Ser1179
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Home > Phosphorylation Site Page: > Ser1179  -  eNOS (cow)

Site Information
TSRIRtQsFsLQERH   SwissProt Entrez-Gene
Blast this site against: NCBI  SwissProt  PDB 
Site Group ID: 447884

In vivo Characterization
Methods used to characterize site in vivo:
2D analysis ( 55 ) , [32P] bio-synthetic labeling ( 40 , 52 , 55 , 56 ) , immunoprecipitation ( 2 ) , mass spectrometry ( 55 ) , mutation of modification site ( 1 , 5 , 9 , 20 , 23 , 25 , 35 , 38 , 40 , 46 , 47 , 53 , 56 , 57 ) , peptide sequencing ( 55 ) , phospho-antibody ( 2 , 3 , 4 , 6 , 7 , 9 , 10 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 47 , 48 , 49 , 50 , 51 , 53 , 56 , 57 ) , phosphoamino acid analysis ( 55 ) , phosphopeptide mapping ( 50 , 52 , 55 ) , western blotting ( 2 , 3 , 4 , 6 , 7 , 9 , 10 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 29 , 30 , 32 , 34 , 36 , 37 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 48 , 51 , 56 , 57 )
Disease tissue studied:
cervical cancer ( 20 ) , cervical adenocarcinoma ( 20 ) , lung cancer ( 20 )
Relevant cell line - cell type - tissue:
293 (epithelial) ( 5 , 12 , 17 , 26 , 35 ) , 3T3-L1 (fibroblast) ( 20 ) , A549 (pulmonary) ( 20 ) , aorta ( 22 ) , BAEC (endothelial) ( 3 , 4 , 6 , 7 , 9 , 10 , 12 , 13 , 14 , 15 , 16 , 17 , 19 , 20 , 23 , 24 , 25 , 29 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 42 , 45 , 46 , 48 , 49 , 50 , 51 , 53 ) , BAE ( 18 , 44 , 47 ) , BLMVEC (endothelial) ( 32 ) , carotid artery ( 46 ) , COS (fibroblast) ( 23 , 25 , 35 , 38 , 40 , 47 , 53 , 56 , 57 ) , CPAE (endothelial) ( 33 ) , E.coli (bacterial) ( 1 ) , endothelial-aorta ( 21 , 26 , 27 , 28 , 30 , 31 , 41 , 43 , 52 , 55 ) , HAEC (endothelial) ( 14 ) , HeLa S3 (cervical) ( 20 ) , HUVEC (endothelial) ( 25 ) , PPAEC (endothelial) ( 2 ) , retina ( 20 ) , vascular smooth muscle cell ('muscle, smooth') ( 20 )

