Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

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

To elucidate the rapid events in signal transduction of human granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL 3), we examined phosphorylation of proteins on both serine and tyrosine residues in a cytokine-stimulated human myeloid cell line. We found increases in tyrosine phosphorylation within 30 s of stimulation with GM-CSF or IL 3, with peak responses occurring within 2 min. IL 3 and GM-CSF also induced serine phosphorylation, though 10 min of stimulation was required for maximum phosphate incorporation. Interestingly, both IL 3 and GM-CSF stimulated phosphate incorporation in identical substrates, a 68 kDa seryl-phosphoprotein (p68) and a 140 kDa tyrosyl-phosphoprotein (p140). Treatment of AML 193 cells with phorbol myristate acetate resulted in serine phosphorylation of p68; however, p140 was not phosphorylated on tyrosine. Depletion of protein kinase C isoenzymes with high concentrations of phorbol myristate acetate resulted in p68 phosphorylation, which was not further increased by IL 3 or GM-CSF. In contrast, cytokine-induced phosphorylation on tyrosine of p140 was observed after protein kinase C depletion. These data demonstrate the co-ordinate yet independent serine and tyrosine phosphorylation in IL 3- and GM-CSF-treated human myeloid cells, and thus suggest a common set of protein kinases stimulated by each separate ligand.
...
PMID:Signal transduction of human interleukin 3 and granulocyte-macrophage colony-stimulating factor through serine and tyrosine phosphorylation. 170 Jun 99

Interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor induce the rapid phosphorylation of the c-raf protein in the growth factor-dependent FDC-P1 and DA-3 murine myeloid cell lines. Furthermore, immunoprecipitates of c-raf isolated from growth factor-stimulated cells demonstrate a marked increase in intrinsic protein kinase activity as measured in vitro. IL-3 and granulocyte-macrophage colony-stimulating factor induce phosphorylation of c-raf at both serine and tyrosine residues. Antiphosphotyrosine immunoprecipitates from IL-3-stimulated cells demonstrate the rapid and coordinate phosphorylation of both c-raf and a protein co-migrating with the 140-kDa putative IL-3 receptor component. Collectively, the findings of rapid and coordinate ligand-induced phosphorylation of a potential IL-3 growth factor receptor component and cytoplasmic c-raf with concomitant c-raf activation provide a cogent sequential molecular model for linking external growth stimuli to intracellular signal transduction events.
...
PMID:Interleukin-3 and granulocyte-macrophage colony-stimulating factor mediate rapid phosphorylation and activation of cytosolic c-raf. 170 Sep 80

Protein tyrosine phosphorylation was studied in macrophages and fibroblasts to identify putative components of post-receptor mitogenic pathways that might be functionally conserved in different cell types. Nondenaturing conditions were established for the approximately quantitative recovery of anti-phosphotyrosine antibody (alpha PY)-reactive proteins from cells. A common, 57-kDa alpha PY-reactive protein was identified by V8 protease peptide mapping in colony-stimulating factor-1 (CSF-1)- or granulocyte-macrophage colony-stimulating factor (GM-CSF)-stimulated BAC1.2F5 macrophages, in platelet-derived growth factor-stimulated NIH-3T3 cells, and in CSF-1-stimulated NIH-3T3 cells expressing the c-fms/CSF-1 receptor. The 57-kDa protein was phosphorylated on serine and tyrosine and was the only alpha PY-reactive protein band whose phosphorylation was reproducibly increased in GM-CSF-stimulated cells. The effect of the growth factors on the tyrosine phosphorylation of the 57-kDa protein could be mimicked by treatment of the cells with orthovanadate, a phosphotyrosine protein phosphatase inhibitor. In the absence of growth factors, tyrosine phosphorylation of the 57-kDa protein was higher in v-fms or c-fms (F969, S301)-transformed NIH-3T3 cells than in untransformed NIH-3T3 (c-fms) and NIH-3T3 (c-fms, F969) cells. These data indicate that the 57-kDa protein is a common target for growth factor-stimulated tyrosine phosphorylation and potentially important for growth factor mitogenic signaling.
...
PMID:Tyrosine phosphorylation of a common 57-kDa protein in growth factor-stimulated and -transformed cells. 170 76

The aim of the present study is to evaluate the involvement of human neutrophil tyrosine kinase(s) in the signal transduction mechanism of granulocyte-macrophage colony-stimulating factor (GM-CSF). Stimulation of neutrophils with GM-CSF resulted in a time- and dose-dependent phosphorylation of several proteins having estimated molecular weights of approximately 40, 55, 74, 97, 118, and 155 Kd, detected by immunoblot using a monoclonal antibody directed against phosphotyrosine. GM-CSF-induced tyrosine phosphorylation was inhibited in a dose- and time-dependent manner by the tyrosine kinase inhibitor erbstatin. Using this inhibitor, we were able to correlate tyrosine phosphorylation with several functional effects of GM-CSF on human neutrophils. Pretreatment of neutrophils with erbstatin before incubation with GM-CSF completely inhibited the GM-CSF-induced intracellular alkalinization, downregulation of the leukotriene B4 receptor, enhancement of fMet-Leu-Phe-induced intracellular calcium mobilization, as well as the accumulation of mRNA for the proto-oncogene c-fos. Taken together, these data suggest that tyrosine kinase activation in human neutrophils plays a critical regulatory role in both the stimulation and priming of neutrophil function by GM-CSF.
...
PMID:Involvement of tyrosine kinases in the activation of human peripheral blood neutrophils by granulocyte-macrophage colony-stimulating factor. 171 73

