NON-PROLINE-DEPENDENT PROTEIN-KINASES PHOSPHORYLATE SEVERAL SITES FOUND IN TAU FROM ALZHEIMER-DISEASE BRAIN

Of 21 phosphorylation sites identified in PHF-tau 11 are on ser/thr-X motifs and are probably phosphorylated by non-proline-dependent protei n kinases (non-PDPKs). The identities of the non-PDPKs and how they in teract to hyperphosphorylate PHF-tau are still unclear. In a previous study we have shown that the rate of phosphorylation of human tau 39 b y a PDPK (GSK-3) was increased several fold if tau were first prephosp horylated by non-PDPKs (Singh et al., FEES Lett 358: 267-272, 1995). I n this study we have examined how the specificity of a non-PDPK for di fferent sites on human tau 39 is modulated when tau is prephosphorylat ed by other non-PDPKs (A-kinase, C-kinase, CK-I, CaM kinase II) as wel l as a PDPK (GSK-3). We found that the rate of phosphorylation of tau 39 by a non-PDPK can be stimulated if tau were first prephosphorylated by other non-PDPKs. Of the four non-PDPKs only CK-1 can phosphorylate sites (thr 231, ser 396, ser 404) known to be present in PHF-tau. Fur ther, these sites were phosphorylated more rapidly and to a greater ex tent by CK-1 if tau 39 were first prephosphorylated by A-kinase, CaM k inase II or GSK-3. These results suggest that the site specificities o f the non-PDPKs that participate in PHF-tau hyperphosphorylation can b e modulated at the substrate level by the phosphorylation state of tau .