Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human mast cells have been purified from uterine tissues, and their surface marker profile and function have been evaluated as part of ongoing studies of mast cell heterogeneity. Using a panel of antibodies, purified uterine mast cells (UMC; 81% +/- 7% purity, n = 10) were analyzed by immunofluorescence and flow cytometry for surface expression of various antigens. Consistent with previous analyses of mast cells from other tissues, UMC expressed HLA class I, IgE, c-kit receptor, CD9, CD33, CD43, CD45, and CD54, while CD11a, CD11b, CD14, CD16, CD23, and CD64 were not detected. Unlike other mast cells, UMC expressed CD11c/CD18 (p150,95) and CD32 (Fc gamma RII). Additional antigens not previously studied on mast cells included the selectin LECAM-1 (Leu-8) and several beta 1 and beta 3 integrins; expression of very late activation antigen-4 (VLA-4) (CD49d/CD29), VLA-5 (CD49e/CD29), and the vitronectin receptor (CD51/CD61) was seen. Functional studies showed that treatment of human umbilical vein endothelial cells with interleukin-1 (5 ng/mL for 4 hours) resulted in a twofold to threefold increase in adhesiveness for UMC. Purification procedures did not alter histamine release responses to anti-IgE or the calcium ionophore A23187, and treatment of UMC with an anti-CD32 monoclonal antibody (IV.3) did not induce histamine release or alter anti-IgE-induced release. These data suggest that UMC may possess unique phenotypic characteristics, and support the concept of mast cell heterogeneity.
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PMID:Immunophenotyping and functional analysis of purified human uterine mast cells. 137 Jun 42

Steel (SI) and white spotting (W) loci encode steel factor (c-kit ligand) and the c-kit tyrosine kinase receptor, respectively. Mutations at these loci affect migration and differentiation of primordial germ cells, neural crest-derived melanoblasts, and hematopoietic cells. In these processes, cell adhesion molecules are hypothesized to be crucial. We have examined the role of steel factor and c-kit in cell-extracellular matrix adhesion using bone marrow-derived mast cells as a model system. Steel factor stimulates mast cells to bind to fibronectin and, to a lesser extent, to vitronectin, whereas interleukin-3 and interleukin-4, which are also mast cell growth factors, do not. Activation of adhesiveness is transient, occurs at concentrations of steel factor 100-fold lower than required for growth stimulation, and requires the integrin VLA-5. Mast cells from c-kit mutant mice adhere to fibronectin on stimulation with phorbol 12-myristate 13-acetate (PMA), but not on stimulation with steel factor, indicating that stimulation of integrin adhesiveness requires activation of the c-kit protein tyrosine kinase. By contrast, c-kit mutant and wild-type mast cells adhere equally well to COS cells expressing membrane-anchored steel factor, showing that the kinase activity of c-kit is not required for adhesion directly mediated by c-kit. Our findings suggest that regulation of adhesion is an important biologic function of steel factor.
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PMID:Steel factor and c-kit regulate cell-matrix adhesion. 750 7

Interaction with stromal cells is known to be crucial for growth and differentiation of hematopoietic cells. To characterize adhesion molecules involved in this interaction, we examined adhesion of a panel of lymphoid, myeloid, and mast cell lines with stromal cells. We found that very late antigen-4 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) were major adhesion molecules in lymphoid and myeloid cells, whereas myeloma cells adhered to stromal cells through hyaluronate. We investigated regulation of VLA-4 during differentiation of myeloid cells using a neutrophil precursor cell line, L-G3. Differentiation of neutrophils induced by granulocyte colony-stimulating factor was accompanied with down-regulation of VLA-4. Induced L-G3 cells adhered to stromal cells in proportion to the expression of VLA-4. Mast cells used two mechanisms to adhere to fibroblasts and stromal cells. They adhered to fibronectin through VLA-5 when stimulated with steel factor and also directly to membrane-anchored steel factor through c-kit.
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PMID:Adhesion molecules in hematopoietic cells. 752 78

