UNIPROT:P04141 - FACTA Search

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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)

Two distinct components, alpha and beta chains, which compose the high affinity receptor for human granulocyte-macrophage colony-stimulating factor (GM-CSF) do not contain any catalytic domains of known enzymes. However, in mouse lymphoid cell lines transfected with cDNAs of the both chains, GM-CSF triggers tyrosine phosphorylation of several cellular proteins and allows continuous proliferation. To elucidate whether the high affinity receptor functions in nonhematopoietic cells, we have reconstituted human GM-CSF receptor in mouse NIH3T3 fibroblasts. In NIH3T3 clones, in which the high affinity receptor is reconstituted, human GM-CSF has triggered rapid tyrosine phosphorylation of cellular proteins, transfected beta chain, and another protein of 40-45 kDa. Moreover, human GM-CSF stimulated DNA synthesis and induced morphological transformation. These observations indicate that coordinately expressed alpha and beta chains of human GM-CSF receptor activates intrinsic protein-tyrosine kinases by the stimulation with human GM-CSF and that the activated protein-tyrosine kinases phosphorylate tyrosine residues of an intrinsic 40-45-kDa protein and the transfected beta chain in NIH3T3 cells. Activation of the protein-tyrosine kinases is likely to have biological functions to induce DNA synthesis and morphological transformation of mouse fibroblasts.
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PMID:Coordinate expression of the alpha and beta chains of human granulocyte-macrophage colony-stimulating factor receptor confers ligand-induced morphological transformation in mouse fibroblasts. 851 1

Nyk/Mer is a recently identified receptor tyrosine kinase with neural cell adhesion molecule-like structure (two immunoglobulin G-like domains and two fibronectin III-like domains) in its extracellular region and belongs to the Ufo/Axl family of receptors. The ligand for Nyk/Mer is presently unknown, as are the signal transduction pathways mediated by this receptor. We constructed and expressed a chimeric receptor (Fms-Nyk) composed of the extracellular domain of the human colony-stimulating factor 1 receptor (Fms) and the transmembrane and cytoplasmic domains of human Nyk/Mer in NIH 3T3 fibroblasts in order to investigate the mitogenic signaling and biochemical properties of Nyk/Mer. Colony-stimulating factor 1 stimulation of the Fms-Nyk chimeric receptor in transfected NIH 3T3 fibroblasts leads to a transformed phenotype and generates a proliferative response in the absence of other growth factors. We show that phospholipase C gamma, phosphatidylinositol 3-kinase/p70 S6 kinase, Shc, Grb2, Raf-1, and mitogen-activated protein kinase are downstream components of the Nyk/Mer signal transduction pathways. In addition, Nyk/Mer weakly activates p90rsk, while stress-activated protein kinase, Ras GTPase-activating protein (GAP), and GAP-associated p62 and p190 proteins are not activated or tyrosine phosphorylated by Nyk/Mer. An analysis comparing the Nyk/Mer signal cascade with that of the epidermal growth factor receptor indicates substrate preferences by these two receptors. Our results provide a detailed description of the Nyk/Mer signaling pathways. Given the structural similarity between the Ufo/Axl family receptors, some of the information may also be applied to other members of this receptor tyrosine kinase family.
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PMID:Mitogenic signals and transforming potential of Nyk, a newly identified neural cell adhesion molecule-related receptor tyrosine kinase. 852 23

The interleukin-2 (IL-2) receptor (IL-2R) consists of three distinct subunits (alpha, beta, and gamma c) and regulates proliferation of T lymphocytes. Intracellular signalling results from ligand-mediated heterodimerization of the cytoplasmic domains of the beta and gamma c chains. To identify the residues of gamma c critical to this process, mutations were introduced into the cytoplasmic domain, and the effects on signalling were analyzed in the IL-2-dependent T-cell line CTLL2 and T-helper clone D10, using chimeric IL-2R chains that bind and are activated by granulocyte-macrophage colony-stimulating factor. Whereas previous studies of fibroblasts and transformed T cells have suggested that signalling by gamma c requires both membrane-proximal and C-terminal subdomains, our results for IL-2-dependent T cells demonstrate that the membrane-proximal 52 amino acids are sufficient to mediate a normal proliferative response, including induction of the proto-oncogenes c-myc and c-fos. Although gamma c is phosphorylated on tyrosine upon receptor activation and could potentially interact with downstream molecules containing SH2 domains, cytoplasmic tyrosine residues were dispensable for mitogenic signalling. However, deletion of a membrane-proximal region conserved among other cytokine receptors (cytoplasmic residues 5 to 37) or an adjacent region unique to gamma c (residues 40 to 52) abrogated functional interaction of the receptor chain with the tyrosine kinase Jak3. This correlated with a loss of all signalling events analyzed, including phosphorylation of the IL-2R beta-associated kinase Jak1, expression of c-myc and c-fos, and induction of the proliferative response. Thus, it appears in T cells that Jak3 is a critical mediator of mitogenic signaling by the gamma c chain.
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PMID:A membrane-proximal region of the interleukin-2 receptor gamma c chain sufficient for Jak kinase activation and induction of proliferation in T cells. 852 10

Herbimycin A, a benzoquinonoid ansamycin antibiotic, reduces intracellular phosphorylation by some protein tyrosine kinases and inhibits the proliferation of malignant cells which express high tyrosine kinase activity. Herbimycin A inhibited the proliferation of human monoblastic leukemia U937 cells, but this inhibition was abrogated by the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF). On the other hand, a derivative of herbimycin A, 19-allylaminoherbimycin A, inhibited the proliferation of such cells without interference by the addition of GM-CSF. Phosphorylation of MAP kinase and c-myc expression induced by GM-CSF in U937 cells were inhibited by both herbimycin A and 19-allylaminoherbimycin A. The time courses of growth inhibition showed that the growth-inhibitory activity of herbimycin A in U937 cells was initially potent, but gradually decreased in the presence of GM-CSF. Thiol compounds, glutathione (GSH) and 2-mercaptoethanol, abrogated the inhibition of the growth of U937 cells by herbimycin A, but not by 19-allylaminoherbimycin A, like GM-CSF. Intracellular GSH content in U937 cells was increased by treatment with GM-CSF, and decreased with herbimycin A, but returned to the control level with the addition of GM-CSF to herbimycin A. In thin-layer chromatography, after in vitro incubation with herbimycin A and GSH, nothing could be detected at the position of intact herbimycin A, while 19-allylaminoherbimycin A was stably detected. These findings suggest that changes in the intracellular concentration of GSH play a role in the abrogation of the inhibition of U937 cell growth by herbimycin A. In the presence of GSH, 19-allylaminoherbimycin A inhibited the proliferation of U937 cells and Philadelphia chromosome-positive K562 cells more effectively than herbimycin A. Since GSH plays a role in detoxicating several anticancer drugs, 19-allylaminoherbimycin A may have therapeutic advantages over herbimycin A against some types of leukemia.
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PMID:19-Allylaminoherbimycin A, an analog of herbimycin A that is stable against treatment with thiol compounds or granulocyte-macrophage colony-stimulating factor in human leukemia cells. 854 53

The high-affinity and functional granulocyte-macrophage colony-stimulating factor receptor (GMR) is composed of two distinct subunits, alpha and beta; and the cytoplasmic domain of the beta subunit is essential to transduce growth-promoting signals. In contrast to the beta subunit, the role of the alpha subunit is not well characterized. We examined the requirement of the cytoplasmic domain of the alpha subunit and its functional region by deletion analyses. We demonstrated that the cytoplasmic domain of the alpha subunit, especially 29 amino acids residues near the transmembrane domain, was absolutely required for various signaling events including activation of immediate early genes, induction of tyrosine phosphorylation of cellular proteins, and cell growth. We further analyzed the role of the cytoplasmic domain of each subunit by constructing chimeric subunits, designated alpha/beta and beta/alpha, by exchanging cytoplasmic domains of the alpha and beta subunits of human (h) GMR. Reconstituted high-affinity chimeric hGMRs, hGMR(alpha/beta,beta/alpha) and hGMR(alpha/beta,beta), transduced signals at levels similar to the wild type hGMR(alpha,beta) in Ba/F3 cells and in NIH3T3 cells. These observations indicate that the original configuration between the extracellular and the cytoplasmic domains of the hGMR(alpha,beta) subunits is not required and that hGMR(alpha/beta,beta) transduced signals through the cytoplasmic domain of the beta subunit in an oligomeric form, without involvement of the cytoplasmic domain of the alpha subunit. Therefore human granulocyte-macrophage colony-stimulating factor signals are mainly transduced through the beta subunit, and the cytoplasmic domain of the alpha subunit is likely to activate the beta subunit in the normal hGMR.
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PMID:Roles of the cytoplasmic domains of the alpha and beta subunits of human granulocyte-macrophage colony-stimulating factor receptor. 854 67

Phosphotyrosine phosphatases (PTPases) regulate cellular metabolic activation by reversing the effects of tyrosine kinases activated earlier in intracellular signaling pathways. We coupled fluorescence-activated cell sorter analysis using anti-CD45 monoclonal antibody with direct measurements of enzyme activity in resolved subcellular fractions to define mechanisms that potentially regulate the availability and activity of CD45-PTPase on neutrophil plasma membranes. Neutrophils in freshly obtained blood as well as neutrophils freshly isolated from blood were found to possess detectable levels of plasma membrane CD45 as assessed by immunofluorescence. However, plasma membranes from these cells were essentially devoid of PTPase catalytic activity, which was largely confined to the specific granules. Granulocyte-macrophage colony-stimulating factor (GM-CSF) upregulated both the catalytic and antigenic components of CD45-PTPase on the plasma membrane of these cells. Upregulation was associated with a shift in the particulate subcellular PTPase catalytic activity from the specific granule fraction to the plasma membrane fraction. The tyrosine kinase inhibitor genistein abrogated GM-CSF-promoted upregulation of plasma membrane CD45 PTPase but did not prevent the GM-CSF-dependent decrease in specific granule catalytic activity. Anti-CD45 antibody immunoprecipitated PTPase activity from both specific granules of resting cells and plasma membranes of GM-CSF-treated cells. However, antiphosphotyrosine immunoprecipitated only activity that had translocated to the plasma membrane, suggesting a role for CD45 phosphorylation in translocation. Western analysis confirmed the tyrosine phosphorylation of CD45 in plasma membranes of GM-CSF-treated neutrophils. Preincubation of plasma membranes of GM-CSF-stimulated neutrophils with cytosol from resting cells resulted in a time- and temperature-dependent loss in membrane PTPase as a consequence of the effects of a cytosolic inactivator. Cytosol obtained from stimulated neutrophils possessed substantially reduced levels of this PTPase inactivator. We conclude that activity of the catalytic component of membrane PTPase in circulating neutrophils is regulated by a cytosolic inactivator. Upon stimulation, intact CD45 PTPase is incorporated into the plasma membrane by a process that requires tyrosine phosphorylation. As a result of inhibition of the cytosolic inactivator, the translocated PTPase expresses full activity, thereby amplifying the potential regulatory influence of the enzyme on the cells' functional response.
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PMID:Cytosolic inactivation of translocated neutrophil plasma membrane protein tyrosine phosphatase. 854 61

Here, we have studied the activity of a novel protein-tyrosine kinase inhibitor that is selective for the Src family of tyrosine kinases. We have focused our study on the effects of this compound on T cell receptor-induced T cell activation, a process dependent on the activity of the Src kinases Lck and FynT. This compound is a nanomolar inhibitor of Lck and FynT, inhibits anti-CD3-induced protein-tyrosine kinase activity in T cells, demonstrates selectivity for Lck and FynT over ZAP-70, and preferentially inhibits T cell receptor-dependent anti-CD3-induced T cell proliferation over non-T cell receptor-dependent phorbol 12-myristate 13-acetate/interleukin-2 (IL-2)-induced T cell proliferation. Interestingly, this compound selectively inhibits the induction of the IL-2 gene, but not the granulocyte-macrophage colony-stimulating factor or IL-2 receptor genes. This compound offers a useful new tool for examining the role of the Lck and FynT tyrosine kinases versus ZAP-70 in T cell activation as well as the role of other Src family kinases in receptor function.
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PMID:Discovery of a novel, potent, and Src family-selective tyrosine kinase inhibitor. Study of Lck- and FynT-dependent T cell activation. 855 75

When granulocyte-macrophage colony-stimulating factor (GM-CSF)-treated human neutrophils were challenged with the chemotactic factor fMet-Leu-Phe, it was possible to detect a time-dependent increase in the hydrolytic (as measured by the production of phosphatidic acid, PA) and the transphosphatidylation (as measured by the production of phosphatidylethanol, PEt) activities of phospholipase D in intact cells prelabeled with a radioactive fatty acid. Both activities were inhibited by preincubation of cells with genistein. Appropriate conditions were developed to test the PLD transphosphatidylation activity against exogenous phosphatidylcholine (PCho) in an in vitro system. As in intact cells, increased PLD activity could be detected in cell lysates obtained from fMet-Leu-Phe-treated cells compared with controls. When lysates were immunoprecipitated with antiphosphotyrosine antibodies, a PLD activity was found only in immune complexes that were prepared from fMet-Leu-Phe-treated cells. Conversely, no activity was found in lysates immunoprecipitated with an irrelevant antibody (GTPase-activating protein, GAP) that nevertheless was able to recognize a tyrosylphosphorylated form of GAP, as demonstrated by western blotting. These data suggest that a PCho-PLD, or a tightly bound protein, is tyrosine phosphorylated during cell activation.
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PMID:Immunoprecipitation of a phospholipase D activity with antiphosphotyrosine antibodies. 856 10

