Identification of Regulatory Sites of Phosphorylation of the Bovine Endothelial Nitric-oxide Synthase at Serine 617 and Serine 635
Open accessAbstract
Endothelial nitric-oxide synthase (eNOS) is regulated by signaling pathways involving multiple sites of phosphorylation. The coordinated phosphorylation of eNOS at Ser(1179) and dephosphorylation at Thr(497) activates the enzyme, whereas inhibition results when Thr(497) is phosphorylated and Ser(1179) is dephosphorylated. We have identified two further phosphorylation sites, at Ser(617) and Ser(635), by phosphopeptide mapping and matrix-assisted laser desorption ionization time of flight mass spectrometry. Purified protein kinase A (PKA) phosphorylates both sites in purified eNOS, whereas purified Akt phosphorylates only Ser(617). In bovine aortic endothelial cells, bradykinin (BK), ATP, and vascular endothelial growth factor stimulate phosphorylation of both sites. BK-stimulated phosphorylation of Ser(617) is Ca(2+)-dependent and is partially inhibited by LY294002 and wortmannin, phosphatidylinositol 3-kinase inhibitors, suggesting signaling via Akt. BK-stimulated phosphorylation of Ser(635) is Ca(2+)-independent and is completely abolished by the PKA inhibitor, KT5720, suggesting signaling via PKA. Activation of PKA with isobutylmethylxanthine also causes Ser(635), but not Ser(617), phosphorylation. Mimicking phosphorylation at Ser(635) by Ser to Asp mutation results in a greater than 2-fold increase in activity of the purified protein, whereas mimicking phosphorylation at Ser(617) does not alter maximal activity but significantly increases Ca(2+)-calmodulin sensitivity. These data show that phosphorylation of both Ser(617) and Ser(635) regulates eNOS activity and contributes to the agonist-stimulated eNOS activation process.
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Thr495 phosphorylation is attributed to protein kinase C and the residue is dephosphorylated by protein phosphatase 1.
“The phosphorylation has been attributed to protein kinase C (PKC) (297, 646), and the residue is dephosphorylated by protein phosphatase 1 (PP1)”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [646]
Phosphorylation of Thr495 is a negative regulator of CaM binding to eNOS.
“Phosphorylation of Thr495 is a negative regulator of CaM binding to eNOS (297, 407, 646).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [646]
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“Phosphorylation of Ser615 has also been observed in response to bradykinin stimulation and has been associated with increased eNOS activity (Michell et al., 2002).”
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“…in regulating eNOS activity, such as increasing intracellular Ca2 level including the receptor-mediated Ca2 influx, protein phosphorylation (Michell et al., 2002), intracellular translocation (Goetz et al., 1999), and association with other proteins (e.g., heat shock protein 90,…”
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“Conversely, the phosphorylation of eNOS at Ser-617 and Ser-635 activates eNOS [68].”
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“More recently, regulation of eNOS has been described by phosphorylation at Ser(615) and Ser(633); however, there is no recognized role for AMPK in regulation of phosphorylation of these sites (32).”
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“The stimulatory phosphorylation of eNOS residues Ser-1177 and Ser-617 occur in response to flow shear stress that activates phosphatidyl-inositol 3kinase (PI3K) and its downstream serine/threonine protein kinase, Akt, which in turn phosphorylates eNOS (PI3K-Akt-eNOS pathway) [16,21,22].”
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“Numerous evidence has demonstrated that eNOS activity can be regulated by PKA-mediated phosphorylation (4, 5, 20, 21), and Ser(1179), Ser(635), and Ser(617) have been identified as target sites of PKA in bovine eNOS (in humans: Ser(1177), Ser(633), and Ser(617), respectively) (1, 33, 36).”
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A novel TRPV4-specific agonist inhibits monocyte adhesion and atherosclerosis
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“Multiple protein kinases are implicated in eNOS Ser1177 phosphorylation and subsequent activation, including Akt, AMPK, Ca2+/calmodulin-dependent protein kinase II (CaMKII), and PKA in a context-dependent manner [27, 32, 37-39].”
BackgroundProtein kinase N2 mediates flow-induced endothelial NOS activation and vascular tone regulation
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“enzyme mediating the phosphorylation of serine 633 (8, 10-12), and AKT has been described as the major protein kinase responsible for flow-induced phosphorylation of serine 1177 (6, 7).”
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“Estrogen also activate phosphatidylinositol 3-kinase/Akt pathway, leading to phosphorylation and activation of eNOS, and increased NO production [98].”
