Lck SH3 domain function is required for T-cell receptor signals regulating thymocyte development.
Mol Cell Biol
; 26(21): 7892-900, 2006 Nov.
Article
en En
| MEDLINE
| ID: mdl-16923964
ABSTRACT
Thymocyte development is shaped by signals from the T-cell antigen receptor. The strength of receptor signaling determines developmental progression as well as deletion of self-reactive T cells. Receptor stimulation of the extracellular signal-regulated kinase (ERK) pathway plays an important regulatory role during thymocyte development. However, it is unclear how differences in receptor signaling are translated into distinctive activation of the ERK pathway. We have investigated the potential role of the Lck tyrosine kinase in regulating intracellular signaling during thymocyte development. While Lck is known to be critical for initial T-cell receptor signaling events, it may have an independent role in regulating intracellular signaling through the function of its SH3 domain. To determine whether such a regulatory mechanism functions during thymocyte development, we generated mice in which the normal lck allele is replaced with an lck SH3 domain mutant. Analysis of these mice revealed that both early thymocyte development and maturation of CD4(+) and CD8(+) lineages is impaired. Investigation of thymocyte responses to antigen receptor stimulation showed a significant reduction in proliferation and ERK pathway activation, although initial signaling events were intact. These findings indicate that Lck SH3 domain function may provide a means to independently couple receptor signaling to regulation of the ERK pathway during thymocyte development.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Timo
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Receptores de Antígenos de Linfocitos T
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Transducción de Señal
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Dominios Homologos src
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Proteína Tirosina Quinasa p56(lck) Específica de Linfocito
Límite:
Animals
Idioma:
En
Revista:
Mol Cell Biol
Año:
2006
Tipo del documento:
Article
País de afiliación:
Estados Unidos