Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tau protein from Alzheimer disease (AD) brain is phosphorylated at eleven Ser/Thr-Pro and nine Ser/Thr-X sites. The former sites are phosphorylated by proline-dependent protein kinases (PDPKs), the latter by non-PDPKs. The identities of both the PDPKs and non-PDPKs involved in AD tau hyperphosphorylation are still to be established. In this study we have analyzed the interactions between a PDPK (GSK-3) and several non-PDPKs (A-kinase, C-kinase, CK-1, CaM kinase II) in the phosphorylation of one isoform (tau 39) of human tau. We found that the rate of phosphorylation of tau 39 by GSK-3 was increased several-fold if tau were first prephosphorylated by the non-PDPKs. Further, several Alzheimer-like epitopes in tau can be induced only slowly after phosphorylation of tau by GSK-3 alone. After a prephosphorylation of tau by the non-PDPKs, however, the rate of induction of these epitopes by GSK-3 is increased several-fold. These results suggest that one role of non-PDPK-catalyzed phosphorylation is the modulation of PDPK-catalyzed phosphorylation of tau in AD brain.
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PMID:Rapid Alzheimer-like phosphorylation of tau by the synergistic actions of non-proline-dependent protein kinases and GSK-3. 753 Nov 59

The phosphorylation of bovine tau, either by GSK-3 alone or by a combination of GSK-3 and several non-proline-dependent protein kinases (non-PDPKs), was studied. GSK-3 alone catalyzed the incorporation of approximately 3 mol 32P/mol tau at a relatively slow rate. Prephosphorylation of tau by A-kinase, C-kinase, or CK-2 (but not by CK-1, CaM kinase II or Gr kinase) increased both the rate and extent of a subsequent phosphorylation catalyzed by GSK-3 by several-fold. These results suggest that the phosphorylation of tau by PDPKs such as GSK-3 (and possibly MAP kinase, cdk5) may be positively modulated at the substrate level by non-PDPK-catalyzed phosphorylations.
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PMID:Modulation of GSK-3-catalyzed phosphorylation of microtubule-associated protein tau by non-proline-dependent protein kinases. 782 26

The paired helical filaments (PHF) found in the brain of patients with Alzheimer disease (AD) are composed primarily of the microtubule-associated protein tau. Six isoforms of tau have been recognized and all are present in a hyperphosphorylated state in PHF. It is not known whether all tau isoforms serve equally well as substrates for various kinases. In this study we have compared the phosphorylation of human tau isoforms containing three microtubule-binding repeats and zero (tau 3), one (tau 3S), or two (tau 3L) N-terminal inserts. Four kinases (A-kinase, CK-1, CaM kinase II, GSK-3) were used for this purpose. With A-kinase, CK-1, and CaM kinase II the extent of phosphorylation was tau 3L > tau 3S > tau 3. With GSK-3 it was tau 3L approximately = tau 3S > tau 3. Tau 3 was a poor substrate for either CaM kinase II or CK-1, 32P incorporation being only 5 and 11%, respectively, of that observed by these kinases when tau 3L was the substrate. After prephosphorylation of the three tau isoforms by A-kinase, a subsequent phosphorylation by GSK-3 was stimulated several fold over tau that was not prephosphorylated. Under these conditions the extent of 32P incorporation was tau 3L > tau 3S > tau 3. Both CK-1 and GSK-3 phosphorylated ser 396 more rapidly in tau 3L compared to tau 3 or tau 3S. Our results suggest that (1) the presence of N-terminal inserts in tau isoforms are important structural determinants that modulate the specificity of several kinases; (2) the different tau isoforms may be present at different states of phosphorylation in PHF.
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PMID:Differential phosphorylation of human tau isoforms containing three repeats by several protein kinases. 863 36

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.
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PMID:Calcium/calmodulin-dependent protein kinase II phosphorylates tau at Ser-262 but only partially inhibits its binding to microtubules. 867 37

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.
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PMID:Non-proline-dependent protein kinases phosphorylate several sites found in tau from Alzheimer disease brain. 871 28

