M. Bennecib et al., Inhibition of PP-2A upregulates CaMKII in rat forebrain and induces hyperphosphorylation of tau at Ser 262/356, FEBS LETTER, 490(1-2), 2001, pp. 15-22
The regulation of the activity of CaMKII by PP-1 and PP-2A, as well as the
role of this protein kinase in the phosphorylation of tau protein in forebr
ain were investigated. The treatment of metabolically active rat brain slic
es with 1.0 muM okadaic acid (OA) inhibited similar to 65% of PP-2A and had
no significant effect on PP-1 in the 16 000 X g tissue extract. Calyculin
A (CL-A), 0.1 muM under the same conditions, inhibited similar to 50% of PP
-1 and similar to 20% of PP-2A activities. In contrast, a mixture of OA and
CL-A practically completely inhibited both PP-2A and PP-1 activities. The
inhibition of the two phosphatase activities or PP-2A alone resulted in an
similar to2-fold increase in CaMKII activity and an similar to8-fold increa
se in the phosphorylation of tau at Ser 262/356 in 60 min. Treatment of the
brain slices with KN-62, an inhibitor of the autophosphorylation of CaMKII
at Thr 286/287, produced similar to 60% inhibition in CaMKII activity and
no significant effect on tau phosphorylation at Ser 262/356, The KN-62-trea
ted brain slices when further treated with OA and CL-A did not show any cha
nge in CaMKII activity. In vitro, both PP-2A and PP-1 dephosphorylated tau
at Ser 262/356 that was phosphorylated with purified CaMKII. These studies
suggest (i) that in mammalian forebrain the cytosolic CaMKII activity is re
gulated mainly by PP-2A, (ii) that CaMKII is the major tau Ser 262/356 kina
se in brain, and (iii) that a decrease in PP-2A/PP-1 activities in the brai
n leads to hyperphosphorylation of tau not only bg inhibition of its dephos
phorylation but also by promoting the CaMKII activity. (C) 2001 Federation
of European Biochemical Societies. Published by Elsevier Science B.V. All r
ights reserved.