Sequential phosphorylation of SLP-76 at tyrosine 173 is required for activation of T and mast cells.
EMBO J
; 30(15): 3160-72, 2011 Jul 01.
Article
en En
| MEDLINE
| ID: mdl-21725281
ABSTRACT
Cooperatively assembled signalling complexes, nucleated by adaptor proteins, integrate information from surface receptors to determine cellular outcomes. In T and mast cells, antigen receptor signalling is nucleated by three adaptors SLP-76, Gads and LAT. Three well-characterized SLP-76 tyrosine phosphorylation sites recruit key components, including a Tec-family tyrosine kinase, Itk. We identified a fourth, evolutionarily conserved SLP-76 phosphorylation site, Y173, which was phosphorylated upon T-cell receptor stimulation in primary murine and Jurkat T cells. Y173 was required for antigen receptor-induced phosphorylation of phospholipase C-γ1 (PLC-γ1) in both T and mast cells, and for consequent downstream events, including activation of the IL-2 promoter in T cells, and degranulation and IL-6 production in mast cells. In intact cells, Y173 phosphorylation depended on three, ZAP-70-targeted tyrosines at the N-terminus of SLP-76 that recruit and activate Itk, a kinase that selectively phosphorylated Y173 in vitro. These data suggest a sequential mechanism whereby ZAP-70-dependent priming of SLP-76 at three N-terminal sites triggers reciprocal regulatory interactions between Itk and SLP-76, which are ultimately required to couple active Itk to its substrate, PLC-γ1.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Fosfoproteínas
/
Proteínas Tirosina Quinasas
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Activación de Linfocitos
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Linfocitos T
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Transducción de Señal
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Proteínas Adaptadoras Transductoras de Señales
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Proteína Tirosina Quinasa ZAP-70
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Mastocitos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
EMBO J
Año:
2011
Tipo del documento:
Article
País de afiliación:
Israel