Involvement of aberrant glycosylation in phosphorylation of tau by cdk5 and GSK‐3β
Open Access
- 2 October 2002
- journal article
- Published by Wiley in FEBS Letters
- Vol. 530 (1-3) , 209-214
- https://doi.org/10.1016/s0014-5793(02)03487-7
Abstract
Microtubule‐associated protein tau is abnormally hyperphosphorylated, glycosylated, and aggregated in affected neurons in the brains of individuals with Alzheimer's disease (AD). We recently found that the glycosylation might precede hyperphosphorylation of tau in AD. In this study, we investigated the effect of glycosylation on phosphorylation of tau catalyzed by cyclin‐dependent kinase 5 (cdk5) and glycogen synthase kinase‐3β (GSK‐3β). The phosphorylation of the longest isoform of recombinant human brain tau, tau441, at various sites was detected by Western blots and by radioimmuno‐dot‐blot assay with phosphorylation‐dependent and site‐specific tau antibodies. We found that cdk5 phosphorylated tau441 at Thr‐181, Ser‐199, Ser‐202, Thr‐205, Thr‐212, Ser‐214, Thr‐217, Thr‐231, Ser‐235, Ser‐396, and Ser‐404, but not at Ser‐262, Ser‐400, Thr‐403, Ser‐409, Ser‐413, or Ser‐422. GSK‐3β phosphorylated all the cdk5‐catalyzed sites above except Ser‐235. Deglycosylation by glycosidases depressed the subsequent phosphorylation of AD‐tau (i) with cdk5 at Thr‐181, Ser‐199, Ser‐202, Thr‐205, and Ser‐404, but not at Thr‐212; and (ii) with GSK‐3β at Thr‐181, Ser‐202, Thr‐205, Ser‐217, and Ser‐404, but not at Ser‐199, Thr‐212, Thr‐231, or Ser‐396. These data suggest that aberrant glycosylation of tau in AD might be involved in neurofibrillary degeneration by promoting abnormal hyperphosphorylation by cdk5 and GSK‐3β.Keywords
This publication has 52 references indexed in Scilit:
- Phosphorylation of tau protein by recombinant GSK‐3β: pronounced phosphorylation at select Ser/Thr‐Pro motifs but no phosphorylation at Ser262 in the repeat domainFEBS Letters, 1999
- τ is phosphorylated by GSK‐3 at several sites found in Alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by A‐kinaseFEBS Letters, 1998
- The regulation of phosphorylation of τ in SY5Y neuroblastoma cells: the role of protein phosphatasesFEBS Letters, 1998
- Glycogen synthase kinase 3 phosphorylates recombinant human tau protein at serine‐262 in the presence of heparin (or tubulin)FEBS Letters, 1995
- Tau protein kinase I/GSK-3Β/kinase FA in heparin phosphorylates tau on Ser199, Thr231, Ser235, Ser262, Ser369, and Ser400 sites phosphorylated in Alzheimer disease brainProtein Journal, 1995
- Alzheimer paired helical filaments Restoration of the biological activity by dephosphorylationFEBS Letters, 1994
- Abnormal Alzheimer‐like phosphorylation of tau‐protein by cyclin‐dependent kinases cdk2 and cdk5Published by Wiley ,1993
- A cdc2‐related kinase PSSALRE/cdk5 is homologous with the 30 kDa subunit of tau protein kinase II, a proline‐directed protein kinase associated with microtubuleFEBS Letters, 1993
- Glycogen synthase kinase 3β is identical to tau protein kinase I generating several epitopes of paired helical filamentsFEBS Letters, 1993
- Microtubule‐associated protein tau Identification of a novel peptide from bovine brainFEBS Letters, 1989