Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells

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 e...

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Autores: Ibiza, Sales, Perez-Rodriguez, Andrea, Ortega, Angel, Martinez-Ruiz, Antonio, Barreiro, Olga, Garcia-Dominguez, Carlota A., Victor, Victor M., Esplugues, Juan V., Rojas, Jose M., Sanchez-Madrid, Francisco, Serrador, Juan M.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2008
País:España
Institución:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
Repositorio:r-FISABIO. Repositorio Institucional de Producción Científica
OAI Identifier:oai:fisabio.fundanetsuite.com:p9958
Acceso en línea:https://fisabio.portalinvestigacion.com/publicaciones/9958
Access Level:acceso abierto
Palabra clave:S-nitrosylation
eNOS
apoptosis
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spelling Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cellsIbiza, SalesPerez-Rodriguez, AndreaOrtega, AngelMartinez-Ruiz, AntonioBarreiro, OlgaGarcia-Dominguez, Carlota A.Victor, Victor M.Esplugues, Juan V.Rojas, Jose M.Sanchez-Madrid, FranciscoSerrador, Juan M.S-nitrosylationeNOSapoptosisRas/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 S-nitrosylation on Cys(118), suggesting that upon TCR engagement, eNOS-derived NO directly activates N-Ras on the Golgi. Moreover, wild-type but not Cys(118), N-Ras increased TCR-dependent apoptosis, suggesting that S-nitrosylation of Cys(118) 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.National Academy of Sciences2008info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fisabio.portalinvestigacion.com/publicaciones/9958PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICAISSN: 10916490ISSNe: 00278424reponame:r-FISABIO. Repositorio Institucional de Producción Científicainstname:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)Inglésinfo:eu-repo/semantics/openAccessoai:fisabio.fundanetsuite.com:p99582026-06-11T12:45:17Z
dc.title.none.fl_str_mv Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells
title Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells
spellingShingle Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells
Ibiza, Sales
S-nitrosylation
eNOS
apoptosis
title_short Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells
title_full Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells
title_fullStr Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells
title_full_unstemmed Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells
title_sort Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells
dc.creator.none.fl_str_mv Ibiza, Sales
Perez-Rodriguez, Andrea
Ortega, Angel
Martinez-Ruiz, Antonio
Barreiro, Olga
Garcia-Dominguez, Carlota A.
Victor, Victor M.
Esplugues, Juan V.
Rojas, Jose M.
Sanchez-Madrid, Francisco
Serrador, Juan M.
author Ibiza, Sales
author_facet Ibiza, Sales
Perez-Rodriguez, Andrea
Ortega, Angel
Martinez-Ruiz, Antonio
Barreiro, Olga
Garcia-Dominguez, Carlota A.
Victor, Victor M.
Esplugues, Juan V.
Rojas, Jose M.
Sanchez-Madrid, Francisco
Serrador, Juan M.
author_role author
author2 Perez-Rodriguez, Andrea
Ortega, Angel
Martinez-Ruiz, Antonio
Barreiro, Olga
Garcia-Dominguez, Carlota A.
Victor, Victor M.
Esplugues, Juan V.
Rojas, Jose M.
Sanchez-Madrid, Francisco
Serrador, Juan M.
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv S-nitrosylation
eNOS
apoptosis
topic S-nitrosylation
eNOS
apoptosis
description 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 S-nitrosylation on Cys(118), suggesting that upon TCR engagement, eNOS-derived NO directly activates N-Ras on the Golgi. Moreover, wild-type but not Cys(118), N-Ras increased TCR-dependent apoptosis, suggesting that S-nitrosylation of Cys(118) 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.
publishDate 2008
dc.date.none.fl_str_mv 2008
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://fisabio.portalinvestigacion.com/publicaciones/9958
url https://fisabio.portalinvestigacion.com/publicaciones/9958
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv National Academy of Sciences
publisher.none.fl_str_mv National Academy of Sciences
dc.source.none.fl_str_mv PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN: 10916490
ISSNe: 00278424
reponame:r-FISABIO. Repositorio Institucional de Producción Científica
instname:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
instname_str Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
reponame_str r-FISABIO. Repositorio Institucional de Producción Científica
collection r-FISABIO. Repositorio Institucional de Producción Científica
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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