Phosphorylation of microtubule-associated protein tau on Ser 262 by an embryonic 100 kDa protein kinase.
This study examined the phosphorylation of tau on Ser 262, within the first microtubule-binding domain, by a developmentally regulated 100 kDa protein kinase exhibiting significantly greater activity in the embryonic rat brain than in the adult rat brain. This protein kinase co-purified with microtubules and co-immunoprecipitated with both tau and MAP-2. In addition to phosphorylating tau, MAP-2, and a Ser 262-containing peptide, the present protein kinase activity was shown to autophosphorylate as determined by the in-gel kinase assay in the absence of any protein or peptide polymerized into the matrix. Phosphorylation of tau with this protein kinase significantly reduced the tau-microtubule interaction, and the effect was significantly greater with microtubule-associated protein (MAP) preparations from embryonic brain than with preparations from the adult. Ser 262 is phosphorylated extensively in paired helical filament (PHF) tau from Alzheimer's disease (AD) brain, to a lesser extent in fetal tau, and only to a very minor extent in biopsy-derived human tau. Because the 100 kDa protein kinase activity phosphorylates Ser 262 and is higher in the fetal brain than the adult brain, it is hypothesized that an inappropriate re-expression and/or re-activation of this or a similar developmentally regulated protein kinase could contribute to the phosphorylation of Ser 262 in PHF-tau, and thus play a role in the pathogenesis of AD.
Jenkins
S M
SM
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 35294-0017, USA.
Johnson
G V
GV
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism*; D005314:Embryonic and Fetal Development; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine; D016875:tau Proteins / Q000378:metabolism*
D008869:Microtubule-Associated Proteins; D016875:tau Proteins; D012694:Serine; D011494:Protein Kinases