Regulation of phosphorylation of tau by protein kinases in rat brain.
Microtubule associated protein tau is abnormally hyperphosphorylated in Alzheimer disease (AD) brain. To investigate the role of protein kinases involved in this lesion, metabolically active slices made from brains of adult rats were treated with or without various specific kinase activators in oxygenated artificial cerebrospinal fluid. The basal kinase activities of protein kinase-A (PKA), CaM Kinase II and GSK-3 were stimulated more than two-fold by isoproterenol, bradykinin and wortmannin, respectively. We found that cdk5 activity was co-stimulated with PKA by isoproterenol. Sequential activation of PKA (+cdk5), CaM Kinase II and GSK-3 produced hyperphosphorylation of tau at Ser-198/Ser-199/Ser-202, Ser-214, Thr-231/Ser-235, Ser-262, Ser-396/Ser-404 and Ser-422 sites. Like AD P-tau, the P-tau from brain slices bound to normal tau and its binding to tubulin was inhibited. These studies suggest that PKA, cdk5, CaM Kinase II and GSK-3 are involved in the regulation of phosphorylation of tau and that AD-type phosphorylation of tau is probably a product of the synergistic action of two or more of these kinases.
Sengupta
Amitabha
A
Department of Neurochemistry, New York State Institute for Basic Research, Staten Island, NY 10314-6399, USA.
Grundke-Iqbal
Inge
I
Iqbal
Khalid
K
D000544:Alzheimer Disease / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D001920:Bradykinin / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008870:Microtubules / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D000077191:Wortmannin; D016875:tau Proteins / Q000378:metabolism*
D000730:Androstadienes; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D016875:tau Proteins; D011494:Protein Kinases; D051360:Cyclin-Dependent Kinase 5; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D007545:Isoproterenol; D001920:Bradykinin; D000077191:Wortmannin