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Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases
M Goedert1, M Hasegawa, R Jakes
1MRC Laboratory of Molecular Biology, Cambridge, UK.
Abstract:
The paired helical filament, which comprises the major fibrous element of the neurofibrillary lesions of Alzheimer's disease, is composed of hyperphosphorylated microtubule-associated protein tau. Many of the hyperphosphorylated sites in tau are serine/threonine-prolines. Here we show that the stress-activated protein (SAP) kinases SAPK1gamma (also called JNK1), SAPK2a (also called p38, RK, CSBPs, Mpk2 and Mxi2), SAPK2b (also called p38beta), SAPK3 (also called ERK6 and p38gamma) and SAPK4 phosphorylate tau at many serine/threonine-prolines, as assessed by the generation of the epitopes of phosphorylation-dependent anti-tau antibodies. Based on initial rates of phosphorylation, tau was found to be a good substrate for SAPK4 and SAPK3, a reasonable substrate for SAPK2b and a relatively poor substrate for SAPK2a and SAPK1gamma. Phosphorylation of tau by SAPK3 and SAPK4 resulted in a marked reduction in its ability to promote microtubule assembly. These findings double the number of candidate protein kinases for the hyperphosphorylation of tau in Alzheimer's disease and other neurodegenerative disorders.
Insights
Stress-activated protein kinases SAPK3 and SAPK4 phosphorylate tau protein, a key component in Alzheimer's disease neurofibrillary lesions. This phosphorylation reduces tau's ability to assemble microtubules, implicating these kinases in neurodegenerative disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Paired helical filaments in Alzheimer's disease are primarily composed of hyperphosphorylated tau protein.
- Many hyperphosphorylation sites on tau occur at serine/threonine-proline residues.
Purpose of the Study:
- To investigate the role of stress-activated protein (SAP) kinases in tau hyperphosphorylation.
- To identify specific SAP kinases that phosphorylate tau at serine/threonine-proline sites.
Main Methods:
- Assessing tau phosphorylation by SAPK1gamma, SAPK2a, SAPK2b, SAPK3, and SAPK4 using phosphorylation-dependent anti-tau antibodies.
- Measuring initial rates of tau phosphorylation by different SAP kinases.
- Evaluating the impact of SAP kinase-mediated tau phosphorylation on microtubule assembly.
Main Results:
- SAPK1gamma, SAPK2a, SAPK2b, SAPK3, and SAPK4 were shown to phosphorylate tau at multiple serine/threonine-proline sites.
- Tau was identified as a good substrate for SAPK4 and SAPK3, a reasonable substrate for SAPK2b, and a poor substrate for SAPK2a and SAPK1gamma.
- Phosphorylation of tau by SAPK3 and SAPK4 significantly impaired its microtubule assembly promoting ability.
Conclusions:
- The study identifies SAPK3 and SAPK4 as significant kinases involved in tau hyperphosphorylation.
- These findings expand the list of candidate protein kinases responsible for tau hyperphosphorylation in Alzheimer's disease and other neurodegenerative conditions.