Upstream Regulation
Regulatory protein:
Akt1 (human) ( 22 , 25 , 56 ) , AMPKA1 (human) ( 22 ) , DHFRL1 (human) ( 10 ) , eNOS (cow) ( 23 ) , GCH1 (human) ( 10 ) , MKK6 (human) ( 25 ) , P38A (human) ( 25 ) , PDK1 (human) ( 22 ) , PKCZ (human) ( 9 , 20 ) , PPP2CA (human) ( 17 ) , PPP2R5D (human) ( 4 ) , PTEN (human) ( 57 ) , RAC1 (human) ( 13 )
Putative in vivo kinases:
Akt1 (human) ( 39 , 47 , 55 , 56 ) , AMPKA1 (human) ( 44 ) , PKACA (cow) ( 29 ) , PKCD (human) ( 15 )
Kinases, in vitro:
Akt1 (human) ( 11 , 37 , 43 , 47 , 55 , 56 )
Phosphatases, in vitro:
PPP2CA (human) ( 40 , 50 )
Treatments:
17-beta-estradiol ( 2 ) , 20-HETE ( 16 ) , 5-HT ( 44 ) , A23187 ( 6 , 15 , 33 , 41 , 44 ) , angiopoietin-1 ( 3 ) , angiotensin ( 44 ) , anti-VEGF ( 34 ) , aphidicolin ( 4 ) , aPL ( 7 ) , apoA-I ( 31 ) , arcyriarubin_A ( 20 ) , atenolol ( 13 ) , ATP ( 38 ) , BADGE ( 34 ) , BAPTA-AM ( 6 , 15 , 37 , 53 ) , bisindolylmaleimide ( 6 ) , black_tea_polyphenols ( 25 ) , BN52021 ( 41 ) , bradykinin ( 51 , 53 ) , butoxamine ( 13 ) , Ca(2+) ( 33 ) , calphostin_C ( 36 , 45 ) , calyculin_A ( 23 , 40 , 50 ) , cAMP_analog ( 42 , 48 ) , cholest-4-en-3-one ( 29 ) , ciclosporin ( 29 , 40 , 45 ) , colforsin ( 29 , 50 ) , compound_C ( 12 ) , CV3988 ( 41 ) , DDMS ( 16 ) , dexamethasone ( 19 ) , DMSO ( 15 ) , EGTA ( 15 ) , faslodex ( 25 ) , FCCP ( 33 ) , fluid_shear_stress ( 29 , 42 , 48 , 52 ) , geldanamycin ( 26 , 37 ) , genistein ( 28 , 32 ) , GF109203X ( 15 , 41 ) , ghrelin ( 14 ) , Go_6983 ( 20 ) , GW_9662 ( 19 ) , H-89 ( 20 , 42 , 48 ) , H2O2 ( 12 , 39 ) , HDL ( 31 ) , hyperglycemia ( 49 ) , IBMX ( 50 ) , IgG ( 7 ) , insulin ( 6 , 14 , 19 , 37 , 52 ) , ionomycin ( 23 , 35 ) , KT5823 ( 20 ) , L-NAME ( 41 ) , lactacystin ( 17 ) , LAU8080 ( 41 ) , lovastatin ( 30 ) , low_Ca(2+) ( 41 ) , LY294002 ( 12 , 15 , 22 , 30 , 41 , 42 , 51 ) , metformin ( 22 ) , MG132 ( 17 ) , mifepristone ( 19 ) , mPKI ( 42 ) , nebivolol ( 24 ) , okadaic_acid ( 4 , 12 , 17 , 40 , 50 ) , ONOO(-) ( 20 , 44 ) , PAF ( 41 ) , PD98059 ( 12 , 14 , 19 , 39 , 41 , 53 ) , phorbol_ester ( 15 , 35 , 50 ) , PKC-zeta_inhibitor ( 20 ) , PP1 ( 39 ) , PP2 ( 13 ) , prasterone ( 19 ) , pravastatin ( 30 ) , PTX ( 53 ) , quercetin ( 18 ) , racepinefrine ( 13 ) , radicicol ( 26 ) , Ro31-8220 ( 41 ) , rottlerin ( 6 , 15 ) , SB203347 ( 41 ) , SB203580 ( 41 ) , siRNA ( 21 ) , sphingosine_1-phosphate ( 21 , 36 , 43 , 53 ) , SR59230A ( 13 ) , thapsigargin ( 6 ) , thrombin ( 15 ) , TNF ( 52 ) , troglitazone ( 34 ) , U0126 ( 13 ) , U73122 ( 41 ) , U73343 ( 41 ) , vanadate ( 32 ) , VEGF ( 3 , 6 , 7 , 10 , 16 , 24 , 35 , 36 , 37 , 38 , 41 , 42 , 43 , 45 , 47 , 48 , 51 ) , W-7 ( 41 ) , wortmannin ( 12 , 13 , 14 , 19 , 22 , 30 , 32 , 39 , 41 , 42 , 43 , 48 , 49 , 51 , 56 ) , YM-254890 ( 15 )

Downstream Regulation
Effects of modification on eNOS:
acetylation ( 8 ) , activity, induced ( 5 ) , enzymatic activity, induced ( 1 , 11 , 23 , 28 , 35 , 38 , 40 , 46 , 50 , 53 , 54 , 55 , 56 ) , molecular association, regulation ( 2 , 35 ) , phosphorylation ( 38 ) , protein conformation ( 1 )
Effects of modification on biological processes:
cell motility, altered ( 46 )
Induce interaction with:
Calmodulin (cow) ( 2 ) , HSP90A (human) ( 35 )

References 

1

Haque MM, Ray SS, Stuehr DJ (2016) Phosphorylation Controls Endothelial Nitric-oxide Synthase by Regulating Its Conformational Dynamics. J Biol Chem 291, 23047-23057
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2

