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Cbl functions downstream of Src kinases in Fc gamma RI signaling in primary human macrophages.
Erdreich-Epstein, A; Liu, M; Kant, A M; Izadi, K D; Nolta, J A; Durden, D L.
Afiliação
  • Erdreich-Epstein A; Neil Bogart Memorial Laboratories, Department of Pediatrics, Childrens Hospital Los Angeles Research Institute, University of Southern California School of Medicine, USA.
J Leukoc Biol ; 65(4): 523-34, 1999 Apr.
Article em En | MEDLINE | ID: mdl-10204582
Cbl is a cytosolic protein that is rapidly tyrosine phosphorylated in response to Fc receptor activation and binds to the adaptor proteins Grb2, CrkL, and Nck. A few reports describe Cbl interactions in primary human hematopoietic cells. We show evidence that Cbl participates in signaling initiated by Fc gammaRI receptor cross-linking in human primary macrophages, and functions downstream of Src family kinases in this pathway. Fc gammaRI stimulation in human macrophages was associated with rapid and transient tyrosine phosphorylation of the Cbl adaptor protein. Immunoprecipitated Cbl was complexed with several tyrosine phosphorylated proteins, the most prominent of which was a 38-kDa band identified as the CrkL adaptor protein. CrkL associated with tyrosine-phosphorylated Cbl and itself became tyrosine phosphorylated after Fc gammaRI cross-linking. SLP-76, a recently cloned Grb2-associated protein, was strongly tyrosine phosphorylated after Fc gammaRI stimulation and was associated with both Cbl and Grb2. Grb2 and Cbl binding to SLP-76 were inducible after Fc gammaRI stimulation of the macrophages. Nck was inducibly bound to Cbl after Fc gammaRI stimulation, whereas Grb2 was constitutively associated with it. Shc was also inducibly tyrosine phosphorylated and bound to Grb2 after Fc gammaRI stimulation of the macrophages. PP1, a specific inhibitor of Src kinases, inhibited the Fc gammaRI-induced respiratory burst, as well as the tyrosine phosphorylation of Cbl and its inducible association with CrkL. These results suggest a fundamental role for the tyrosine phosphorylation of Cbl, CrkL, SLP-76, and Shc and the association of Cbl with CrkL, SLP-76, and Nck in Fc gammaRI signaling in human macrophages. Experiments performed with PP1, the specific Src kinase inhibitor, demonstrate the first evidence that Cbl and the Cbl-Crkl interaction are downstream targets for myeloid Src kinases required for the activation of myeloid NADPH oxidase activity.
Assuntos
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Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Proteínas Proto-Oncogênicas / Receptores de IgG / Quinases da Família src / Proteínas Adaptadoras de Transporte Vesicular / Ubiquitina-Proteína Ligases / Proteínas Adaptadoras de Transdução de Sinal / Macrófagos Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 1999 Tipo de documento: Article
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Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Proteínas Proto-Oncogênicas / Receptores de IgG / Quinases da Família src / Proteínas Adaptadoras de Transporte Vesicular / Ubiquitina-Proteína Ligases / Proteínas Adaptadoras de Transdução de Sinal / Macrófagos Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 1999 Tipo de documento: Article