Tyrosine phosphorylation of tau by the Src family kinases Lck and Gyn

Timothy M. E. Scales, Pascal Derkinderen, Kit-Yi Leung, Helen L. Byers, Malcolm A. Ward, Caroline Price, Ian N. Bird, Timothy Perera, Stuart Kellie, Ritchie Williamson, Brian H. Anderton, C. Hugh Reynolds

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    30 Citations (Scopus)

    Abstract

    Background: 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 Tyr18. Recently another Src-family kinase, Lck, has been identified as a genetic risk factor for this disease.

    Results: In 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.

    Conclusions: Fyn 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.

    Original languageEnglish
    Article number12
    Number of pages11
    JournalMolecular Neurodegeneration
    Volume6
    Issue number1
    DOIs
    Publication statusPublished - 1 Jan 2011

    Keywords

    • Alzheimer's disease
    • Protein kinase Fyn
    • Protein kinase Lck
    • Protein tyrosine kinase
    • Tau protein
    • Tyrosine
    • Protein phosphorylation

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