Tran QK, et al. (2016) Estrogen Enhances Linkage in the Vascular Endothelial Calmodulin Network via a Feedforward Mechanism at the G Protein-coupled Estrogen Receptor 1. J Biol Chem 291, 10805-23
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3

Chidiac R, et al. (2016) Comparative Phosphoproteomics Analysis of VEGF and Angiopoietin-1 Signaling Reveals ZO-1 as a Critical Regulator of Endothelial Cell Proliferation. Mol Cell Proteomics 15, 1511-25
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4

Park JH, et al. (2015) B56δ subunit of protein phosphatase 2A decreases phosphorylation of endothelial nitric oxide synthase at serine 116: Mechanism underlying aphidicolin-stimulated NO production. Nitric Oxide 50, 46-51
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5

Peng H, et al. (2015) Serine 1179 Phosphorylation of Endothelial Nitric Oxide Synthase Increases Superoxide Generation and Alters Cofactor Regulation. PLoS One 10, e0142854
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6

Haines RJ, Corbin KD, Pendleton LC, Eichler DC (2012) Protein Kinase Cα Phosphorylates a Novel Argininosuccinate Synthase Site at Serine 328 during Calcium-dependent Stimulation of Endothelial Nitric-oxide Synthase in Vascular Endothelial Cells. J Biol Chem 287, 26168-76
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7

Ramesh S, et al. (2011) Antiphospholipid antibodies promote leukocyte-endothelial cell adhesion and thrombosis in mice by antagonizing eNOS via β2GPI and apoER2. J Clin Invest 121, 120-31
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8

Chen Z, et al. (2010) Shear stress, SIRT1, and vascular homeostasis. Proc Natl Acad Sci U S A 107, 10268-73
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9

Oubaha M, Gratton JP (2009) Phosphorylation of endothelial nitric oxide synthase by atypical PKC zeta contributes to angiopoietin-1-dependent inhibition of VEGF-induced endothelial permeability in vitro. Blood 114, 3343-51
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10

Sugiyama T, Levy BD, Michel T (2009) Tetrahydrobiopterin recycling, a key determinant of endothelial nitric-oxide synthase-dependent signaling pathways in cultured vascular endothelial cells. J Biol Chem 284, 12691-700
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11

Tran QK, et al. (2009) Effects of combined phosphorylation at Ser-617 and Ser-1179 in endothelial nitric-oxide synthase on EC50(Ca2+) values for calmodulin binding and enzyme activation. J Biol Chem 284, 11892-9
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12

Hu Z, Chen J, Wei Q, Xia Y (2008) Bidirectional actions of hydrogen peroxide on endothelial nitric-oxide synthase phosphorylation and function: co-commitment and interplay of Akt and AMPK. J Biol Chem 283, 25256-63
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13

Kou R, Michel T (2007) Epinephrine regulation of the endothelial nitric-oxide synthase: roles of RAC1 and beta3-adrenergic receptors in endothelial NO signaling. J Biol Chem 282, 32719-29
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14

Iantorno M, et al. (2007) Ghrelin has novel vascular actions that mimic PI 3-kinase-dependent actions of insulin to stimulate production of NO from endothelial cells. Am J Physiol Endocrinol Metab 292, E756-64
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15

Motley ED, et al. (2007) Mechanism of endothelial nitric oxide synthase phosphorylation and activation by thrombin. Hypertension 49, 577-83
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16

Chen Y, et al. (2006) Mechanisms of activation of eNOS by 20-HETE and VEGF in bovine pulmonary artery endothelial cells. Am J Physiol Lung Cell Mol Physiol 291, L378-85
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17

Wei Q, Xia Y (2006) Proteasome inhibition down-regulates endothelial nitric-oxide synthase phosphorylation and function. J Biol Chem 281, 21652-9
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18

Jackson SJ, Venema RC (2006) Quercetin inhibits eNOS, microtubule polymerization, and mitotic progression in bovine aortic endothelial cells. J Nutr 136, 1178-84
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19

Formoso G, et al. (2006) Dehydroepiandrosterone mimics acute actions of insulin to stimulate production of both nitric oxide and endothelin 1 via distinct phosphatidylinositol 3-kinase- and mitogen-activated protein kinase-dependent pathways in vascular endothelium. Mol Endocrinol 20, 1153-63
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20

