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

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dc.contributor.authorIbiza, Sales
dc.contributor.authorPérez-Rodríguez, Andrea
dc.contributor.authorOrtega, Ángel
dc.contributor.authorMartínez Ruiz, Antonio
dc.contributor.authorBarreiro, Olga
dc.contributor.authorCarlota A. García-Domínguez
dc.contributor.authorVíctor M. Víctor
dc.contributor.authorJuan V. Esplugues
dc.contributor.authorJosé M. Rojas
dc.contributor.authorFrancisco Sánchez-Madrid
dc.contributor.authorJuan M. Serrador
dc.date.accessioned2024-05-22T12:23:51Z
dc.date.available2024-05-22T12:23:51Z
dc.date.issued2008-07-29
dc.description.abstractRas/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 antigenpresenting 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 Cys118, 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 S-nitrosylation of Cys118 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.
dc.description.departmentDepto. de Bioquímica y Biología Molecular
dc.description.facultyFac. de Farmacia
dc.description.refereedTRUE
dc.description.sponsorshipFondo de Investigaciones
dc.description.sponsorshipInstituto de Salud Carlos III
dc.description.sponsorshipFundación ‘‘la Caixa"
dc.description.sponsorshipCentro Nacional de Investigaciones Cardiovasculares
dc.description.sponsorshipBancaja
dc.description.sponsorshipComunidad Autonoma de Madrid
dc.description.statuspub
dc.identifier.doi10.1073/pnas.0711062105
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.officialurlhttps://doi.org/10.1073/pnas.071106210
dc.identifier.urihttps://hdl.handle.net/20.500.14352/104316
dc.issue.number30
dc.language.isoeng
dc.page.final10512
dc.page.initial10507
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO//BFU2005-08435/BMC
dc.relation.projectIDinfo:eu-repo/grantAgreement/MEC//SAF2006-04247/ES/ANALISIS DE LOS MECANISMOS DE REGULACION DE LAS VIAS DE TRANSMISION DE SEÑALES DEPENDIENTES DE LAS PROTEINAS RAS: EFECTOS DIFERENCIALES, SISTEMAS DOCKING%2FSCAFFOLD Y NUEVOS ESTIMULOS/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MEC//SAF2005-01366
dc.relation.projectIDinfo:eu-repo/grantAgreement/MSC//CP07%2F00171/ES/CP07%2F00171/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MSC//CP07%2F00143/ES/CP07%2F00143/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MSC//CP02%23024/ES/CP02%23024
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.accessRightsopen access
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.cdu577.1
dc.subject.ucmBioquímica (Farmacia)
dc.subject.unesco2302 Bioquímica
dc.titleEndothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number105
dspace.entity.typePublication
relation.isAuthorOfPublicationeec0b303-34c9-47dd-9ec6-704b6c6c7acd
relation.isAuthorOfPublication.latestForDiscoveryeec0b303-34c9-47dd-9ec6-704b6c6c7acd
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