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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A previous study using random mutagenesis identified an activating mutation in the common beta subunit (hbetac) of the human granulocyte-macrophage colony-stimulating factor, interleukin-3, and interleukin-5 receptors in which an isoleucine residue (Ile374) in the extracellular region of hbetac is replaced by asparagine (Jenkins, B. J., D'Andrea, R., and Gonda, T. J. (1995) EMBO J 14, 4276-4287). To investigate the mechanism by which this mutation (I374N) acts, we employed site-directed mutagenesis to explore predictions based on a structural model of hbetac. We focused on possible interactions between Ile374 and other hydrophobic residues in its vicinity and found that replacement of two such residues, Leu356 and Trp358, with asparagine resulted in constitutive activation of hbetac. Hydrophilic substitutions at both of these positions and at position 374 resulted in the greatest degree of activation, as measured by the growth rate of factor-independent cells, while hydrophobic substitutions had lesser or no effects. Moreover, these "weak" substitutions appeared to synergize, since factor-independent cells expressing the double mutants I374F/W358F and I374F/L356A showed substantially higher growth rates than the single mutants. Taken together, these results suggest that Ile374 normally interacts with Leu356 and Trp358, and that disruption of these interactions results in a conformational change in hbetac that leads to constitutive activity. A model relating this notion to the predicted structure and to ligand- and alpha subunit-dependent activation of hbetac is proposed.
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PMID:Interacting residues in the extracellular region of the common beta subunit of the human granulocyte-macrophage colony-stimulating factor, interleukin (IL)-3, and IL-5 receptors involved in constitutive activation. 893 4

Several activating mutations have recently been described in the common beta subunit for the human interleukin(IL)-3, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) receptors (hbetac). Two of these, FIDelta and I374N, result, respectively, in a 37-amino acid duplication and an isoleucine-to-asparagine substitution in the extracellular domain. A third, V449E, leads to valine-to-glutamic acid substitution in the transmembrane domain. Previous studies have shown that when expressed in murine hemopoietic cells in vitro, the extracellular mutants can confer factor independence on only the granulocyte-macrophage lineage while the transmembrane mutant can do so to all cell types of the myeloid and erythroid compartments. To further study the signaling properties of the constitutively active hbetac mutants, we have used novel murine hemopoietic cell lines, which we describe in this report. These lines, FDB1 and FDB2, proliferate in murine IL-3 and undergo granulocyte-macrophage differentiation in response to murine GM-CSF. We find that while the transmembrane mutant, V449E, confers factor-independent proliferation on these cell lines, the extracellular hbetac mutants promote differentiation. Hence, in addition to their ability to confer factor independence on distinct cell types, transmembrane and extracellular activated hbetac mutants deliver distinct signals to the same cell type. Thus, the FDB cell lines, in combination with activated hbetac mutants, constitute a powerful new system to distinguish between signals that determine hemopoietic proliferation or differentiation. (Blood. 2000;95:120-127)
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PMID:Novel murine myeloid cell lines that exhibit a differentiation switch in response to IL-3 or GM-CSF, or to different constitutively active mutants of the GM-CSF receptor beta subunit. 1060 94

Pulmonary alveolar proteinosis (PAP) is a rare disorder of unknown origin characterized by alveolar fillings with periodic acid-Schiff (PAS)-positive material mainly consisting of phospholipids. Mice defective in the granulocyte-macrophage colony-stimulating factor (GM-CSF) gene or the GM-CSF/interleukin (IL)-3/IL-5-receptor common beta chain (beta c) demonstrate a pathology resembling PAP. A recent study revealed defects in the beta c chain of the GM-CSF receptor in four out of eight paediatric patients. This study investigates the role of the GM-CSF coding region and components of the GM-CSF receptor in adult patients. Four adult patients with proven PAP were analysed for GM-CSF and GM-CSF-beta c receptor in regard to protein level, messenger ribonucleic acid (mRNA) expression and sequence composition. None of the adult patients displayed the mutation at position 1,835 of the beta c-receptor previously described in paediatric patients. Expression of the beta c receptor was found to be normal on the surface of peripheral blood cells. In three out of four patients GM-CSF release from blood cells failed to respond adequately to lipopolysaccharide (LPS). In one of these patients a heterozygous mutation was found in the GM-CSF complementary deoxyribonucleic acid (cDNA) from thymine (T) to cytosine (C) at position 382 of the published sequence putatively causing a change in the protein from isoleucine to threonine at position 117. This study indicates that the mutation of the beta chain receptors found in some of the paediatric patients suffering from pulmonary alveolar proteinosis is not a common problem in adult patients.
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PMID:GM-CSF and GM-CSF beta c receptor in adult patients with pulmonary alveolar proteinosis. 1070 4

Interleukin-3 (IL-3) is a cytokine produced by activated T-cells and mast cells that is active on a broad range of hematopoietic cells and in the nervous system and appears to be important in several chronic inflammatory diseases. In this study, alanine substitutions were used to investigate the role of residues of the human beta-common (hbetac) receptor and the murine IL-3-specific (beta(IL-3)) receptor in IL-3 binding. We show that the domain 1 residues, Tyr(15) and Phe(79), of the hbetac receptor are important for high affinity IL-3 binding and receptor activation as shown previously for the related cytokines, interleukin-5 and granulocyte-macrophage colony-stimulating factor, which also signal through this receptor subunit. From the x-ray structure of hbetac, it is clear that the domain 1 residues cooperate with domain 4 residues to form a novel ligand-binding interface involving the two protein chains of the intertwined homodimer receptor. We demonstrate by ultracentrifugation that the beta(IL-3) receptor is also a homodimer. Its high sequence homology with hbetac suggests that their structures are homologous, and we identified an analogous binding interface in beta(IL-3) for direct IL-3 binding to the high affinity binding site in hbetac. Tyr(21) (A-B loop), Phe(85), and Asn(87) (E-F loop) of domain 1; Ile(320) of the interdomain loop; and Tyr(348) (B'-C' loop) and Tyr(401) (F'-G' loop) of domain 4 were shown to have critical individual roles and Arg(84) and Tyr(317) major secondary roles in direct murine IL-3 binding to the beta(IL-3)receptor. Most surprising, none of the key residues for direct IL-3 binding were critical for high affinity binding in the presence of the murine IL-3 alpha receptor, indicating a fundamentally different mechanism of high affinity binding to that used by hbetac.
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PMID:Interleukin-3 binding to the murine betaIL-3 and human betac receptors involves functional epitopes formed by domains 1 and 4 of different protein chains. 1506 62