Novel screening cascade identifies MKK4 as key kinase regulating Tau phosphorylation at Ser422

Phosphorylation of Tau at serine 422 promotes Tau aggregation. The kinase that is responsible for this key phosphorylation event has so far not been identified but could be a potential drug target for Alzheimer’s disease. We describe here an assay strategy to identify this kinase. Using a combinatio...

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Bibliographic Details
Published in:Molecular and cellular biochemistry 2011-11, Vol.357 (1-2), p.199-207
Main Authors: Grueninger, Fiona, Bohrmann, Bernd, Christensen, Klaus, Graf, Martin, Roth, Doris, Czech, Christian
Format: Article
Language:English
Subjects:
Alzheimer Disease - metabolism
Alzheimer's disease
Amyloid beta-protein
Biochemistry
Biomedical and Life Sciences
Cardiology
Cell Line, Tumor
Drug Evaluation, Preclinical
High-Throughput Screening Assays
Humans
Life Sciences
MAP Kinase Kinase 4 - metabolism
Medical Biochemistry
Molecular Structure
Oncology
Phosphorylation
Phosphotransferases - antagonists & inhibitors
Phosphotransferases - genetics
Phosphotransferases - metabolism
Protein Kinase Inhibitors - chemistry
Serine - chemistry
Serine - metabolism
tau Proteins - metabolism
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Summary:Phosphorylation of Tau at serine 422 promotes Tau aggregation. The kinase that is responsible for this key phosphorylation event has so far not been identified but could be a potential drug target for Alzheimer’s disease. We describe here an assay strategy to identify this kinase. Using a combination of screening a library of 65’000 kinase inhibitors and in vitro inhibitor target profiling of the screening hits using the Ambit kinase platform, MKK4 was identified as playing a key role in Tau-S422 phosphorylation in human neuroblastoma cells.
ISSN:0300-8177
1573-4919
DOI:10.1007/s11010-011-0890-6