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The Journal of Neuroscience, July 13, 2005, 25(28):6584-6593; doi:10.1523/JNEUROSCI.1487-05.2005

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Cellular/Molecular
Tyrosine 394 Is Phosphorylated in Alzheimer's Paired Helical Filament Tau and in Fetal Tau with c-Abl as the Candidate Tyrosine Kinase

Pascal Derkinderen,^1 * Timothy M. E. Scales,^1 * Diane P. Hanger,¹ Kit-Yi Leung,² Helen L. Byers,² Malcolm A. Ward,² Christof Lenz,³ Caroline Price,⁴ Ian N. Bird,⁴ Timothy Perera,⁴ Stuart Kellie,^4,5 Ritchie Williamson,¹ Wendy Noble,¹ Richard A. Van Etten,⁶ Karelle Leroy,⁷ Jean-Pierre Brion,⁷ C. Hugh Reynolds,¹ and Brian H. Anderton¹

¹Department of Neuroscience and ²Proteome Sciences plc, Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom, ³Mass Spectrometry Laboratories, Applied Biosystems, 64293 Darmstadt, Germany, ⁴Yamanouchi Research Institute, Oxford OX4 4SX, United Kingdom, ⁵School of Molecular and Microbial Sciences/Institute for Molecular Biosciences and Cooperative Research Centre for Chronic Inflammatory Diseases, University of Queensland, Brisbane QLD4072, Australia, ⁶Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 02111, and ⁷Laboratory of Histology and Neuropathology, Université Libre de Bruxelles, School of Medicine, 1070 Brussels, Belgium

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.

Key words: Alzheimer's disease; Abl; tau; tyrosine phosphorylation; paired helical filaments; mass spectrometry

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Received Dec 21, 2004; revised May 19, 2005; accepted May 19, 2005.

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