Tyrosine 394 is phosphorylated in Alzheimer's paired helical filament tau and in fetal tau with c-Abl as the candidate tyrosine kinase

Derkinderen, Pascal, Scales, Timothy M. E., Hanger, Diane P., Leung, Kit-Yi, Byers, Helen L., Ward, Malcolm A., Lenz, Christof, Price, Caroline, Bird, Ian N., Perera, Timothy, Kellie, Stuart, Williamson, Ritchie, Noble, Wendy, Van Etten, Richard A. and Leroy, Karelle (2005) Tyrosine 394 is phosphorylated in Alzheimer's paired helical filament tau and in fetal tau with c-Abl as the candidate tyrosine kinase. Journal of Neuroscience, 25 28: 6584-6593. doi:10.1523/JNEUROSCI.1487-05.2005

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Author Derkinderen, Pascal
Scales, Timothy M. E.
Hanger, Diane P.
Leung, Kit-Yi
Byers, Helen L.
Ward, Malcolm A.
Lenz, Christof
Price, Caroline
Bird, Ian N.
Perera, Timothy
Kellie, Stuart
Williamson, Ritchie
Noble, Wendy
Van Etten, Richard A.
Leroy, Karelle
Title Tyrosine 394 is phosphorylated in Alzheimer's paired helical filament tau and in fetal tau with c-Abl as the candidate tyrosine kinase
Journal name Journal of Neuroscience   Check publisher's open access policy
ISSN 0270-6474
Publication date 2005-07
Sub-type Article (original research)
DOI 10.1523/JNEUROSCI.1487-05.2005
Open Access Status File (Publisher version)
Volume 25
Issue 28
Start page 6584
End page 6593
Total pages 10
Place of publication Washington
Publisher Society of Neuroscience
Collection year 2005
Language eng
Subject C1
270107 Cell Neurochemistry
730104 Nervous system and disorders
270106 Cell Development (incl. Cell Division and Apoptosis)
270201 Gene Expression
Abstract 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.
Keyword Alzheimer's disease
tyrosine phosphorylation
paired helical filaments
mass spectrometry
Glycogen-synthase Kinase-3-beta
Activated Protein-kinases
Src Family Kinases
N-terminal Kinase
Transgenic Mice
Q-Index Code C1
Additional Notes Authors of this document: Derkinderen, P; Scales, TME; Hanger, DP; Leung, KY; Byers, HL; Ward, MA; Lenz, C; Price, C; Bird, IN; Perera, T; Kellie, S; Williamson, R; Noble, W; Van Etten, RA; Leroy, K; Brion, JP; Reynolds, CH; Anderton, BH. DOI: 10.1523/JNEUROSCI.1487-05.2005

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Created: Wed, 15 Aug 2007, 06:04:30 EST