Kinase inhibition profiles as a tool to identify kinases for specific phosphorylation sites

Nikolaus A. Watson, Tyrell N. Cartwright, Conor Lawless, Marcos Cámara-Donoso, Onur Sen, Kosuke Sako, Toru Hirota, Hiroshi Kimura and Jonathan M. G. Higgins ()
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Nikolaus A. Watson: Newcastle University
Tyrell N. Cartwright: Newcastle University
Conor Lawless: Newcastle University
Marcos Cámara-Donoso: Newcastle University
Onur Sen: Newcastle University
Kosuke Sako: The Cancer Institute, Japanese Foundation for Cancer Research
Toru Hirota: The Cancer Institute, Japanese Foundation for Cancer Research
Hiroshi Kimura: Cell Biology Center, Institute of Innovative Research, Tokyo Institute of Technology
Jonathan M. G. Higgins: Newcastle University

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract There are thousands of known cellular phosphorylation sites, but the paucity of ways to identify kinases for particular phosphorylation events remains a major roadblock for understanding kinase signaling. To address this, we here develop a generally applicable method that exploits the large number of kinase inhibitors that have been profiled on near-kinome-wide panels of protein kinases. The inhibition profile for each kinase provides a fingerprint that allows identification of unknown kinases acting on target phosphosites in cell extracts. We validate the method on diverse known kinase-phosphosite pairs, including histone kinases, EGFR autophosphorylation, and Integrin β1 phosphorylation by Src-family kinases. We also use our approach to identify the previously unknown kinases responsible for phosphorylation of INCENP at a site within a commonly phosphorylated motif in mitosis (a non-canonical target of Cyclin B-Cdk1), and of BCL9L at S915 (PKA). We show that the method has clear advantages over in silico and genetic screening.

Date: 2020
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DOI: 10.1038/s41467-020-15428-0

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