Non-proline-dependent protein kinases phosphorylate several sites found in tau from Alzheimer disease brain |
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Authors: | Toolsee J Singh Tanweer Zaidi Inge Grundke-Iqbal Khalid Iqbal |
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Institution: | (1) New York State Institute for Basic Research in Developmental Disabilities, 10314 Staten Island, New York, USA;(2) NYS Institute for Basic Research, 1050 Forest Hill Road, 10314 Staten Island, New York, USA |
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Abstract: | Of 21 phosphorylation sites identified in PHF-tau 11 are on ser/thr-X motifs and are probably phosphorylated by non-proline-dependent protein kinases (non-PDPKs). The identities of the non-PDPKs and how they interact to hyperphosphorylate PHF-tau are still unclear. In a previous study we have shown that the rate of phosphorylation of human tau 39 by a PDPK (GSK-3) was increased several fold if tau were first prephosphorylated by non-PDPKs (Singh et al., FEBS Lett 358: 267-272, 1995). In this study we have examined how the specificity of a non-PDPK for different sites on human tau 39 is modulated when tau is prephosphorylated by other non-PDPKs (A-kinase, C-kinase, CK-1, CaM kinase II) as well 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. Further, these sites were phosphorylated more rapidly and to a greater extent by CK-1 if tau 39 were first prephosphorylated by A-kinase, CaM kinase II or GSK-3. These results suggest that the site specificities of the non-PDPKs that participate in PHF-tau hyperphosphorylation can be modulated at the substrate level by the phosphorylation state of tau.Abbreviations PHF
paired helical filaments
- A-kinase
cyclic AMP-dependent protein kinase
- CaM kinase II
calcium/calmodulin-dependent protein kinase II
- C-kinase
calcium/phospholipid-dependent protein kinase
- CK-1
casein kinase-1
- CK-2
casein kinase-2
- GSK-3
glycogen synthase kinase-3
- MAP kinase
mitogen-activated protein kinase
- PDPK
proline-dependent protein kinase |
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Keywords: | GSK-3 tau protein protein kinases Alzheimer disease paired helical filaments microtubules |
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