Ligation of CD28 stimulates the formation of a multimeric signaling complex involving grb-2-associated binder 2 (gab2), SRC homology phosphatase-2, and phosphatidylinositol 3-kinase: evidence that negative regulation of CD28 signaling requires the gab2 pleckstrin homology domain.

Parry, Richard V; Whittaker, Gillian C; Sims, Martin; Edmead, Christine E; Welham, Melanie J; Ward, Stephen G

Parry, Richard V; Whittaker, Gillian C; Sims, Martin; Edmead, Christine E; Welham, Melanie J; Ward, Stephen G.

Afiliación

Parry RV; Lymphocyte Activation Group, Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.

J Immunol ; 176(1): 594-602, 2006 Jan 01.

Article en En | MEDLINE | ID: mdl-16365455

RESUMEN

Grb-2-associated binder (Gab)2 is a scaffolding adaptor protein that has been reported to promote growth factor and cytokine receptor signal transduction, but inhibit TCR-mediated signaling events. In this study, we show that ligation of CD28 by its natural ligand B7-1/CD80, induces tyrosine phosphorylation of Gab2 and its coassociation with Src homology phosphatase (SHP)-2 and class IA PI3K in Jurkat cells. Overexpression of wild-type Gab2 revealed a negative role in regulation of CD3/CD28 induction of the transcription factors NF-kappaB and AP-1. To characterize this inhibitory function further, we used Gab2 mutants unable to bind either PI3K or SHP-2 and a PH domain deletion mutant. Although PI3K has previously been implicated as necessary for Gab2-mediated inhibition of TCR signaling, Gab2 mutants defective in their ability to bind PI3K or SHP-2 retained their inhibitory function, whereas deletion of the PH domain ablated the inhibitory effect of Gab2. Together, these data demonstrate that CD28 stimulation of T cells is sufficient to induce an inhibitory multimeric signaling complex involving Gab2, SHP-2, and PI3K. Furthermore, the inhibitory capacity of Gab2 is strictly dependent upon the integrity of its PH domain, suggesting phosphoinositide-mediated membrane recruitment is important to Gab2 function in T cells.

Asunto(s)

Antígenos CD28/inmunología; Péptidos y Proteínas de Señalización Intracelular/inmunología; Fosfatidilinositol 3-Quinasas/inmunología; Fosfoproteínas/inmunología; Proteínas Tirosina Fosfatasas/inmunología; Dominios Homologos src/inmunología; Proteínas Adaptadoras Transductoras de Señales; Proteínas Sanguíneas/inmunología; Proteínas Sanguíneas/metabolismo; Antígenos CD28/metabolismo; Humanos; Immunoblotting; Péptidos y Proteínas de Señalización Intracelular/metabolismo; Células Jurkat; Activación de Linfocitos/inmunología; FN-kappa B/inmunología; FN-kappa B/metabolismo; Fosfatidilinositol 3-Quinasas/metabolismo; Fosfoproteínas/metabolismo; Fosforilación; Proteína Fosfatasa 2; Proteína Tirosina Fosfatasa no Receptora Tipo 11; Proteínas Tirosina Fosfatasas/metabolismo; Proteínas Tirosina Fosfatasas con Dominio SH2; Linfocitos T/inmunología; Factor de Transcripción AP-1/inmunología; Factor de Transcripción AP-1/metabolismo; Transfección

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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfoproteínas / Proteínas Tirosina Fosfatasas / Antígenos CD28 / Dominios Homologos src / Fosfatidilinositol 3-Quinasas / Péptidos y Proteínas de Señalización Intracelular Tipo de estudio: Risk_factors_studies Límite: Humans Idioma: En Revista: J Immunol Año: 2006 Tipo del documento: Article Pais de publicación: Estados Unidos

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