{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,13]],"date-time":"2026-01-13T16:12:41Z","timestamp":1768320761539,"version":"3.49.0"},"reference-count":35,"publisher":"Proceedings of the National Academy of Sciences","issue":"30","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,7,29]]},"abstract":"<jats:p>\n            Ras\/ERK signaling plays an important role in T cell activation and development. We recently reported that endothelial nitric oxide synthase (eNOS)-derived NO regulates T cell receptor (TCR)-dependent ERK activation by a cGMP-independent mechanism. Here, we explore the mechanisms through which eNOS exerts this regulation. We have found that eNOS-derived NO positively regulates Ras\/ERK activation in T cells stimulated with antigen on antigen-presenting cells (APCs). Intracellular activation of N-, H-, and K-Ras was monitored with fluorescent probes in T cells stably transfected with eNOS-GFP or its G2A point mutant, which is defective in activity and cellular localization. Using this system, we demonstrate that eNOS selectively activates N-Ras but not K-Ras on the Golgi complex of T cells engaged with APC, even though Ras isoforms are activated in response to NO from donors. We further show that activation of N-Ras involves eNOS-dependent\n            <jats:italic>S<\/jats:italic>\n            -nitrosylation on Cys\n            <jats:sup>118<\/jats:sup>\n            , suggesting that upon TCR engagement, eNOS-derived NO directly activates N-Ras on the Golgi. Moreover, wild-type but not C118S N-Ras increased TCR-dependent apoptosis, suggesting that\n            <jats:italic>S<\/jats:italic>\n            -nitrosylation of Cys\n            <jats:sup>118<\/jats:sup>\n            contributes to activation-induced T cell death. Our data define a signaling mechanism for the regulation of the Ras\/ERK pathway based on the eNOS-dependent differential activation of N-Ras and K-Ras at specific cell compartments.\n          <\/jats:p>","DOI":"10.1073\/pnas.0711062105","type":"journal-article","created":{"date-parts":[[2008,7,19]],"date-time":"2008-07-19T00:54:33Z","timestamp":1216428873000},"page":"10507-10512","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":71,"title":["Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells"],"prefix":"10.1073","volume":"105","author":[{"given":"Sales","family":"Ibiza","sequence":"first","affiliation":[{"name":"*Departamento de Biolog\u00eda Vascular e Inflamaci\u00f3n, Centro Nacional de Investigaciones Cardiovasculares, E-28029 Madrid, Spain;"}]},{"given":"Andrea","family":"P\u00e9rez-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Unidad de Biolog\u00eda Celular, Centro Nacional de Microbiolog\u00eda, Majadahonda, E-28220 Madrid, Spain;"}]},{"given":"\u00c1ngel","family":"Ortega","sequence":"additional","affiliation":[{"name":"Unidad Central de Investigaci\u00f3n Medicina, Facultad de Medicina, and"}]},{"given":"Antonio","family":"Mart\u00ednez-Ruiz","sequence":"additional","affiliation":[{"name":"Servicio de Inmunolog\u00eda, Hospital de la Princesa, Universidad Aut\u00f3noma de Madrid, E-28006 Madrid, Spain; and"}]},{"given":"Olga","family":"Barreiro","sequence":"additional","affiliation":[{"name":"*Departamento de Biolog\u00eda Vascular e Inflamaci\u00f3n, Centro Nacional de Investigaciones Cardiovasculares, E-28029 Madrid, Spain;"},{"name":"Servicio de Inmunolog\u00eda, Hospital de la Princesa, Universidad Aut\u00f3noma de Madrid, E-28006 Madrid, Spain; and"}]},{"given":"Carlota A.","family":"Garc\u00eda-Dom\u00ednguez","sequence":"additional","affiliation":[{"name":"Unidad de Biolog\u00eda Celular, Centro Nacional de Microbiolog\u00eda, Majadahonda, E-28220 Madrid, Spain;"}]},{"given":"V\u00edctor M.","family":"V\u00edctor","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Hospital Universitario Doctor Peset, E-46017 Valencia, Spain"}]},{"given":"Juan V.","family":"Esplugues","sequence":"additional","affiliation":[{"name":"Departamento de Farmacolog\u00eda and Ciberehd, Universitat de Valencia, E-46010 Valencia, Spain;"}]},{"given":"Jos\u00e9 M.","family":"Rojas","sequence":"additional","affiliation":[{"name":"Unidad de Biolog\u00eda Celular, Centro Nacional de Microbiolog\u00eda, Majadahonda, E-28220 Madrid, Spain;"}]},{"given":"Francisco","family":"S\u00e1nchez-Madrid","sequence":"additional","affiliation":[{"name":"*Departamento de Biolog\u00eda Vascular e Inflamaci\u00f3n, Centro Nacional de Investigaciones Cardiovasculares, E-28029 Madrid, Spain;"},{"name":"Servicio de Inmunolog\u00eda, Hospital de la Princesa, Universidad Aut\u00f3noma de Madrid, E-28006 Madrid, Spain; and"}]},{"given":"Juan M.","family":"Serrador","sequence":"additional","affiliation":[{"name":"*Departamento de Biolog\u00eda Vascular e Inflamaci\u00f3n, Centro Nacional de Investigaciones Cardiovasculares, E-28029 Madrid, Spain;"}]}],"member":"341","published-online":{"date-parts":[[2008,7,29]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1001-907"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.092259799"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.10.5188"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830260302"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/21224"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/21218"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M510421200"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M413058200"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.137.7.1525"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.04.006"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.7.4323"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.33.19705"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0952-7915(00)00089-3"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/346719a0"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.8.3485-3496.2004"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.24.021605.090723"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1105654"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.20.091301.131133"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01806"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M207299200"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/35055104"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200601051"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2007.03.023"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/35082594"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.embor.7400560"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1592"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407294102"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.02.046"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0605907103"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2007.04.013"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M304813200"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.10.5773"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2006.07.011"},{"key":"e_1_3_3_34_2","first-page":"1615","article-title":"Mice deficient for N-ras: Impaired antiviral immune response and T-cell function","volume":"63","author":"Perez de Castro I","year":"2003","unstructured":"I Perez de Castro, et al., Mice deficient for N-ras: Impaired antiviral immune response and T-cell function. Cancer Res 63, 1615\u20131622 (2003).","journal-title":"Cancer Res"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05269"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0711062105","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T20:09:39Z","timestamp":1649794179000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0711062105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,7,29]]},"references-count":35,"journal-issue":{"issue":"30","published-print":{"date-parts":[[2008,7,29]]}},"alternative-id":["10.1073\/pnas.0711062105"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0711062105","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,7,29]]},"assertion":[{"value":"2007-11-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2008-07-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}