title: Calcium/calmodulin-dependent protein kinase II phosphorylates tau at Ser-262 but only partially inhibits its binding to microtubules.
abstract: PHF-tau, which is phosphorylated at 10 Ser/Thr-Pro and 11 non-Ser/Thr-Pro sites, is unable to promote microtubule assembly. Phosphorylation of the non-Ser/Thr-Pro site, Ser-262, is reported to be primarily responsible for this. The identities of kinase(s) responsible for Ser-262 phosphorylation are still to be clarified. In this study we have used the monoclonal antibody 12E8, which recognizes P-Ser-262 and P-Ser-356 on tau, to survey different kinases for their abilities to phosphorylate Ser-262 on human tau 3L (tau410). In decreasing order of effectiveness we found that Ser-262 and Ser-356 phosphorylation can be catalyzed by CaM kinase II >> C-kinase >> GSK-3 approximately = A-kinase >> CK-1. CaM kinase II and C-kinase were shown to phosphorylate both Ser-262 and Ser-356. The binding of tau to taxol-stabilized microtubules was decreased by 35 and 42% after phosphorylation by CaM kinase II and C-kinase, respectively. Of the fraction of tau that bound to microtubules, about 50% was phosphorylated at Ser-262 and Ser-356. These results suggest that Ser-262 and Ser-356 are very good substrates for CaM kinase II but their phosphorylations are not sufficient to achieve maximal inhibition of tau binding to microtubules.
authors.affiliation: New York State Institute for Basic Research in Development Disabilities, Staten Island, New York, NY 10314, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Singh
authors.forename: J Z
authors.initials: JZ
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Novak
authors.forename: E
authors.initials: E
authors.lastname: Kontzekova
authors.forename: I
authors.initials: I
authors.lastname: Grundke-Iqbal
authors.forename: K
authors.initials: K
authors.lastname: Iqbal
mesh_terms: D001665:Binding Sites; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D012694:Serine; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases