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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 surface plasmon resonance (SPR) based biosensor has been used for studying the interaction of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) with genetically engineered alpha-chain subunits of its specific receptor (GM-Ralpha). Western blot analysis of GM-Ralpha confirmed the correct size (80 kDa) and reactivity of these proteins against anti-GM-Ralpha polyclonal or monoclonal antibodies. GM-CSF was immobilized, using standard amine coupling methods, to the dextran-modified gold biosensor surface in order to capture GM-Ralpha subsequently injected over the sensing layer. GM-Ralpha were shown to specifically form complexes with the immobilized ligand. Pre-incubation of constant amounts of GM-Ralpha with dilutions of soluble GM-CSF before injection of the mixture over the GM-CSF matrix, prevented ligand binding in a dose dependent manner. In contrast, unrelated soluble cytokines or serum proteins (e.g. G-CSF, albumin, etc.) were found to exert no inhibition. Complexes formation blockage by pre-incubation of constant amounts of GM-Ralpha with dilutions of neutralizing anti-GM-Ralpha antibodies was concentration dependent, further assessing the specificity of the interaction. To investigate the possibility of relating the effect on binding affinity of critical conformational changes at the contact site, experiments of multisite binding were performed, flowing a set of neutralizing monoclonal antibodies reacting to different epitopes on GM-CSF over the GM-CSF matrix, before injecting GM-Ralpha. The results indicated that antibody interaction with helix D and helix A of GM-CSF markedly inhibited GM-CSF binding to GM-Ralpha. Comparable results were obtained using the biosensor technology and enzyme-linked immunoassays, in representative experiments performed with the same reagents. These experiments demonstrate that SPR can be successfully used for studying complementary interactions between GM-CSF and its receptor alpha-chains in solution without using labels or secondary tracers and, compared with conventional immunoanalysis methods, significantly saving time.
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PMID:Human GM-CSF interaction with the alpha-chain of its receptor studied using surface plasmon resonance. 1145 1

The receptors for human granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 are composed of a ligand-specific alpha-chain (eg, alpha-GM-CSF receptor [alpha-GMR]) and a common beta-subunit (beta-GMR). Ligand binding is believed to induce assembly or conformational changes in preformed complexes containing more than one alpha- and beta-subunit in the activated receptor complex. To analyze the function of a splice variant of beta-GMR with a truncation in the intracellular domain (beta-GMR(IT)), BaF-3 cells expressing human alpha-GMR plus beta-GMR were transfected with beta-GMR(IT). In these cells, coexpression of beta-GMR(IT) inhibits GM-CSF-mediated survival and proliferation in a GM-CSF concentration-dependent manner. To analyze the effect of cytoplasmic assembly of truncated and full-length intracellular beta-GMR sequences, beta-GMR and beta-GMR(IT) were coexpressed with different chimeric alpha/beta-GMR constructs. Whereas both beta-GMR and beta-GMR(IT) generate high-affinity GMR complexes in the presence of alpha/beta-GMR, beta-GMR(IT) inhibits while beta-GMR supports proliferation and cell survival mediated by alpha/beta-GMR. Correspondingly, beta-GMR, but not beta-GMR(IT), generates functional GMR complexes when coexpressed with a defective alpha/beta-GMR construct. These data indicate that beta-GMR(IT) can inhibit survival and mitogenic signaling of the wild-type GMR and demonstrate that recruitment of alternatively spliced receptor subunits may regulate the function of heteromeric cytokine receptors.
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PMID:Inhibition of granulocyte-macrophage colony-stimulating factor receptor function by a splice variant of the common beta-receptor subunit. 1167 39

Granulocyte-macrophage colony-stimulating factor (GMCSF) has a central role in proliferation and differentiation of hematopoetic cells. Furthermore, it influences the proliferation and migration of endothelial cells. GMCSF elicits these functions by activating a receptor consisting of a ligand-specific alpha-chain and a beta-chain, which is common for GMCSF, interleukin-3 (IL-3), and IL-5. It is known that various signaling molecules such as Janus kinase 2 or transcription factors of the signal transducer and activator of transcription (STAT) family bind to the common beta-chain and initiate signaling cascades. However, alpha-chain-specific signal transduction adapters have to be postulated given that IL-3, IL-5, and GMCSF induce partly distinct biologic responses. Using a yeast 2-hybrid system, we identified the alpha-chain of the GMCSF receptor (GMRalpha) as putative interaction partner of IkappaB kinase beta, one of the central signaling kinases activating the transcription factor nuclear factor-kappaB (NF-kappaB). Using endogenous protein levels of endothelial cell extracts, we could verify the interaction by coimmunoprecipitation experiments. Fluorescence resonance energy transfer (FRET) microscopy confirmed the direct interaction of CFP-IKKbeta and YFPGMRalpha in living cells. Functional studies demonstrated GMCSF-dependent activation of IkappaB kinase activity in endothelial cells, degradation of IkappaB, and activation of NF-kappaB. Further biologic studies using GMCSF-dependent TF-1 cells indicated that GMCSF-triggered activation of NF-kappaB is important for cell survival and proliferation.
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PMID:GMCSF activates NF-kappaB via direct interaction of the GMCSF receptor with IkappaB kinase beta. 1263 24

Human immunodeficiency virus type 1 (HIV-1) infects cells of the monocyte/macrophage lineage. While infection of macrophages by HIV-1 is generally not cytopathic, it does impair macrophage function. In this study, we examined the effect of HIV-1 infection on intracellular signaling in human monocyte-derived macrophages (MDM) stimulated with the growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is an important growth factor for cells of both the macrophage and granulocyte lineages and enhances effector functions of these cells via the heterodimeric GM-CSF receptor (GM-CSFR). A major pathway which mediates the effects of GM-CSF on macrophages involves activation of the latent transcription factor STAT5A via a Janus kinase 2 (JAK2)-dependent pathway. We demonstrate that GM-CSF-induced activation of STAT5A is inhibited in MDM after infection in vitro with the laboratory-adapted R5 strain of HIV-1, HIV-1(Ba-L), but not after infection with adenovirus. HIV-1 infection of MDM did not decrease the STAT5A or JAK2 mRNA level or STAT5A protein level or result in increased constitutive activation of STAT5A. Surface expression of either the alpha-chain or common beta(c)-chain of GM-CSFR was also unaffected. We conclude that HIV-1 inhibits GM-CSF activation of STAT5A without affecting expression of the known components of the signaling pathway. These data provide further evidence of disruption of cellular signaling pathways after HIV-1 infection, which may contribute to immune dysfunction and HIV-1 pathogenesis.
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PMID:Human immunodeficiency virus type 1 infection inhibits granulocyte-macrophage colony-stimulating factor-induced activation of STAT5A in human monocyte-derived macrophages. 1461 Jan 85

We quantitatively assessed the expression of cytokine receptors (interleukin-2 receptor (IL-2R), IL-3R, IL-4R, IL-5R, IL-6R, IL-7R, granulocyte-macrophage colony-stimulating factor R (GM-CSFR), G-CSFR, c-fms, c-mpl, c-kit and FLT3) in cells from 211 adults with acute lymphoblastic leukemia (ALL) by flow cytometry and determined their prevalence and clinical significance. Although all cytokine receptors were expressed to various degrees, the levels of IL-3R alpha-chain (IL-3Ralpha), IL-2Ralpha, IL-2Rbeta, IL-7Ralpha, common-Rgamma(gammac), c-mpl, c-kit and FLT3 exhibited a wide spectrum > or =2000 sites/cell. Among them, IL-3Ralpha, IL-2Ralpha and FLT3 were highly expressed in B-lineage ALL, whereas IL-7Ralpha, gammac and c-kit predominated in T-lineage ALL. Higher levels of IL-3Ralpha, IL-2Ralpha, c-kit and FLT3 correlated with the expression of CD13/33. Increased IL-2Ralpha levels related to the presence of Philadelphia chromosome (Ph), leukocytosis and shorter event-free survival (EFS). C-kit preferred in male. Elevated FLT3 levels correlated with age > or =60 years. Multivariate analysis in B-lineage ALL revealed only IL-2Ralpha (P=0.028) and Ph (P=0.020) as independent factors for EFS. These findings suggest that several cytokine receptors associated with certain cellular and clinical features, but IL-2Ralpha solely had a prognostic value and should be considered as a major prognostic factor for adult ALL that is comparable with Ph.
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PMID:Clinical and prognostic significance of cytokine receptor expression in adult acute lymphoblastic leukemia: interleukin-2 receptor alpha-chain predicts a poor prognosis. 1720 58

The granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic cytokine able to regulate a variety of cell functions including differentiation of macrophages and granulocytes, dendritic cell development and the maintenance of homeostasis. It binds specifically to its receptor, which is composed of a cytokine-specific alpha-chain (GM-CSF receptor alpha-chain, GMRalpha) and a beta-chain shared with the receptors for interleukin-3 and interleukin-5. In this report, we present a comprehensive study of GMRalpha in the mouse. We have found that the mouse GMRalpha is polymorphic and alternatively spliced. In the absence of specific antibodies, we generated a novel chimeric protein containing the Fc fragment of human IgG1 coupled to mouse GM-CSF, which was able to specifically bind to GMRalpha and induce proliferation of GMRalpha-transduced Ba/F3 cells. We used this reagent to perform the first detailed FACS study of the surface expression of mouse GMRalpha by leucocytes. Highest expression was found on monocytes and granulocytes, and variable expression on tissue macrophages. The GM-CSF receptor in mice is specifically expressed by myeloid cells and is useful for the detection of novel uncharacterised myeloid populations. The ability to detect GM-CSF receptor expression in experimental studies should greatly facilitate the analysis of its role in immune pathologies.
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PMID:Characterisation of the expression and function of the GM-CSF receptor alpha-chain in mice. 1769 71

Already 20 years have passed since the cloning of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor alpha-chain, the first member of the GM-CSF/interleukin (IL)-3/IL-5 family of hemopoietic cytokine receptors to be molecularly characterized. The intervening 2 decades have uncovered a plethora of biologic functions transduced by the GM-CSF receptor (pleiotropy) and revealed distinct signaling networks that couple the receptor to biologic outcomes. Unlike other hemopoietin receptors, the GM-CSF receptor has a significant nonredundant role in myeloid hematologic malignancies, macrophage-mediated acute and chronic inflammation, pulmonary homeostasis, and allergic disease. The molecular mechanisms underlying GM-CSF receptor activation have recently been revealed by the crystal structure of the GM-CSF receptor complexed to GM-CSF, which shows an unexpected higher order assembly. Emerging evidence also suggests the existence of intracellular signosomes that are recruited in a concentration-dependent fashion to selectively control cell survival, proliferation, and differentiation by GM-CSF. These findings begin to unravel the mystery of cytokine receptor pleiotropy and are likely to also apply to the related IL-3 and IL-5 receptors as well as other heterodimeric cytokine receptors. The new insights in GM-CSF receptor activation have clinical significance as the structural and signaling nuances can be harnessed for the development of new treatments for malignant and inflammatory diseases.
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PMID:The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease. 1943 55

The granulocyte-macrophage colony-stimulating factor (GM-CSF)/interleukin (IL)-3/IL-5 receptor family regulates the production and function of myeloid cells. These cytokines signal through receptor complexes that consist of unique ligand-binding alpha-chains and common signaling beta-chains. IL-5 is distinct from IL-3 and GM-CSF in its capacity to induce eosinophil development, however, the molecular mechanisms that generate functional diversity within this receptor family are mostly unknown. Here, we characterized the selective IL-5Ralpha-binding adapter protein syntenin in IL-5R function. Syntenin and IL-5Ralpha colocalize at the plasma membrane and in early endosomal compartments. Manipulation of syntenin expression by ectopic expression or knockdown selectively modulated IL-5R but not GM-CSF receptor signaling, and severely affected IL-5-induced eosinophil differentiation from primary human CD34+ hematopoietic progenitor cells. We found syntenin up-regulated during eosinophilopoiesis but down-regulated during neutropoiesis. Syntenin forms complexes with multiple IL-5Ralpha chains, suggesting that syntenin-enhanced IL-5R output may result from stabilization of an IL-5-induced oligomeric receptor complex. These data demonstrate that cytokine-specific functions can be transduced by unique receptor alpha-chain-associating adapter proteins.
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PMID:Regulation of myelopoiesis through syntenin-mediated modulation of IL-5 receptor output. 1965 10


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