PHOSPHORYLATION OF MICROTUBULE-ASSOCIATED PROTEIN-TAU BY STRESS-ACTIVATED PROTEIN-KINASES

The paired helical filament, which comprises the major fibrous element of the neurofibrillary lesions of Alzheimer's disease, is composed of hyperphosphorylated microtubule-associated protein tau. Many of the h yperphosphorylated sites in tau are serine/threonine-prolines. Here we show that the stress-activated protein (SAP) kinases SAPK1 gamma (als o called JNK1), SAPK2a (also called p38, RK, CSBPs, Mpk2 and Mxi2), SA PK2b (also called p38 beta), SAPK3 (also called ERK6 and p38 gamma) an d SAPK4 phosphorylate tau at many serine/threonine-prolines, as assess ed by the generation of the epitopes of phosphorylation-dependent anti -tau antibodies, Based on initial rates of phosphorylation, tau was fo und to be a good substrate for SAPK4 and SAPK3, a reasonable substrate for SAPK2b and a relatively poor substrate for SAPK2a and SAPK1 gamma , Phosphorylation of tau by SAPK3 and SAPK4 resulted in a marked reduc tion in its ability to promote microtubule assembly, These findings do uble the number of candidate protein kinases for the hyperphosphorylat ion of tau in Alzheimer's disease and other neurodegenerative disorder s. (C) 1997 Federation of European Biochemical Societies.