A phospholipase C-γ1-independent, RasGRP1-ERK-dependent pathway drives lymphoproliferative disease in linker for activation of T cells-Y136F mutant mice.
J Immunol
; 190(1): 147-58, 2013 Jan 01.
Article
en En
| MEDLINE
| ID: mdl-23209318
ABSTRACT
Mice expressing a germline mutation in the phospholipase C-γ1-binding site of linker for activation of T cells (LAT) show progressive lymphoproliferation and ultimately die at 4-6 mo age. The hyperactivated T cells in these mice show defective TCR-induced calcium flux but enhanced Ras/ERK activation, which is critical for disease progression. Despite the loss of LAT-dependent phospholipase C-γ1 binding and activation, genetic analysis revealed RasGRP1, and not Sos1 or Sos2, to be the major Ras guanine exchange factor responsible for ERK activation and the lymphoproliferative phenotype in these mice. Analysis of isolated CD4(+) T cells from LAT-Y136F mice showed altered proximal TCR-dependent kinase signaling, which activated a Zap70- and LAT-independent pathway. Moreover, LAT-Y136F T cells showed ERK activation that was dependent on Lck and/or Fyn, protein kinase C-θ, and RasGRP1. These data demonstrate a novel route to Ras activation in vivo in a pathological setting.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fosfoproteínas
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Activación de Linfocitos
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Linfocitos T CD4-Positivos
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Sistema de Señalización de MAP Quinasas
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Factores de Intercambio de Guanina Nucleótido
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Quinasas MAP Reguladas por Señal Extracelular
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Proteínas Adaptadoras Transductoras de Señales
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Fosfolipasa C gamma
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Trastornos Linfoproliferativos
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Proteínas de la Membrana
Límite:
Animals
Idioma:
En
Revista:
J Immunol
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos