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Vol. 9, Issue 6, 1495-1512, June 1998
Max-Planck-Unit for Structural Molecular Biology, D-22603 Hamburg,
Germany
In Alzheimer's disease the neuronal microtubule-associated protein
tau becomes highly phosphorylated, loses its binding properties, and
aggregates into paired helical filaments. There is increasing evidence
that the events leading to this hyperphosphorylation are related to
mitotic mechanisms. Hence, we have analyzed the physiological
phosphorylation of endogenous tau protein in metabolically labeled
human neuroblastoma cells and in Chinese hamster ovary cells stably
transfected with tau. In nonsynchronized cultures the phosphorylation
pattern was remarkably similar in both cell lines, suggesting a similar
balance of kinases and phosphatases with respect to tau. Using
phosphopeptide mapping and sequencing we identified 17 phosphorylation
sites comprising 80-90% of the total phosphate incorporated. Most of
these are in SP or TP motifs, except S214 and S262. Since
phosphorylation of microtubule-associated proteins increases during
mitosis, concomitant with increased microtubule dynamics, we analyzed
cells mitotically arrested with nocodazole. This revealed that S214 is
a prominent phosphorylation site in metaphase, but not in interphase.
Phosphorylation of this residue strongly decreases the tau-microtubule
interaction in vitro, suppresses microtubule assembly, and may be a key
factor in the observed detachment of tau from microtubules during
mitosis. Since S214 is also phosphorylated in Alzheimer's disease tau, our results support the view that reactivation of the cell cycle machinery is involved in tau hyperphosphorylation.
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