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

Mathias Cobbaut, Rita Derua, Heike Döppler, Hua Jane Lou, Sandy Vandoninck, Peter Storz, Benjamin E. Turk, Thomas Seufferlein, Etienne Waelkens, Veerle Janssens, Johan Van Lint

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number00800
JournalScientific Reports
Volume7
Issue number1
DOIs
StatePublished - Dec 1 2017

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Protein Isoforms
Oxidative Stress
Phosphorylation
Phosphotransferases
syntide-2
Substrate Specificity
Proteomics
Protein Kinases
protein kinase D2

ASJC Scopus subject areas

  • General

Cite this

Differential regulation of PKD isoforms in oxidative stress conditions through phosphorylation of a conserved Tyr in the P+1 loop. / Cobbaut, Mathias; Derua, Rita; Döppler, Heike; Lou, Hua Jane; Vandoninck, Sandy; Storz, Peter; Turk, Benjamin E.; Seufferlein, Thomas; Waelkens, Etienne; Janssens, Veerle; Van Lint, Johan.

In: Scientific Reports, Vol. 7, No. 1, 00800, 01.12.2017.

Research output: Contribution to journalArticle

Cobbaut, M, Derua, R, Döppler, H, Lou, HJ, Vandoninck, S, Storz, P, Turk, BE, Seufferlein, T, Waelkens, E, Janssens, V & Van Lint, J 2017, 'Differential regulation of PKD isoforms in oxidative stress conditions through phosphorylation of a conserved Tyr in the P+1 loop', Scientific Reports, vol. 7, no. 1, 00800. https://doi.org/10.1038/s41598-017-00800-w
Cobbaut, Mathias ; Derua, Rita ; Döppler, Heike ; Lou, Hua Jane ; Vandoninck, Sandy ; Storz, Peter ; Turk, Benjamin E. ; Seufferlein, Thomas ; Waelkens, Etienne ; Janssens, Veerle ; Van Lint, Johan. / Differential regulation of PKD isoforms in oxidative stress conditions through phosphorylation of a conserved Tyr in the P+1 loop. In: Scientific Reports. 2017 ; Vol. 7, No. 1.
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