Differential regulation of PKD isoforms in oxidative stress conditions through phosphorylation of a conserved Tyr in the P+1 loop
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 l...
Guardado en:
| Autores principales: | , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2017
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/896f3c5473c54c7cb5cb393a684923cf |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:896f3c5473c54c7cb5cb393a684923cf |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:896f3c5473c54c7cb5cb393a684923cf2021-12-02T12:30:53ZDifferential regulation of PKD isoforms in oxidative stress conditions through phosphorylation of a conserved Tyr in the P+1 loop10.1038/s41598-017-00800-w2045-2322https://doaj.org/article/896f3c5473c54c7cb5cb393a684923cf2017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00800-whttps://doaj.org/toc/2045-2322Abstract 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.Mathias CobbautRita DeruaHeike DöpplerHua Jane LouSandy VandoninckPeter StorzBenjamin E. TurkThomas SeufferleinEtienne WaelkensVeerle JanssensJohan Van LintNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-17 (2017) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q 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 Differential regulation of PKD isoforms in oxidative stress conditions through phosphorylation of a conserved Tyr in the P+1 loop |
| description |
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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Mathias Cobbaut |
| title |
Differential regulation of PKD isoforms in oxidative stress conditions through phosphorylation of a conserved Tyr in the P+1 loop |
| title_short |
Differential regulation of PKD isoforms in oxidative stress conditions through phosphorylation of a conserved Tyr in the P+1 loop |
| title_full |
Differential regulation of PKD isoforms in oxidative stress conditions through phosphorylation of a conserved Tyr in the P+1 loop |
| title_fullStr |
Differential regulation of PKD isoforms in oxidative stress conditions through phosphorylation of a conserved Tyr in the P+1 loop |
| title_full_unstemmed |
Differential regulation of PKD isoforms in oxidative stress conditions through phosphorylation of a conserved Tyr in the P+1 loop |
| title_sort |
differential regulation of pkd isoforms in oxidative stress conditions through phosphorylation of a conserved tyr in the p+1 loop |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/896f3c5473c54c7cb5cb393a684923cf |
| work_keys_str_mv |
AT mathiascobbaut differentialregulationofpkdisoformsinoxidativestressconditionsthroughphosphorylationofaconservedtyrinthep1loop AT ritaderua differentialregulationofpkdisoformsinoxidativestressconditionsthroughphosphorylationofaconservedtyrinthep1loop AT heikedoppler differentialregulationofpkdisoformsinoxidativestressconditionsthroughphosphorylationofaconservedtyrinthep1loop AT huajanelou differentialregulationofpkdisoformsinoxidativestressconditionsthroughphosphorylationofaconservedtyrinthep1loop AT sandyvandoninck differentialregulationofpkdisoformsinoxidativestressconditionsthroughphosphorylationofaconservedtyrinthep1loop AT peterstorz differentialregulationofpkdisoformsinoxidativestressconditionsthroughphosphorylationofaconservedtyrinthep1loop AT benjamineturk differentialregulationofpkdisoformsinoxidativestressconditionsthroughphosphorylationofaconservedtyrinthep1loop AT thomasseufferlein differentialregulationofpkdisoformsinoxidativestressconditionsthroughphosphorylationofaconservedtyrinthep1loop AT etiennewaelkens differentialregulationofpkdisoformsinoxidativestressconditionsthroughphosphorylationofaconservedtyrinthep1loop AT veerlejanssens differentialregulationofpkdisoformsinoxidativestressconditionsthroughphosphorylationofaconservedtyrinthep1loop AT johanvanlint differentialregulationofpkdisoformsinoxidativestressconditionsthroughphosphorylationofaconservedtyrinthep1loop |
| _version_ |
1718394290310217728 |