Regulation of endothelium-derived nitric oxide production by the protein kinase Akt.
David Fulton,Jean-Philippe Gratton,Timothy J. McCabe,Jason Fontana,Yasushl Fujio,Kenneth Walsh,Thomas F. Franke,Andreas Papapetropoulos,William C. Sessa +8 more
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It is shown that the serine/threonine protein kinase Akt (protein kinase B) can directly phosphorylate eNOS on serine 1179 and activate the enzyme, leading to NO production, whereas mutant eN OS (S1179A) is resistant to phosphorylation and activation by Akt.Abstract:
Endothelial nitric oxide synthase (eNOS) is the nitric oxide synthase isoform responsible for maintaining systemic blood pressure, vascular remodelling and angiogenesis. eNOS is phosphorylated in response to various forms of cellular stimulation, but the role of phosphorylation in the regulation of nitric oxide (NO) production and the kinase(s) responsible are not known. Here we show that the serine/threonine protein kinase Akt (protein kinase B) can directly phosphorylate eNOS on serine 1179 and activate the enzyme, leading to NO production, whereas mutant eNOS (S1179A) is resistant to phosphorylation and activation by Akt. Moreover, using adenovirus-mediated gene transfer, activated Akt increases basal NO release from endothelial cells, and activation-deficient Akt attenuates NO production stimulated by vascular endothelial growth factor. Thus, eNOS is a newly described Akt substrate linking signal transduction by Akt to the release of the gaseous second messenger NO.read more
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AKT/PKB signaling: navigating downstream.
TL;DR: Those Akt substrates that are most likely to contribute to the diverse cellular roles of Akt, which include cell survival, growth, proliferation, angiogenesis, metabolism, and migration are discussed.
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Cellular survival: a play in three Akts
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Nitric oxide synthases: structure, function and inhibition
TL;DR: This review concentrates on advances in nitric oxide synthase (NOS) structure, function and inhibition made in the last seven years, during which time substantial advances have been made in the authors' understanding of this enzyme family.
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Nitric oxide synthases: regulation and function.
TL;DR: Nitric oxide (NO), the smallest signalling molecule known, is produced by three isoforms of NO synthase (NOS), which can be expressed in many cell types in response to lipopolysaccharide, cytokines, or other agents.
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VEGF receptor signalling - in control of vascular function.
TL;DR: Recent insights have shed light onto VEGFR signal transduction and the interplay between different V EGFRs and VEGF co-receptors in development, adult physiology and disease.
References
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Regulation of Cell Death Protease Caspase-9 by Phosphorylation
Michael H. Cardone,Natalie Roy,Henning R. Stennicke,Guy S. Salvesen,Thomas F. Franke,Eric J. Stanbridge,Steven M. Frisch,John C. Reed +7 more
TL;DR: In this paper, the kinase Akt and p21-Ras, an Akt activator, induced phosphorylation of pro-caspase-9 (pro-Casp9) in cells.
Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15 (23):6541-6551
TL;DR: It is demonstrated that activation of PKBalpha by insulin or insulin‐like growth factor‐1 (IGF‐1) results from phosphorylation of both Thr308 and Ser473, that phosphorylate of both residues is critical to generate a high level of P KBalpha activity and that the phosphorylated of Thr308 in vivo is not dependent on phosphorylations of Ser473 or vice versa.
Journal ArticleDOI
Mechanism of activation of protein kinase B by insulin and IGF-1.
Dario R. Alessi,Mirjana Andjelkovic,Barry Caudwell,Peter Cron,Nick Morrice,Philip Cohen,Brian A. Hemmings +6 more
TL;DR: In this paper, the activation of PKBalpha was accompanied by its phosphorylation at Thr308 and Ser473 and, like activation, likeactivation was prevented by the phosphatidylinositol 3-kinase inhibitor wortmannin.
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Hypertension in mice lacking the gene for endothelial nitric oxide synthase
Paul L. Huang,Zhihong Huang,Hiroshi Mashimo,Kenneth D. Bloch,Michael A. Moskowitz,John A. Bevan,Mark C. Fishman +6 more
TL;DR: Responses to NOS blockade in the mutant mice suggest that non-endothelial isoforms of NOS may be involved in maintaining blood pressure, and eNOS mediates basal vasodilation.
Journal ArticleDOI
Vascular Endothelial Growth Factor Regulates Endothelial Cell Survival through the Phosphatidylinositol 3′-Kinase/Akt Signal Transduction Pathway REQUIREMENT FOR Flk-1/KDR ACTIVATION
Hans-Peter Gerber,Amy McMurtrey,Joe Kowalski,Minhong Yan,Bruce Keyt,Vishva M. Dixit,Napoleone Ferrara +6 more
TL;DR: The Flk-1/KDR receptor and the PI3-kinase/Akt signal transduction pathway are identified as crucial elements in the processes leading to endothelial cell survival induced by VEGF, and inhibition of apoptosis may represent a major aspect of the regulatory activity of V EGF on the vascular endothelium.