Tyrosine phosphorylation of tau by the SRC family kinases lck and fyn.
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.
MRC Centre for Neurodegeneration Research, Department of Neuroscience, Institute of Psychiatry, King's College London, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK. tim.scales@kcl.ac.uk.
Timothy Me
TM
Scales
Pascal
P
Derkinderen
Kit-Yi
KY
Leung
Helen L
HL
Byers
Malcolm A
MA
Ward
Caroline
C
Price
Ian N
IN
Bird
Timothy
T
Perera
Stuart
S
Kellie
Ritchie
R
Williamson
Brian H
BH
Anderton
C Hugh
CH
Reynolds
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