Site‐specific effects of tau phosphorylation on its microtubule assembly activity and self‐aggregation
- 4 December 2007
- journal article
- Published by Wiley in European Journal of Neuroscience
- Vol. 26 (12), 3429-3436
- https://doi.org/10.1111/j.1460-9568.2007.05955.x
Abstract
Microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in brains with Alzheimer's disease. The phosphorylation sites of tau are mainly localized in the proline-rich (residues 172–251) and C-terminal tail (residues 368–441) regions, which flank the microtubule-binding repeats. Here, we investigated the effects of tau phosphorylation at these distinct sites/regions on its activity of stimulating microtubule assembly and its self-aggregation. We found that tau phosphorylation at the proline-rich region by dual-specificity tyrosine-phosphorylated and -regulated kinase 1A inhibited its microtubule assembly activity moderately and promoted its self-aggregation slightly. Tau phosphorylation at the C-terminal tail region by glycogen synthase kinase-3β increased its activity and promoted its self-aggregation markedly. Tau phosphorylation at both regions plus the microtubule-binding region by cAMP-dependent protein kinase diminished its activity (∼70% inhibition) and disrupted microtubules. These studies reveal the differential regulation of tau's biological activity and self-aggregation by phosphorylation at various sites/regions.Keywords
This publication has 48 references indexed in Scilit:
- Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell modelProceedings of the National Academy of Sciences of the United States of America, 2007
- Disruption of microtubule network by Alzheimer abnormally hyperphosphorylated tauActa Neuropathologica, 2007
- Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degenerationEuropean Journal of Neuroscience, 2007
- PKA modulates GSK‐3β‐ and cdk5‐catalyzed phosphorylation of tau in site‐ and kinase‐specific mannersFEBS Letters, 2006
- Regulation of phosphorylation of tau by cyclin‐dependent kinase 5 and glycogen synthase kinase‐3 at substrate levelFEBS Letters, 2006
- Dysregulation of Protein Phosphorylation/Dephosphorylation in Alzheimer's Disease: A Therapeutic TargetJournal of Biomedicine and Biotechnology, 2006
- Post-translational modifications of tau protein in Alzheimer’s diseaseJournal of Neural Transmission, 2004
- Promotion of Hyperphosphorylation by Frontotemporal Dementia Tau MutationsPublished by Elsevier BV ,2004
- 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
- Subcellular distribution of protein phosphatases and abnormally phosphorylated τ in the temporal cortex from Alzheimer's disease and control brainsJournal of Neural Transmission, 1998