title: Novel screening cascade identifies MKK4 as key kinase regulating Tau phosphorylation at Ser422.
abstract: 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.
authors.affiliation: CNS Discovery and Translation Pharma Research and Exploratory Development, F. Hoffmann-La Roche AG, Basel, Switzerland. fiona.grueninger@roche.com
authors.forename: Fiona
authors.initials: F
authors.lastname: Grueninger
authors.forename: Bernd
authors.initials: B
authors.lastname: Bohrmann
authors.forename: Klaus
authors.initials: K
authors.lastname: Christensen
authors.forename: Martin
authors.initials: M
authors.lastname: Graf
authors.forename: Doris
authors.initials: D
authors.lastname: Roth
authors.forename: Christian
authors.initials: C
authors.lastname: Czech
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D015394:Molecular Structure; D010766:Phosphorylation; D010770:Phosphotransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D012694:Serine / Q000737:chemistry / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D016875:tau Proteins; D012694:Serine; D010770:Phosphotransferases; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human