The diagnostic and prognostic value of immunophenotyping with 18 murine monoclonal antibodies (MoAbs) to a variety of leukocyte differentiation antigens was assessed in 168 adults aged 15 to 60 years with acute myeloid leukemia (AML). Patients were entered on the multicentre Australian Leukaemia Study Group M4 protocol, and were randomized to receive either standard or high-dose Ara-C together with daunorubicin and etoposide as induction chemotherapy, followed by standard consolidation and maintenance therapy. Diagnostic bone marrow aspirate (152 cases) or peripheral blood samples (16) were analyzed by indirect immunofluorescence and flow cytometry. MoAbs used were directed at myeloid (CD11b, CD13, CD14, CD15, CD33, CD41), lymphoid (CD2, CD3, CD7, CD9, CD10, CD19), or stem cell (HLA-DR, CD34, c-kit receptor) antigens, as well as the leukocyte integrins CD18 and CD49e, and the transferrin receptor CD71. Of the myeloid markers, CD13 and CD33 were the most useful diagnostically (71% and 79% of cases positive, respectively), with CD11b, CD14, and CD15 less commonly positive. A minority of cases expressed lymphoid antigens, either T cell (CD2 16%, CD3 7%, CD7 28%) or B cell (CD10 2%, CD19 7%). CD34 was detected on 42% and c-kit receptor on 48%. When patients were analyzed for response to treatment, CD2, CD9, and CD14 were significantly associated with complete remission rate: cases expressing these antigens had a poorer response than negative cases. In univariate analysis, CD11b+ cases had shorter periods of remission (relative risk of relapse, 2.33; P = .003) and shorter survival (relative death rate, 1.91; P = .006). In multivariate analysis, adjusting for other prognostic factors, CD9 and CD11b were significantly predictive of shorter survival. No other marker had a significant predictive effect. We conclude that myeloid MoAbs are useful in confirming the diagnosis of AML, but their prognostic value may be limited to CD11b. Lymphoid antigen expression is a consistent phenomenon in a minority of cases of AML, but appears to have little clinical significance.
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PMID:Prognostic value of immunophenotyping in acute myeloid leukemia. Australian Leukaemia Study Group. 804 37

Cell-cell and cell-matrix adhesive interactions mediated by integrins play crucial roles in leukocyte migration to inflamed tissues, and also in cell migration during embryogenesis. Much remains to be learned about the molecular mechanisms of regulation of adhesion mediated by integrins. Recently we found that steel factor and c-kit induce adhesion to fibronectin by VLA-5 in mast cells. Activation of adhesiveness is transient, and occurs at concentrations of steel factor 100-fold lower than required for growth stimulation. This suggests that regulation of adhesion is an important biological function of steel factor and c-kit. Other receptor tyrosine kinases such as the PDGF receptor can substitute for c-kit. Signaling through receptor tyrosine kinases may offer a general mechanism for the regulation of integrin avidity.
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PMID:Regulation of cell-matrix adhesion by receptor tyrosine kinases. 853 83

There is increasing evidence for an interaction between acute leukemia cells and the microenvironment of the bone marrow. Blast cells from cases of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) bind to cellular and extracellular matrix components of the bone marrow stroma. In AML, adhesion to stroma is mediated by the combined action of beta 1 (principally VLA-4) and beta 2 integrins, while in precursor-B ALL VLA-4 and VLA-5 integrins play a major role. Adhesion molecules such as CD31, CD44, non-beta 1, beta 2 integrins, growth factor receptors such as c-kit, and other molecules are also likely to play a role. Binding of acute leukemia blasts to ligands on stroma has several pathophysiological consequences. Stromal contact is able to inhibit programmed cell death (apoptosis) in a proportion of cases of both AML and ALL. In ALL, diffusible molecules derived from stroma appear to contribute. Marrow stroma also plays a part in regulating leukemic cell proliferation. While this is partly due to stromal production of hemopoietic growth factors, in soluble or transmembrane form or bound to extracellular matrix, signalling mediated directly by binding of adhesion molecules on leukemic cells may also have a role. Contact of ALL blasts with marrow fibroblasts is followed by migration of leukemic cells, utilizing VLA-4 and VLA-5 integrins, potentially allowing homing of blasts to favourable microenvironmental sites, or controlling egress into the circulation. AML cells compete for stromal binding sites with natural killer cells and cytotoxic lymphocytes, which are known to inhibit their clonogenic growth. We speculate that these complex interactions between leukemic blasts, cellular and matrix components of stroma, and cytotoxic lymphocytes, play a critical role in determining the fate of small numbers of leukemic cells surviving after cytotoxic chemotherapy.
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PMID:Interaction of acute leukemia cells with the bone marrow microenvironment: implications for control of minimal residual disease. 858 Aug 10

Abnormal adhesive interaction between bone marrow stroma and progenitors, one of the causes of unregulated proliferation in chronic myelocytic leukaemia (CML), may be caused by some alterations in adhesion molecules on CML progenitors. We investigated the expression of adhesion molecules (CD44, VLA-5, VLA-4, LFA-1, ICAM-1, L-selectin and c-kit) on bone marrow CD34++ cells from 16 CML patients by three-colour flow cytometry. The mean percentage of cells expressing L-selectin in the CD34++CD38+(or)++ fraction from untreated CML patients was significantly lower, and that in the CD34++CD38- fraction tended to be lower than that from normal controls. Among 11 CML patients treated with interferon-alpha (IFN-alpha), the mean percentage of the cells expressing L-selectin in the CD34++CD38- fraction from three patients with a low percentage of Ph1(+) cells in bone marrow was significantly higher than that from five patients with a high percentage of Ph1(+) cells. In addition, L-selectin expression rate was inversely correlated to the percentage of Ph1(+) cells. There was no significant difference between the untreated patients and normal controls with regard to the expression rates of the other adhesion molecules in each CD34++ fraction except LFA-1. These data suggest that decreased L-selectin expression in CML CD34++ cells reflects one of the features of malignant CML progenitors.
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PMID:Decreased L-selectin expression in CD34-positive cells from patients with chronic myelocytic leukaemia. 863 30