Xie Z, et al. (2006) Activation of protein kinase C zeta by peroxynitrite regulates LKB1-dependent AMP-activated protein kinase in cultured endothelial cells. J Biol Chem 281, 6366-75
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21

Gonzalez E, Kou R, Michel T (2006) Rac1 modulates sphingosine 1-phosphate-mediated activation of phosphoinositide 3-kinase/Akt signaling pathways in vascular endothelial cells. J Biol Chem 281, 3210-6
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22

Davis BJ, Xie Z, Viollet B, Zou MH (2006) Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes 55, 496-505
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23

Church JE, Fulton D (2006) Differences in eNOS activity because of subcellular localization are dictated by phosphorylation state rather than the local calcium environment. J Biol Chem 281, 1477-88
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24

Dessy C, et al. (2005) Endothelial beta3-adrenoreceptors mediate nitric oxide-dependent vasorelaxation of coronary microvessels in response to the third-generation beta-blocker nebivolol. Circulation 112, 1198-205
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25

Anter E, et al. (2005) p38 mitogen-activated protein kinase activates eNOS in endothelial cells by an estrogen receptor alpha-dependent pathway in response to black tea polyphenols. Circ Res 96, 1072-8
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26

Wei Q, Xia Y (2005) Roles of 3-phosphoinositide-dependent kinase 1 in the regulation of endothelial nitric-oxide synthase phosphorylation and function by heat shock protein 90. J Biol Chem 280, 18081-6
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27

Li C, et al. (2005) Interaction of the endothelial nitric oxide synthase with the CAT-1 arginine transporter enhances NO release by a mechanism not involving arginine transport. Biochem J 386, 567-74
15743275   Curated Info

28

Liu D, Homan LL, Dillon JS (2004) Genistein acutely stimulates nitric oxide synthesis in vascular endothelial cells by a cyclic adenosine 5'-monophosphate-dependent mechanism. Endocrinology 145, 5532-9
15319357   Curated Info

29

Lungu AO, et al. (2004) Cyclosporin A inhibits flow-mediated activation of endothelial nitric-oxide synthase by altering cholesterol content in caveolae. J Biol Chem 279, 48794-800
15383526   Curated Info

30

Harris MB, et al. (2004) Acute activation and phosphorylation of endothelial nitric oxide synthase by HMG-CoA reductase inhibitors. Am J Physiol Heart Circ Physiol 287, H560-6
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31

Drew BG, et al. (2004) High-density lipoprotein and apolipoprotein AI increase endothelial NO synthase activity by protein association and multisite phosphorylation. Proc Natl Acad Sci U S A 101, 6999-7004
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32

Papapetropoulos A, et al. (2004) Vanadate is a potent activator of endothelial nitric-oxide synthase: evidence for the role of the serine/threonine kinase Akt and the 90-kDa heat shock protein. Mol Pharmacol 65, 407-15
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33

Dedkova EN, Ji X, Lipsius SL, Blatter LA (2004) Mitochondrial calcium uptake stimulates nitric oxide production in mitochondria of bovine vascular endothelial cells. Am J Physiol Cell Physiol 286, C406-15
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34

Cho DH, Choi YJ, Jo SA, Jo I (2004) Nitric oxide production and regulation of endothelial nitric-oxide synthase phosphorylation by prolonged treatment with troglitazone: evidence for involvement of peroxisome proliferator-activated receptor (PPAR) gamma-dependent and PPARgamma-independent signaling pathways. J Biol Chem 279, 2499-506
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35

Lin MI, et al. (2003) Phosphorylation of threonine 497 in endothelial nitric-oxide synthase coordinates the coupling of L-arginine metabolism to efficient nitric oxide production. J Biol Chem 278, 44719-26
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36

Igarashi J, et al. (2003) VEGF induces S1P1 receptors in endothelial cells: Implications for cross-talk between sphingolipid and growth factor receptors. Proc Natl Acad Sci U S A 100, 10664-9
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37

Takahashi S, Mendelsohn ME (2003) Synergistic activation of endothelial nitric-oxide synthase (eNOS) by HSP90 and Akt: calcium-independent eNOS activation involves formation of an HSP90-Akt-CaM-bound eNOS complex. J Biol Chem 278, 30821-7
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38