The c-kit proto-oncogene encodes a receptor tyrosine kinase that is thought to play an important role in hematopoiesis. In a series of human acute myeloblastic leukemia (AML), the expression of the c-kit proto-oncogene and its product was studied by means of Northern blot and immunoblot analyses. The c-kit mRNA was expressed in 20 of 25 cases of AML, and in those cases the product of the c-kit proto-oncogene was detected by immunoblotting with anti-c-kit antibody. The expression of c-kit transcripts and protein was barely detectable in normal bone marrow cells as a control. The expression of c-kit transcript did not correlate with the French-American-British classification nor clinical manifestations. In 6 of 11 cases that expressed c-kit product, AML cells were found to proliferate in response to recombinant human stem cell factor (rhSCF), the ligand for c-kit, and the synergistic stimulation of AML cells was observed by rhSCF and granulocyte-macrophage colony-stimulating factor. Immunoblotting with anti-phosphotyrosine antibody showed that the c-kit receptor protein was detectably phosphorylated in 7 of 12 cases tested before the stimulation with rhSCF, while the rhSCF treatment resulted in an increased tyrosine phosphorylation of c-kit in AML cells. These results indicate that c-kit proto-oncogene is expressed in most cases of AML and is functional in terms of supporting proliferation.
...
PMID:Expression and functional role of the proto-oncogene c-kit in acute myeloblastic leukemia cells. 172 40

The c-kit proto-oncogene encodes a receptor having tyrosine-specific kinase activity and has been mapped to chromosome 4 in the human and chromosome 5 in the mouse, at the dominant white spotting locus (W). Mutations at the W locus affect various aspects of murine hematopoiesis. The c-kit proto-oncogene has been shown to be expressed by leukemic myeloblasts, but not by normal unseparated human bone marrow cells. The role of this oncogene in differentiation and proliferation of human hematopoietic progenitors is presently undefined. To determine c-kit expression by normal hematopoietic progenitors, CD34+ cells were isolated from disease-free human bone marrow, and RNA-based polymerase chain reaction (PCR) techniques were used to assess expression. By this method, we have demonstrated c-kit expression by CD34+ bone marrow progenitors. To address the functional requirement for c-kit expression in normal human hematopoiesis, CD34+ cells were incubated in the presence of sense, antisense, or missense oligonucleotides to c-kit, and subsequently cultured in the presence of either recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) or recombinant human interleukin-3 (rhIL-3). Exposure of CD34+ cells to c-kit antisense oligonucleotides significantly inhibited colony-forming ability of cells cultured in the presence of rhIL-3, but had no effect on colony formation of cells cultured in rhGM-CSF. Together, these data suggest a possible role for c-kit in hematopoietic proliferation and differentiation that may be linked to some, but not all, stimulatory factors.
...
PMID:c-kit expression by CD34+ bone marrow progenitors and inhibition of response to recombinant human interleukin-3 following exposure to c-kit antisense oligonucleotides. 172 Jun 96

Mast cell growth factor (MGF, the ligand for c-kit receptor) can stimulate proliferation of factor dependent myeloid cell line, M07e, and MGF synergizes with granulocyte-macrophage colony-stimulating factor (GM-CSF) or IL-3 in this effect. The effect of MGF on protein tyrosine kinase activity in M07e cells was investigated by immunoblotting with anti-phosphotyrosine mAb and this was compared with effects of GM-CSF. MGF stimulation rapidly induced or enhanced at least 12 tyrosine phosphorylated bands. Major bands had molecular weights of 145, 120, 110, 98, 62, 55 and 42 kD. P145, the most prominent phosphorylated protein, was identified as c-kit product using anti-c-kit-mAb (YB5.B8), suggesting ligand-dependent receptor autophosphorylation. Five of six tyrosine phosphorylated bands induced or enhanced by GM-CSF stimulation comigrated with those tyrosine phosphorylated by MGF (138, 120, 76, 55 and 42 kD). P42 was identified, at least in part, as mitogen-activated protein (MAP) kinase. MGF induced tyrosine phosphorylation of a complex of GTPase-activating protein (GAP, 120 kD) and GAP associated proteins (p62/p190) as detected by anti-GAP Ab immunoprecipitation followed by immunoblotting with anti-phosphotyrosine mAb. GM-CSF also stimulated slightly but consistently tyrosine phosphorylation of GAP and p190 but not p62. Both MGF and GM-CSF enhanced Raf-1 phosphorylation and increased Raf-1 associated kinase activity in vitro. Phosphoamino acid analysis revealed Raf-1 phosphorylation by these two growth factors occurred almost exclusively on serine residues. No tyrosine phosphorylation of Raf-1 protein was detected. These data suggest shared and unshared components of signaling pathways of both factors, which may be involved in cell proliferation.
...
PMID:Comparative analysis of signaling pathways between mast cell growth factor (c-kit ligand) and granulocyte-macrophage colony-stimulating factor in a human factor-dependent myeloid cell line involves phosphorylation of Raf-1, GTPase-activating protein and mitogen-activated protein kinase. 172 91

Interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulate the proliferation of several kinds of cultured hematopoietic cell lines. Growth signals from IL-3 and GM-CSF cause accumulation of active Ras.GTP complexes in PT18 mouse mast cell line (Satoh, T., Nakafuku, M., Miyajima, A., and Kaziro, Y. (1991) Proc. Natl. Acad. Sci. U. S. A. 88, 3314-3318). In this paper we describe the effect of herbimycin A, a tyrosine kinase-specific inhibitor, on the activation of Ras. The increase of Ras.GTP induced by IL-3 and GM-CSF diminished in cells treated with 0.5 approximately 1 micrograms/ml of herbimycin A for 24 h prior to the addition of the growth factors. Under this condition, the extent of phosphorylation on tyrosine residues of proteins decreased. However, the activity of cAMP-dependent protein kinase and protein kinase C did not change. Growth of cells in the presence of IL-3 or GM-CSF was also completely inhibited. These observations suggest that tyrosine kinases are involved in the pathways between IL-3 and GM-CSF receptors and Ras and that they are essential for the growth stimulated by these growth factors.
...
PMID:Inhibition of interleukin 3 and granulocyte-macrophage colony-stimulating factor stimulated increase of active ras.GTP by herbimycin A, a specific inhibitor of tyrosine kinases. 173 50

Granulocyte-macrophage colony-stimulating factor (GM-CSF) exerts its biologic activities through binding to specific high-affinity cell surface receptors. After binding, the ligand/receptor complex is rapidly internalized in most hematopoietic cells. Using a human factor-dependent cell line, MO7, and normal human neutrophils, we found that the internalization is exquisitely temperature-dependent, such that ligand/receptor internalization does not detectably occur at 4 degrees C. Activation of the GM-CSF receptor has previously been shown to stimulate a number of postreceptor signal transduction pathways, including activation of a tyrosine kinase and activation of the serine/threonine kinase, Raf-1. The GM-CSF-stimulated increase in tyrosine kinase activity occurs rapidly at both 4 degrees C and 37 degrees C, and therefore is likely to be independent of receptor internalization. At 37 degrees C, the protein tyrosine phosphorylation was transient in MO7 cells, with maximum phosphorylation observed after 5 to 15 minutes, followed by a rapid decline. At 4 degrees C, the protein tyrosine phosphorylation of the same substrates was greater than at 37 degrees C, and no decline in substrate phosphorylation was observed for at least 90 minutes. In contrast to tyrosine phosphorylation, the activation and hyper-phosphorylation of Raf-1 observed at 37 degrees C in both MO7 cells and neutrophils was markedly diminished at 4 degrees C. These results indicate that at least one postreceptor signal transduction mechanism, activation of a tyrosine kinase, does not require ligand/receptor internalization, and indicate that receptor internalization may be a consequence, rather than the initiator, of signal transduction.
...
PMID:Internalization of the granulocyte-macrophage colony-stimulating factor receptor is not required for induction of protein tyrosine phosphorylation in human myeloid cells. 183 97

Colony-stimulating factor-1 (CSF1) is a cell lineage-specific hemopoietin required for the growth, differentiation, and survival of macrophages and their precursors. The human CSF1 receptor (CSF1R) is a 150-kDa transmembrane glycoprotein whose cytoplasmic tyrosine kinase domain is split by a kinase insert (KI) region of approximately 70 amino acids. We tested the ability of CSF1R KI domain deletion mutants to stimulate phosphatidylinositol-3-kinase (PtdIns-3-kinase), an enzyme whose activity is augmented by tyrosine kinase oncogenes and receptor tyrosine kinases, and to support mitogenesis in transfected cells. Receptor immunoprecipitates from CSF1-stimulated cells contained greater than 5-fold more PtdIns-3-kinase activity compared to nonstimulated cells. High performance liquid chromatography analysis of the PtdIns-3-kinase product scraped from thin layer chromatography plates indicated that PtdIns-3-P was produced. CSF1R KI domain deletion mutants retained tyrosine kinase activity in vitro. Receptor immunoprecipitates of two partially overlapping 28 and 30 amino acid KI deletion mutants of CSF1R retained some PtdIns-3-kinase activity, in contrast to immunoprecipitates of CSF1R lacking 67 amino acids of the KI domain. Each deletion mutant stimulated CSF1-dependent DNA synthesis in transfected cells at much reduced levels compared to wild-type receptor expressing cells. These data suggest a role for the CSF1R KI domain in PtdIns-3-kinase association and for CSF1-induced thymidine incorporation into DNA.
...
PMID:A mutational analysis of phosphatidylinositol-3-kinase activation by human colony-stimulating factor-1 receptor. 185 Jul 34


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---