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

doi:10.1186/1750-1326-6-12

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

Research output: Contribution to journal › Article › peer-review

40 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 language	English
Article number	12
Number of pages	11
Journal	Molecular Neurodegeneration
Volume	6
Issue number	1
DOIs	https://doi.org/10.1186/1750-1326-6-12
Publication status	Published - 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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title = "Tyrosine phosphorylation of tau by the Src family kinases Lck and Gyn",

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.",

keywords = "Alzheimer's disease, Protein kinase Fyn, Protein kinase Lck, Protein tyrosine kinase, Tau protein, Tyrosine, Protein phosphorylation",

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

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T1 - Tyrosine phosphorylation of tau by the Src family kinases Lck and Gyn

AU - Scales, Timothy M. E.

AU - Derkinderen, Pascal

AU - Leung, Kit-Yi

AU - Byers, Helen L.

AU - Ward, Malcolm A.

AU - Price, Caroline

AU - Bird, Ian N.

AU - Perera, Timothy

AU - Kellie, Stuart

AU - Williamson, Ritchie

AU - Anderton, Brian H.

AU - Reynolds, C. Hugh

PY - 2011/1/1

Y1 - 2011/1/1

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Protein kinase Fyn

KW - Protein kinase Lck

KW - Protein tyrosine kinase

KW - Tau protein

KW - Tyrosine

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JO - Molecular Neurodegeneration

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

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