Bauer PM, et al. (2003) Compensatory phosphorylation and protein-protein interactions revealed by loss of function and gain of function mutants of multiple serine phosphorylation sites in endothelial nitric-oxide synthase. J Biol Chem 278, 14841-9
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39

Cai H, et al. (2003) Akt-dependent phosphorylation of serine 1179 and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 cooperatively mediate activation of the endothelial nitric-oxide synthase by hydrogen peroxide. Mol Pharmacol 63, 325-31
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40

Greif DM, Kou R, Michel T (2002) Site-specific dephosphorylation of endothelial nitric oxide synthase by protein phosphatase 2A: evidence for crosstalk between phosphorylation sites. Biochemistry 41, 15845-53
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41

Gélinas DS, et al. (2002) Immediate and delayed VEGF-mediated NO synthesis in endothelial cells: role of PI3K, PKC and PLC pathways. Br J Pharmacol 137, 1021-30
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42

Boo YC, et al. (2002) Shear stress stimulates phosphorylation of eNOS at Ser(635) by a protein kinase A-dependent mechanism. Am J Physiol Heart Circ Physiol 283, H1819-28
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43

Gonzalez E, et al. (2002) Subcellular targeting and agonist-induced site-specific phosphorylation of endothelial nitric-oxide synthase. J Biol Chem 277, 39554-60
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44

Zou MH, et al. (2002) Modulation by peroxynitrite of Akt- and AMP-activated kinase-dependent Ser1179 phosphorylation of endothelial nitric oxide synthase. J Biol Chem 277, 32552-7
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45

Kou R, Greif D, Michel T (2002) Dephosphorylation of endothelial nitric-oxide synthase by vascular endothelial growth factor. Implications for the vascular responses to cyclosporin A. J Biol Chem 277, 29669-73
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46

Scotland RS, et al. (2002) Functional reconstitution of endothelial nitric oxide synthase reveals the importance of serine 1179 in endothelium-dependent vasomotion. Circ Res 90, 904-10
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47

Fulton D, et al. (2002) Localization of endothelial nitric-oxide synthase phosphorylated on serine 1179 and nitric oxide in Golgi and plasma membrane defines the existence of two pools of active enzyme. J Biol Chem 277, 4277-84
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48

Boo YC, et al. (2002) Shear stress stimulates phosphorylation of endothelial nitric-oxide synthase at Ser1179 by Akt-independent mechanisms: role of protein kinase A. J Biol Chem 277, 3388-96
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49

Du XL, et al. (2001) Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J Clin Invest 108, 1341-8
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50

Michell BJ, et al. (2001) Coordinated control of endothelial nitric-oxide synthase phosphorylation by protein kinase C and the cAMP-dependent protein kinase. J Biol Chem 276, 17625-8
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51

Harris MB, et al. (2001) Reciprocal phosphorylation and regulation of endothelial nitric-oxide synthase in response to bradykinin stimulation. J Biol Chem 276, 16587-91
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52

Kim F, Gallis B, Corson MA (2001) TNF-alpha inhibits flow and insulin signaling leading to NO production in aortic endothelial cells. Am J Physiol Cell Physiol 280, C1057-65
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53

Igarashi J, Bernier SG, Michel T (2001) Sphingosine 1-phosphate and activation of endothelial nitric-oxide synthase. differential regulation of Akt and MAP kinase pathways by EDG and bradykinin receptors in vascular endothelial cells. J Biol Chem 276, 12420-6
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54

McCabe TJ, Fulton D, Roman LJ, Sessa WC (2000) Enhanced electron flux and reduced calmodulin dissociation may explain "calcium-independent" eNOS activation by phosphorylation. J Biol Chem 275, 6123-8
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55

Gallis B, et al. (1999) Identification of flow-dependent endothelial nitric-oxide synthase phosphorylation sites by mass spectrometry and regulation of phosphorylation and nitric oxide production by the phosphatidylinositol 3-kinase inhibitor LY294002. J Biol Chem 274, 30101-8
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56

Fulton D, et al. (1999) Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399, 597-601
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57

Church JE, et al. Inhibition of endothelial nitric oxide synthase by the lipid phosphatase PTEN. Vascul Pharmacol 52, 191-8
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