All six isoforms of the microtubule-associated protein tau are present in hyperphosphorylated states in the brains of patients with Alzheimer's disease (AD). It is presently unclear how such hyperphosphorylation of tau is controlled. In a previous study (Singh et al. Arch Biochem Biophys 328: 43-50, 1996) we have shown that three-repeat taus containing two N-terminal inserts were phosphorylated to higher levels and at different sites compared to those either lacking or containing only one such insert. We have extended these observations in this study by comparing the phosphorylation of tau isoforms containing three-repeats (tau 3, tau 3 L) and four-repeats (tau 4, tau 4 L). In the absence of N-terminal inserts in tau structure (tau 3, tau 4) both CaM kinase II and C-kinase phosphorylated four-repeat tau (tau 4) to a higher extent than three-repeat tau (tau 3). When two N-terminal inserts are present in tau structure (tau 3 L, tau 4 L), then three-repeat tau (tau 3 L) is phosphorylated to a higher extent than four-repeat tau (tau 4 L) by these kinases. CK-1 and GSK-3 phosphorylated each of the above pairs of three-repeat and four-repeat taus to the same extents. However, after an initial prephosphorylation of the taus by CaM kinase II, GSK-3 differentially phosphorylated three-repeat and four-repeat taus. Under these conditions thr 231, ser 235, ser 396, and ser 404 were phosphorylated to greater extents in four-repeat tau (tau 4) compared to three-repeat tau (tau 3) in the absence of N-terminal inserts. In the presence of such inserts these sites were phosphorylated to greater extents in three-repeat (tau 3 L) compared to four-repeat (tau 4 L) tau. Our results indicate that the extents to which tau isoforms are phosphorylated in normal and AD brain depends on (a) the number of repeats (3 or 4), (b) the number of N-terminal inserts (0, 1, or 2), and (c) the initial phosphorylation state of tau.
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PMID:Protein kinase C and calcium/calmodulin-dependent protein kinase II phosphorylate three-repeat and four-repeat tau isoforms at different rates. 906 3

The paired helical filaments (PHFs) found in Alzheimer's disease (AD) brains are composed primarily of the microtubule-associated protein tau. PHF-tau is in a hyperphosphorylated state and is unable to promote microtubule assembly. We investigated whether the inhibition of tau binding to microtubules is increased when tau is phosphorylated by different kinases in combination with GSK-3. We found that when tau was first phosphorylated by A-kinase, C-kinase, cdk5, or CaM kinase II and then by GSK-3, its binding to microtubules was inhibited by 45, 61, 78, and 79%, respectively. Further, the kinase combinations cdk5/GSK-3 and CaM kinase II/GSK-3 rapidly phosphorylated the sites Thr 231 and Ser 235. When these sites were individually replaced by Ala and the phosphorylation experiments repeated, tau binding to microtubules was inhibited by 54 and 71%, respectively. By comparison, when Ser 262 was replaced by Ala, tau binding to microtubules was inhibited by only 8% after phosphorylation by CaM kinase II. From these observations we estimate that the phosphorylation of Thr 231, Ser 235, and Ser 262 contributes approximately 26, approximately 9, and approximately 33%, respectively, of the overall inhibition of tau binding to microtubules. Together, our results indicate that the binding of tau to microtubules is controlled by the phosphorylation of several sites, among which are Thr 231, Ser 235, and Ser 262.
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PMID:Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. 973 71

The involvement of tau phosphorylation in apoptosis resembling Alzheimer's disease (AD) was investigated using a cell model of P19 cells stably expressing human tau441 (tau/P19 cells). Apoptotic cell death was observed specifically in tau/P19 cells during neural differentiation with retinoic acid (RA) treatment. A CaM kinase II inhibitor, KN-93, protected tau/P19 cells from apoptosis, although it stimulated the cell death of wild-type P19 cells (wt/P19 cells). W-7 and calmidazolium, calmodulin antagonists, also specifically inhibited the apoptosis of tau/P19 cells. LiCl, an inhibitor of glycogen synthase 3, a tau kinase, was effective in protecting tau/P19 cells from apoptosis, but the protective effect was less than that of CaM kinase II inhibitor and calmodulin antagonists. Tau in the nuclei of tau/P19 cells was phosphorylated at the sites for CaM kinase II detected by an antibody recognizing a phosphorylated form of tau. These results indicated that CaM kinase II was involved in the apoptosis of tau/P19 cells induced by RA treatment.
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PMID:Ca2+/calmodulin-dependent protein kinase II mediates apoptosis of P19 cells expressing human tau during neural differentiation with retinoic acid treatment. 1883 Aug 78