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Updated: Jun 1, 2026

Identification of Kinase-substrate Pairs Using High Throughput Screening
11:13

Identification of Kinase-substrate Pairs Using High Throughput Screening

Published on: August 29, 2015

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

Fiona Grueninger1, Bernd Bohrmann, Klaus Christensen

  • 1CNS Discovery and Translation Pharma Research and Exploratory Development, F. Hoffmann-La Roche AG, Basel, Switzerland. fiona.grueninger@roche.com

Molecular and Cellular Biochemistry
|June 4, 2011
PubMed

Insights

Identifying the kinase responsible for Tau phosphorylation at serine 422 is crucial for Alzheimer's disease drug development. Researchers screened kinase inhibitors and identified MKK4 as a key player in Tau-S422 phosphorylation.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Pharmacology

Background:

  • Tau protein phosphorylation at serine 422 (Tau-S422) is a critical event promoting Tau aggregation.
  • Aberrant Tau aggregation is a hallmark of Alzheimer's disease (AD).
  • The specific kinase mediating Tau-S422 phosphorylation remains unidentified, representing a potential therapeutic target for AD.

Purpose of the Study:

  • To develop an assay strategy for identifying the kinase responsible for Tau-S422 phosphorylation.
  • To identify novel drug targets for Alzheimer's disease by pinpointing the key kinase involved in Tau pathology.

Main Methods:

  • A large-scale screening of approximately 65,000 kinase inhibitors was performed.
  • In vitro inhibitor target profiling of identified hits was conducted using the Ambit kinase platform.
  • Assays were performed using human neuroblastoma cells to assess Tau-S422 phosphorylation.

Main Results:

  • The screening and profiling approach successfully identified a key kinase involved in Tau-S422 phosphorylation.
  • Mitogen-activated protein kinase kinase 4 (MKK4) was identified as playing a significant role in Tau-S422 phosphorylation.
  • This finding implicates MKK4 as a potential therapeutic target for Alzheimer's disease.

Conclusions:

  • MKK4 is identified as a crucial kinase in the phosphorylation of Tau at serine 422.
  • The developed assay strategy is effective for identifying kinases involved in pathological protein modifications.
  • Targeting MKK4 presents a promising therapeutic avenue for Alzheimer's disease treatment.

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