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Flt‐1, but not Flk‐1 mediates hyperpermeability through activation of the PI3‐K/Akt pathway
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“…phosphorylate endothelial nitric-oxide synthase (eNOS) resulting in eNOS activation and NO production (Dimmeler et al., 1999; Fulton et al., 1999; Michell et al., 2002), which is in agreement with our results demonstrating the activation of NOS and PKG but not of PKC andMAP kinases p38 and…”
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“Depending on the vascular origin of endothelial cells, VEGF may promote eNOS activation not only through phosphorylation of Ser1177 but also through phosphorylation of other positive regulatory sites, such as Ser635 [32, 40] and Ser617 [40), and dephosphorylation of Thr495 [37, 41] and Ser116 [39] (negative regulatory…”
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“A set of “known” AKT1 substrates have been identified and in some cases validated using multiple experimental approaches, including in vitro biochemical (18) and cell-based activity assays (19), proteomic analyses (20), aswell as phosphospecific immunoblotting of AKT1 substrates (21) from cells (22) and animals (23).”
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“Additionally, eNOS activity is regulated by phosphorylation at Ser(615), Ser(633), and Ser(114), depending on the cell type and stimulus utilized (26, 28, 29, 51, 52).”
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“The list of other phosphorylation sites identified on eNOS, which may regulate eNOS activity, is continually expanding [36, 37].”
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“In addition, phosphorylation of the Ser617 and Ser635 residues of eNOS mediated by PKA in response to bradykinin and ATP in bovine aortic endothelial cells are quantitatively different (Michell et al., 2002).”
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“Phosphorylation at serine 1179 can be catalyzed by at least five kinases (7), Akt (17, 18, 22, 26, 33, 34), protein kinase A (8, 12, 34), protein kinase G (12), AMP-activated protein kinase (15), and CaM kinase II (19).”
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“The phosphorylation of T495 of eNOS inhibits activity by promoting autoinhibition via ACEs and preventing calmodulin binding (18, 33, 41).”
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Insulin resistance does not diminish eNOS expression, phosphorylation, or binding to HSP-90
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“Additionally, it has been reported that bradykinin treatment induces Thr497 dephosphorylation and enhances Ca/CaM binding with eNOS in BAECs [43].”
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“Phosphorylation of eNOS leads to a flux of electrons through its reductase domain and thus facilitates the oxidative reaction in which L-arginine is transformed to L-citrulline and NO [48, 54-57].”
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“Ser1177 on eNOS can be phosphorylated by a variety of protein kinases, including PKB (11, 16, 18, 24, 25, 26) and PKA (3, 5, 6, 27).”
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“The 497D result confirmed what had been concluded previously that phosphorylation of this site is inhibitory (Bauer et al, 2003;Michell et al, 2002).”
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- Authors
- Michell, B. J., Harris, M. B., Chen, Z.-P., Ju, H., Venema, V. J., Blackstone, M. A., Huang, W., Venema, R. C., & Kemp, B. E.
- Affiliations
- St Vincents Institute of Medical Research (AU)
- Center for Vascular Biology Research (US)
- Augusta University (US)
- Corresponding author
- Venema, Richard C.
- Kemp, Bruce E.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2002-11
- Volume
- 277
- Issue
- 44
- Pages
- 42344-42351
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2024185487
- Cited by
- 212
- References
- 29
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2022: 1 · 2021: 7 · 2020: 4 · 2019: 5 · 2018: 4 · 2017: 8 · 2016: 9 · 2015: 5 · 2014: 13 · 2013: 7 · 2012: 15
- FWCI
- 9.39
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- American Heart Association
- National Institutes of Health
- Medical Research Council
- National Health and Medical Research Council
- 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
- Health Sciences › Medicine › Surgery › Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Keywords
- endothelial nitric oxide synthase, eNOS phosphorylation, protein kinase A, Akt, bradykinin signaling, phosphatidylinositol 3-kinase, enzyme activation, phosphopeptide mapping, bovine aortic endothelial cells
- MeSH terms
- Adenosine Triphosphate, Amino Acid Sequence, Animals, Bradykinin, Calcium, Calmodulin, Cattle, Humans, Lymphokines, Molecular Sequence Data, Phosphorylation, Proto-Oncogene Proteins, Serine, Endothelial Growth Factors, Protein Serine-Threonine Kinases, Cyclic AMP-Dependent Protein Kinases, Nitric Oxide Synthase, Intercellular Signaling Peptides and Proteins, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A, Proto-Oncogene Proteins c-akt, Nitric Oxide Synthase Type III
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