Protein kinase D activity controls endothelial nitric oxide synthesis

Aicart-Ramos, Clara; Sánchez-Ruiloba, Lucía; Gómez-Parrizas, Mónica; Zaragoza, Carlos; Iglesias, Teresa; Rodríguez-Crespo, Ignacio

doi:10.1242/jcs.148601

Cited by 12Nitric Oxide and Endothelin EffectsProtein Kinase Regulation and GTPase SignalingAngiogenesis and VEGF in Cancer

Protein kinase D activity controls endothelial nitric oxide synthesis

Aicart-Ramos, Clara, Sánchez-Ruiloba, Lucía, Gómez-Parrizas, Mónica, Zaragoza, Carlos, Iglesias, Teresa, Rodríguez-Crespo, Ignacio·2014·Journal of Cell Science

DOI 10.1242/jcs.148601

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Abstract

Vascular endothelial growth factor (VEGF) regulates key functions of the endothelium such as angiogenesis or vessel repair in processes involving endothelial Nitric Oxide Synthase (eNOS) activation. On the other hand, one of the effector kinases that become activated in endothelial cells upon VEGF treatment is Protein Kinase D (PKD). We show herein that PKD uses eNOS as substrate leading to its activation with the concomitant increased ·NO synthesis. Using mass spectrometry, we show that the purified active kinase specifically phosphorylates recombinant eNOS on Ser1179. Treatment of endothelial cells with VEGF or PDBu activates PKD and increases eNOS Ser1179 phosphorylation. In addition, pharmacological inhibition of PKD and gene silencing of both PKD1 and PKD2 abrogate VEGF signaling, resulting in a clear diminished migration of endothelial cells in a wound-healing assay. Finally, inhibition of PKD in mice results in an almost complete disappearance of the VEGF-induced vasodilatation as monitored through the determination of the diameter of the carotid artery. Hence, our data indicate that PKD is a novel regulatory kinase of eNOS in endothelial cells whose activity orchestrates mammalian vascular tone.

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Hydrogen peroxide was able to regulate the phosphorylation of 512 and 523 tyrosine residues of protein kinase C.
“For example, hydrogen peroxide was able to regulate the phosphorylation of 512 and 523 tyrosine residues of protein kinase C (Aicart-Ramos et al. 2014).”
From Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging (2023) · cites this paper as Aicart-Ramos et al. 2014

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Authors: Aicart-Ramos, C., Sánchez-Ruiloba, L., Gómez-Parrizas, M., Zaragoza, C., Iglesias, T., & Rodríguez-Crespo, I.
Affiliations: Universidad Complutense de Madrid (ES)
Universidad Francisco de Vitoria (ES)
Consejo Superior de Investigaciones Científicas (ES)
Corresponding author: Iglesias, Teresa
ORCID: Aicart-Ramos, Clara
Zaragoza, Carlos
Iglesias, Teresa
Venue: Journal of Cell Science
Publisher: The Company of Biologists
Published: 2014-01-01
Volume: 127
Issue: Pt 15
Pages: 3360-72
ISSN: 0021-9533 (ISSN-L)
1477-9137
DOI: 10.1242/jcs.148601
OpenAlex: W2163215766
Cited by: 12
References: 76
Citations by year: 2023: 1 · 2021: 2 · 2020: 2 · 2017: 2 · 2016: 3 · 2015: 1 · 2014: 1
FWCI: 1.55
Type: journal article
Language: en
Update notices: correction (2018-06-04)
expression_of_concern (2017-08-30)
Open access: closed
Licence: www.biologists.com/user-licence-1-1 (vor, 396 d)
Locations: Journal of Cell Science (publishedVersion)
PubMed (publishedVersion)
DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
HighWire Press Open Archive (submittedVersion)
Topics: Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Keywords: protein kinase D, endothelial nitric oxide synthase, VEGF signaling, endothelial cells, nitric oxide production, PKD1, PKD2, endothelial cell migration, wound healing, vasodilation, vascular tone, phorbol 12,13-dibutyrate
MeSH terms: Animals, Carbazoles, Carotid Arteries, Cell Movement, Chlorocebus aethiops, Epithelial Cells, Humans, Mice, Inbred Strains, Nitric Oxide, Phosphorylation, Protein Kinase C, Serine, Vasodilation, Signal Transduction, COS Cells, RNA, Small Interfering, Vascular Endothelial Growth Factor A, Angiogenesis Inducing Agents, Mice, Nitric Oxide Synthase Type III, HEK293 Cells

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Protein kinase D activity controls endothelial nitric oxide synthesis

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