pathology, Glycogen-synthase Kinase-3-beta, Neurofibrillary Tangles -- chemistry, 571, Neurons: metabolism, 572, Abl, Molecular Sequence Data, 610, Alzheimer Disease -- metabolism, Nerve Tissue Proteins, Src Family Kinases, CHO Cells, Transfection, Transgenic Mice, Cell Line, Cercopithecus aethiops, Central-nervous-system, Phosphorylation: drug effects, F-actin, C1, Cricetulus, Activated Protein-kinases, Alzheimer Disease, Phosphotyrosine: metabolism, Cell Line, Tumor, Animals, Humans, Neurons -- metabolism, Brain: embryology, Amino Acid Sequence, Protein Processing, Proto-Oncogene Proteins c-abl: physiology, 270201 Gene Expression, Aged, Brain Chemistry, tau Proteins -- metabolism, Proto-Oncogene Proteins c-fyn: physiology, tau Proteins -- genetics, 270107 Cell Neurochemistry, Phosphorylation -- drug effects, tau Proteins: chemistry, Nerve Tissue Proteins -- physiology, tyrosine phosphorylation, Phosphotyrosine -- metabolism, 270106 Cell Development (incl. Cell Division and Apoptosis), Amino Acid Substitution, Mutagenesis, src-Family Kinases: metabolism, Mutagenesis, Site-Directed, Vanadates: pharmacology, paired helical filaments, Tau, N-terminal Kinase, metabolism, Brain -- embryology, Proto-Oncogene Proteins c-abl -- physiology
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