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Abstract
BackgroundTau protein is the principal component of the neurofibrillary tangles found in Alzheimer's disease, where it is hyperphosphorylated on serine and threonine residues, and recently phosphotyrosine has been demonstrated. The Src-family kinase Fyn has been linked circumstantially to the pathology of Alzheimer's disease, and shown to phosphorylate Tyr18. Recently another Src-family kinase, Lck, has been identified as a genetic risk factor for this disease.ResultsIn this study we show that Lck is a tau kinase. In vitro, comparison of Lck and Fyn showed that while both kinases phosphorylated Tyr18 preferentially, Lck phosphorylated other tyrosines somewhat better than Fyn. In co-transfected COS-7 cells, mutating any one of the five tyrosines in tau to phenylalanine reduced the apparent level of tau tyrosine phosphorylation to 25-40% of that given by wild-type tau. Consistent with this, tau mutants with only one remaining tyrosine gave poor phosphorylation; however, Tyr18 was phosphorylated better than the others.ConclusionsFyn and Lck have subtle differences in their properties as tau kinases, and the phosphorylation of tau is one mechanism by which the genetic risk associated with Lck might be expressed pathogenically.
Highlights
Tau protein is the principal component of the neurofibrillary tangles found in Alzheimer’s disease, where it is hyperphosphorylated on serine and threonine residues, and recently phosphotyrosine has been demonstrated
The microtubule-associated protein tau is the main component of paired helical filaments (PHF) which are aggregated structures found in neurofibrillary tangles (NFT) in the brains of patients with Alzheimer’s disease (AD)
This level of phosphorylation was expected to be adequate for site identification by mass spectrometry, while not being so high as to force the phosphorylation of non-physiological sites
Summary
Tau protein is the principal component of the neurofibrillary tangles found in Alzheimer’s disease, where it is hyperphosphorylated on serine and threonine residues, and recently phosphotyrosine has been demonstrated. The Src-family kinase Fyn has been linked circumstantially to the pathology of Alzheimer’s disease, and shown to phosphorylate Tyr. The Src-family kinase Fyn has been linked circumstantially to the pathology of Alzheimer’s disease, and shown to phosphorylate Tyr18 Another Src-family kinase, Lck, has been identified as a genetic risk factor for this disease. The microtubule-associated protein tau is the main component of paired helical filaments (PHF) which are aggregated structures found in neurofibrillary tangles (NFT) in the brains of patients with Alzheimer’s disease (AD). Of the five tyrosine residues in human tau (Figure 1), phosphorylation of Tyr197 [18] and of Tyr394 [17] have been identified in PHF-tau, and of Tyr394 in foetal tau [17] using mass spectrometry
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