Phosphorylation of microtubule-associated protein tau by stress-activated protein kinases in intact cells.
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.
Buée-Scherrer
Valérie
V
Medical Research Council Laboratory of Molecular Biology, Hills Road, CB2 2QH, Cambridge, UK.
Goedert
Michel
M
D000818:Animals; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D048669:MAP Kinase Kinase 6; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D048290:Mitogen-Activated Protein Kinase 11; D048291:Mitogen-Activated Protein Kinase 12; D048292:Mitogen-Activated Protein Kinase 13; D048055:Mitogen-Activated Protein Kinase 8; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
D008869:Microtubule-Associated Proteins; D020033:Protein Isoforms; D016875:tau Proteins; D048291:Mitogen-Activated Protein Kinase 12; D048292:Mitogen-Activated Protein Kinase 13; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048290:Mitogen-Activated Protein Kinase 11; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; D020929:Mitogen-Activated Protein Kinase Kinases