Tau phosphorylation at serine 396 and serine 404 by human recombinant tau protein kinase II inhibits tau's ability to promote microtubule assembly.
In Alzheimer's disease, hyperphosphorylated tau is an integral part of the neurofibrillary tangles that form within neuronal cell bodies and fails to promote microtubule assembly. Dysregulation of the brain-specific tau protein kinase II is reported to play an important role in the pathogenesis of Alzheimer's disease (Patrick, G. N., Zukerberg, L., Nikolic, M., De La Monte, S., Dikkes, P., and Tsai, L.-H. (1999) Nature 402, 615-622). We report here that in vitro phosphorylation of human tau by human recombinant tau protein kinase II severely inhibits the ability of tau to promote microtubule assembly as monitored by tubulin polymerization. The ultrastructure of tau-mediated polymerized tubulin was visualized by electron microscopy and compared with phosphorylated tau. Consistent with the observed slower kinetics of tubulin polymerization, phosphorylated tau is compromised in its ability to generate microtubules. Moreover, we show that phosphorylation of microtubule-associated tau results in tau's dissociation from the microtubules and tubulin depolymerization. Mutational studies with human tau indicate that phosphorylation by tau protein kinase II at serine 396 and serine 404 is primarily responsible for the functional loss of tau-mediated tubulin polymerization. These in vitro results suggest a possible role for tau protein kinase II-mediated tau phosphorylation in initiating the destabilization of microtubules.
Evans
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Pharmacia Corporation, Kalamazoo, Michigan 49007, USA.
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Bhattacharya
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Thomsen
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Gurney
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Sharma
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D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D051360:Cyclin-Dependent Kinase 5; D006801:Humans; D007313:Insecta; D007700:Kinetics; D008870:Microtubules / Q000502:physiology* / Q000648:ultrastructure; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012694:Serine; D013379:Substrate Specificity; D014162:Transfection; D014404:Tubulin / Q000502:physiology* / Q000648:ultrastructure; D016875:tau Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
D011994:Recombinant Proteins; D014404:Tubulin; D016875:tau Proteins; D012694:Serine; D051360:Cyclin-Dependent Kinase 5; D017346:Protein Serine-Threonine Kinases; C079134:tau protein kinase II