Interaction of a tyrosine kinase type receptor and its ligand induces receptor-dimerization or -oligomerization followed by transphosphorylation and activation of its intrinsic kinase, which leads to a series of intracellular signals. We have previously reported that the membrane-bound form of Steel factor (SLF) induces more persistent tyrosine kinase activation and longer life span of c-kit encoded protein (KIT) than its soluble form (Miyazawa et al, Blood 85:641, 1995). In this study, we used YB5.B8 monoclonal antibody (MoAb) that recognizes the extracellular domain of KIT to investigate whether immobilized anti-KIT MoAb can substitute for SLF as a potent activator of KIT by cross-linking receptors and further compared its effect with each SLF isoform in a factor-dependent cell line M07e. YB5.B8 MoAb in a soluble state suppressed SLF-induced M07e cell proliferation in a dose-dependent manner. By contrast, once this antibody was immobilized on the goat-antimouse MoAb (GAM)-coated culture plates, it supported the growth of M07e cells in the absence of any growth factors, whereas culture the cells in GAM alone or YB5.B8 without GAM-coated plates resulted in rapid cell-death within 24 hours. As with the natural ligand SLF, immobilized YB5.B8 MoAb synergized with granulocyte-macrophage colony-stimulating factor (GM-CSF) in inducing cell proliferation compared with either YB5.B8 MoAb or GM-CSF alone. Immunoblotting with antiphosphotyrosine MoAb showed that interaction of M07e cells with immobilized YB5.B8 induced tyrosine phosphorylation of a series of intracellular proteins including KIT (145 kD). In addition, cross-linking studies using a water-soluble cross linking reagent bis-sulfosuccinimidyl-suberate showed that immobilized YB5.B8 MoAb induced dimerization and activation of KIT. However, as with stimulation by the membrane-bound form of SLF, the kinetics of KIT activation with YB5.B8 MoAb was more prolonged compared with the cells treated with recombinant soluble SLF. Flow cytometry showed that, unlike the cells treated with soluble SLF, no downmodulation of cell-surface KIT expression was observed in M07e cells cultured with immobilzed YB5.B8 MoAb. These data suggest that immobilized antibodies against hematopoietic receptors may replace their ligand-stimulators; however, their activities may resemble the membrane-bound form rather than the soluble form of natural ligands.
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PMID:Immobilized anti-KIT monoclonal antibody induces ligand-independent dimerization and activation of Steel factor receptor: biologic similarity with membrane-bound form of Steel factor rather than its soluble form. 863 Mar 83

Granulocyte-macrophage colony-stimulating factor (GM-CSF) provokes a proliferative response and induction of early-response genes such as c-fos in target cells. It also induces rapid tyrosine phosphorylation of cellular proteins, including the beta subunit (betac) of its functional receptor. However, locations and functions of phosphorylated tyrosine residues within the betac are unclear. To elucidate the mechanism of the human GM-CSF receptor signal transduction, mutational analyses were made of the cytoplasmic domain of the beta-c, using murine BA/F3 cells. Deletion of the conserved box 1 motif resulted in loss of tyrosine phosphorylation of the betac, thereby indicating an essential role for this motif in activating the tyrosine kinase which phosphorylates betac. A C-terminal truncated mutant at position 589 activated the c-fos promoter, and this activation was diminished by a substitution at tyrosine 577 (Tyr577). However, the same substitution in the full-length betac did not completely abrogate the c-fos promoter activation, hence, redundant signaling pathways probably exist. When we analyzed signaling molecules functioning downstream of the beta-c we found that Tyr577 is essential for Shc phosphorylation, while tyrosine phosphorylation of PTP1D was mediated through Tyr577 as well as through other site(s). We suggest that GM-CSF stimulates at least two modes of signals leading to Ras activation, an event which ultimately gives rise to promoter activation of c-fos.
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PMID:Granulocyte-macrophage colony-stimulating factor provokes RAS activation and transcription of c-fos through different modes of signaling. 863 92

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