Three-color immunofluorescence cytometry was used to quantify the expression of different adhesion molecules on CD34+ cells of steady-state bone marrow (BM) and peripheral blood stem cells (PBSC) after mobilizing with G-CSF (10 micrograms/kg/body weight) in nine cancer patients undergoing high-dose chemotherapy with subsequent autologous blood stem cell rescue. The expression rate of each adhesion molecule on CD34+ cells showed great inter-individual variations. High expression (> 50%) on CD34+ cells from PBSC and BM was found for CD58 (leukocyte function-associated antigen-3), CD31 (platelet-endothelial cell adhesion molecule-1), CD11a (leukocyte function-associated antigen-1) and CD49d (very late activation antigen-4); a moderate expression (20%-40%) was seen for CD49e (very late activation antigen-5), CD62L (leukocyte-endothelial cell adhesion molecule), CD54 (ICAM-1) and CD117 (c-kit). c-kit, CD58, CD62L and CD49d were less expressed on CD34+ cells of PBSC than of BM, the difference being statistically significant for CD49d (p < 0.05). CD49e and CD37 were expressed more in PBSC than BM without being statistically significant. The mean fluorescence intensity for all adhesion molecules on CD34+ cells did not differ significantly between PBSC and BM. The significantly lower expression of CD49d on G-CSF-mobilized PBSCs might suggest that downregulation of this molecule may be involved in the process of peripheral stem cell mobilization.
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PMID:Difference between expression of adhesion molecules on CD34+ cells from bone marrow and G-CSF-stimulated peripheral blood. 947 47

Acute myeloid leukaemia (AML) cells express the SCF receptor c-kit (CD117) on their cell surface and demonstrate enhanced adhesion to fibronectin (FN) following exposure to stem cell factor (SCF). Increased adhesion occurs within 5 min, is dose dependent, and persists beyond 2 h. Baseline and enhanced adhesion occur through the surface FN receptor very late antigen-5 (VLA-5, CD49e/CD29) which is expressed by AML cells. Unstimulated AML cells exposed to FN undergo less apoptosis than controls (inhibition 22.5 +/- 7.0%, P = 0.02, n = 8). Exposure to SCF alone without FN also inhibits AML cell apoptosis (by 19.0 +/- 7.7% compared to controls, P = 0.06, n = 8). Simultaneous exposure to SCF and FN increases the inhibition of AML cell apoptosis to 37.8 +/- 7.9% (P = 0.005 compared to control, P = 0.04 compared to FN alone, P = 0.06 compared to SCF alone) demonstrating that SCF not only enhances the propensity of AML cells to adhere to FN, but also results in an additive survival benefit following FN contact. Some but not all the reduction in apoptosis is mediated through VLA-5. The combination of SCF and FN also affects proliferation, resulting in a synergistic enhancement of AML cell proliferation in half the cases studied. When normal CD34+ human haemopoietic progenitors were studied, FN had little effect on their apoptosis and failed to enhance the anti-apoptotic effect of SCF. It did, however, synergise with SCF in promoting CD34+ cell proliferation. Exposure of AML cells to SCF and FN, both of which can be found in high concentration in the bone marrow stroma, inhibits apoptosis. Cytokines and extracellular matrix proteins augment each others' effects since SCF enhances adhesion to fibronectin, which in turn augments the survival signal delivered by the cytokine alone. Cytokine and adhesion receptors can combine to affect cell characteristics including proliferation and survival.
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PMID:Stem cell factor enhances the adhesion of AML cells to fibronectin and augments fibronectin-mediated anti-apoptotic and proliferative signals. 973 85

We have previously demonstrated that PU.1 is required for the production of lymphoid and myeloid, but not of erythroid progenitors in the fetal liver. In this study, competitive reconstitution assays show that E14.5 PU.1(-/-) hematopoietic progenitors (HPC) fail to sustain definitive/adult erythropoiesis or to contribute to the lymphoid and myeloid lineages. PU.1(-/-) HPC are unable to respond synergistically to erythropoietin plus stem cell factor and have reduced expression of c-kit, which may explain the erythroid defect. Fluorescently labeled, PU.1(-/-), AA4.1(+), fetal liver HPC were transferred into irradiated recipients, where they demonstrated a severely impaired ability to home to and colonize the bone marrow. PU.1(-/-) HPC were found to lack integrins alpha(4) (VLA-4/CD49d), alpha(5) (VLA-5/CD49e), and CD11b (alpha(M)). Collectively, this study has shown that PU.1 plays an important role in controlling migration of hematopoietic progenitors to the bone marrow and the establishment of long-term multilineage hematopoiesis.
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PMID:A critical role for PU.1 in homing and long-term engraftment by hematopoietic stem cells in the bone marrow. 1043 16


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