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Sci Rep. 2017 Apr 20;7(1):887. doi: 10.1038/s41598-017-00800-w.

Differential regulation of PKD isoforms in oxidative stress conditions through phosphorylation of a conserved Tyr in the P+1 loop.

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Department of Cellular and Molecular Medicine, Faculty of Medicine, KU Leuven, Leuven, Belgium.
Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium.
Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, USA.
Department of Internal Medicine I, University of Ulm, Ulm, Germany.
Department of Cellular and Molecular Medicine, Faculty of Medicine, KU Leuven, Leuven, Belgium.
Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium.


Protein kinases are essential molecules in life and their crucial function requires tight regulation. Many kinases are regulated via phosphorylation within their activation loop. This loop is embedded in the activation segment, which additionally contains the Mg2+ binding loop and a P + 1 loop that is important in substrate binding. In this report, we identify Abl-mediated phosphorylation of a highly conserved Tyr residue in the P + 1 loop of protein kinase D2 (PKD2) during oxidative stress. Remarkably, we observed that the three human PKD isoforms display very different degrees of P + 1 loop Tyr phosphorylation and we identify one of the molecular determinants for this divergence. This is paralleled by a different activation mechanism of PKD1 and PKD2 during oxidative stress. Tyr phosphorylation in the P + 1 loop of PKD2 increases turnover for Syntide-2, while substrate specificity and the role of PKD2 in NF-κB signaling remain unaffected. Importantly, Tyr to Phe substitution renders the kinase inactive, jeopardizing its use as a non-phosphorylatable mutant. Since large-scale proteomics studies identified P + 1 loop Tyr phosphorylation in more than 70 Ser/Thr kinases in multiple conditions, our results do not only demonstrate differential regulation/function of PKD isoforms under oxidative stress, but also have implications for kinase regulation in general.

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