Distinct domains of the human granulocyte-macrophage colony-stimulating factor receptor alpha subunit mediate activation of Jak/Stat signaling and differentiation.
Blood
; 97(6): 1662-70, 2001 Mar 15.
Article
en En
| MEDLINE
| ID: mdl-11238105
The alpha subunit of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor has several isoforms that result from alternative splicing events. Two forms, alpha-1 and alpha-2, have intracytoplasmic sequences that are identical within a membrane-proximal domain but differ completely distally. Variant and mutated GM-CSF receptor alpha subunits, along with the beta subunit (beta(c) protein) were expressed in M1 murine leukemia cells. and the ability of the receptors to signal for differentiation events and to activate Jak/Stat signaling pathways was examined. All cell lines expressing both alpha and beta(c) proteins exhibited high-affinity binding of radiolabeled human GM-CSF. Receptor alpha subunits with intact membrane-proximal intracellular domains could induce expression of the macrophage antigen F4/80 and down-regulate the expression of CD11b. Addition of recombinant human GM-CSF to cells expressing alpha-1 subunits induced the expression of CD86 and tyrosine phosphorylation of Jak-2 and its putative substrates SHPTP-2, Stat-5, and the GM-CSF receptor beta(c) subunit. Cells containing alpha subunits that lacked a distal domain (term-3) or had the alternatively spliced alpha-2 distal domain showed markedly decreased ability to support tyrosine phosphorylation of Jak-2 and its substrates or to up-regulate CD86. Ligand binding induced stable association of the alpha-1 subunit and beta(c) protein. In contrast, the alpha-2 subunit did not stably associate with the beta(c) subunit. These data identify potential molecular mechanisms for differential signaling of the alpha-1 and alpha-2 proteins. The association of unique signaling events with the 2 active GM-CSF alpha subunit isoforms offers a model for variable response phenotypes to the same ligand.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas Tirosina Quinasas
/
Antígenos de Diferenciación
/
Transactivadores
/
Proteínas Proto-Oncogénicas
/
Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos
/
Proteínas de Unión al ADN
/
Proteínas de la Leche
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Blood
Año:
2001
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Estados Unidos