Abstract
Tau is a microtubule-associated protein that is abnormally hyperphosphorylated in the filamentous lesions that define a number of neurodegenerative diseases collectively referred to as tauopathies. We previously showed that stress-activated protein (SAP) kinases phosphorylate tau protein at many of the hyperphosphorylated sites in vitro. Here we have developed a system to study the effects of five SAP kinases (SAPK1c/JNK1, SAPK2a/p38alpha, SAPK2b/p38beta, SAPK3/p38gamma and SAPK4/p38delta) on tau phosphorylation in intact cells. All kinases phosphorylated tau, albeit at different efficiencies. Tau was a good substrate for SAPK3/p38gamma and SAPK4/p38delta, a reasonable substrate for SAPK2b/p38beta and a relatively poor substrate for SAPK2a/p38alpha and SAPK1c/JNK1. These findings indicate that the aberrant activation of SAP kinases, especially SAPK3/p38gamma and SAPK4/p38delta, could play an important role in the abnormal hyperphosphorylation of tau that is an invariant feature of the tauopathies.
MeSH terms
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Animals
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COS Cells
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Immunoblotting
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Kidney / cytology
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Kidney / metabolism
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MAP Kinase Kinase 6
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Microtubule-Associated Proteins / genetics
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Microtubule-Associated Proteins / metabolism*
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Mitogen-Activated Protein Kinase 11
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Mitogen-Activated Protein Kinase 12
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Mitogen-Activated Protein Kinase 13
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism*
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Phosphorylation
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Substrate Specificity
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Transfection
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p38 Mitogen-Activated Protein Kinases
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tau Proteins / genetics
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tau Proteins / metabolism
Substances
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Microtubule-Associated Proteins
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Protein Isoforms
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tau Proteins
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Mitogen-Activated Protein Kinase 12
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Mitogen-Activated Protein Kinase 13
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 11
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Mitogen-Activated Protein Kinase 8
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Mitogen-Activated Protein Kinases
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 6
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Mitogen-Activated Protein Kinase Kinases