RT Journal Article
T1 Endothelial nitric oxide synthase regulates N-Ras activation on the Golgi complex of antigen-stimulated T cells
A1 Ibiza, Sales
A1 Pérez-Rodríguez, Andrea
A1 Ortega, Ángel
A1 Martínez Ruiz, Antonio
A1 Barreiro, Olga
A1 Carlota A. García-Domínguez, 
A1 Víctor M. Víctor, 
A1 Juan V. Esplugues, 
A1 José M. Rojas, 
A1 Francisco Sánchez-Madrid, 
A1 Juan M. Serrador, 
AB 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 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 thateNOS 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.
SN 0027-8424
SN 1091-6490
YR 2008
FD 2008-07-29
LK https://hdl.handle.net/20.500.14352/104316
UL https://hdl.handle.net/20.500.14352/104316
LA eng
NO Fondo de Investigaciones
NO Instituto de Salud Carlos III
NO Fundación ‘‘la Caixa"
NO Centro Nacional de Investigaciones Cardiovasculares
NO Bancaja
NO Comunidad Autonoma de Madrid
DS Docta Complutense
RD 28 jul 2024