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

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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.

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Acknowledgments

We thank Alexandra Kronenberger, Annie Girardeau, Markus Haenggi and Fabienne Goepfert and Jürg Messer for excellent technical assistance and Sannah Jensen-Zoffmann for the images of LAN-5 cells.

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Authors and Affiliations

  1. CNS Discovery and Translation Pharma Research and Exploratory Development, F. Hoffmann-La Roche AG, Basel, Switzerland

    Fiona Grueninger, Bernd Bohrmann & Christian Czech

  2. Discovery Technologies Pharma Research and Exploratory Development, F. Hoffmann-La Roche AG, Basel, Switzerland

    Klaus Christensen, Martin Graf & Doris Roth

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  1. Fiona Grueninger
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  2. Bernd Bohrmann
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Correspondence to Fiona Grueninger.

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Grueninger, F., Bohrmann, B., Christensen, K. et al. Novel screening cascade identifies MKK4 as key kinase regulating Tau phosphorylation at Ser422. Mol Cell Biochem 357, 199–207 (2011). https://doi.org/10.1007/s11010-011-0890-6

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  • DOI: https://doi.org/10.1007/s11010-011-0890-6

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