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)

In the presence of hemopoietic cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3), mast cell growth factor (MGF; also known as steel factor, stem cell factor, and c-kit ligand) has proven to be a potent hemopoietic regulator in vitro. In these studies, we examined the in vivo effects of MGF in combination with GM-CSF or GM-CSF plus IL-3. Effects were based on the ability of these cytokines to stimulate recovery from radiation-induced hemopoietic aplasia. Female B6D2F1 mice were exposed to a sublethal 7.75-Gy dose of 60Co radiation followed by subcutaneous administration of either saline, recombinant murine (rm) MGF (100 micrograms/kg/day), rmGM-CSF (100 micrograms/kg/day), rmIL-3 (100 micrograms/kg/day), or combinations of these cytokines on days 1-17 postirradiation. Recoveries of bone marrow and splenic spleen colony-forming units (CFU-s), granulocyte macrophage colony-forming cells (GM-CFC), and peripheral white blood cells (WBC), red blood cells (RBC) and platelets (PLT) were determined on days 14 and 17 during the postirradiation recovery period. MGF administered in combination with GM-CSF or in combination with GM-CSF plus IL-3 either produced no greater response than GM-CSF alone or down-regulated the GM-CSF-induced recovery. These results sharply contrasted results of in vitro studies evaluating the effects of these cytokines on induction of GM-CFC colony formation from bone marrow cells obtained from normal or irradiated B6D2F1 mice, in which MGF synergized with GM-CSF or GM-CSF plus IL-3 to increase both GM-CFC colony numbers and colony size. These studies demonstrate a dichotomy between MGF-induced effects in vivo and in vitro and emphasize that caution should be taken in attempting to predict cytokine interactions in vivo in hemopoietically injured animals based on in vitro cytokine effects.
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PMID:Mast cell growth factor (C-kit ligand) in combination with granulocyte-macrophage colony-stimulating factor and interleukin-3: in vivo hemopoietic effects in irradiated mice compared to in vitro effects. 752 Jul 25

Human cord blood cells cultured in suspension with soluble c-kit ligand produce immature mast cells from their agranular precursors; cocultures of cord blood and mouse 3T3 fibroblasts produce fully mature human mast cells. We noted cells of the neutrophil lineage in the c-kit ligand-supplemented suspension cultures. Similar cultures were prepared from individual cord bloods with several sources of the c-kit ligand, including mouse fibroblast conditioned media, a partially purified mouse 3T3 fibroblast factor(s), recombinant human stem cell factor, recombinant murine mast cell growth factor, and were sampled sequentially for routine and cytochemical ultrastructural studies. These studies show that peroxidase-positive azurophilic granule-containing neutrophilic myelocytes develop in quantity from their agranular precursors in cord blood when the c-kit ligand is present, but little to no maturation to mature neutrophils with specific granules occurs. Specific granules were also absent in the neutrophil precursors. The effect of c-kit ligand in vitro on two cell lineages in man is similar--i.e., it permits the development of immature cells to differentiate from their agranular precursors in cord blood, but complete maturation to fully mature mast cells or neutrophils does not occur.
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PMID:C-kit ligand induction of immature neutrophils in cultures of human umbilical cord blood. 752 27

The c-kit proto-oncogene encodes a transmembrane tyrosine kinase receptor, which is important for the normal development of hematopoietic cells, melanoblasts, and germ cells. Autophosphorylation of c-kit receptor on tyrosine creates binding sites for cellular src homology 2 (SH2)-containing signaling molecules. The discovery of phosphotyrosine phosphatases that contain SH2 domains suggests roles for these molecules in growth factor signaling pathways. We found that Syp, a phosphotyrosine phosphatase widely expressed in all the tissues in mammals, associates with c-kit receptor after activation with its ligand, steel factor, in the factor-dependent cell line, M07e. Both NH2-terminal and COOH-terminal SH2 domains of Syp, made as glutathione S-transferase fusion proteins, were able to bind to the activated c-kit receptor in vitro. Furthermore, Syp became marginally phosphorylated on tyrosine upon c-kit receptor activation, and tyrosine-phosphorylated Syp was found to be complexed with Grb2 in steel factor-stimulated M07e cells. Direct binding between Syp and Grb2 was also observed in vitro. Last, Ras and Raf interacts in vitro as a result of steel factor-stimulated Ras activation. These results suggest that Syp may be an important signaling component downstream of the c-kit receptor and involved in activation of the Ras signaling pathway in hematopoietic cells.
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PMID:The ubiquitously expressed Syp phosphatase interacts with c-kit and Grb2 in hematopoietic cells. 752 81

The receptor tyrosine kinase Kit and Kit ligand (KL), encoded at the murine white spotting (W) and steel (Sl) loci, respectively, function in hematopoiesis, melanogenesis, and gametogenesis. To understand the mechanism of turnover of Kit in mast cells, mutant receptors generated in vitro were heterologously expressed in Wsb/Wsh mast cells lacking endogenous c-kit expression, and the effects of mutations on KL-induced internalization and ubiquitination/degradation of Kit were studied. Upon binding of KL, KL.Kit receptor complexes were rapidly internalized, and the turnover was accelerated by ubiquitin-mediated degradation. Inactivation of the Kit kinase resulted in a reduced rate of internalization of KL.Kit complexes, degradation of kinase-inactive receptor complexes was relatively slow, and receptor ubiquitination was absent. But abolishment of KL-induced receptor association and activation of phosphatidylinositol 3'-kinase and of tyrosine 821 autophosphorylation did not affect KL-induced internalization and ubiquitination/degradation of Kit. Furthermore, Kit receptors can be down-regulated by proteolytic cleavage induced by either activation of protein kinase C or by isopropyl alcohol. In summary, KL-induced internalization of KL.Kit complexes and ubiquitination/degradation require an active kinase. By contrast, proteolytic cleavage of Kit mediated by protein kinase C activation is independent of kinase activity.
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PMID:Mechanism of down-regulation of c-kit receptor. Roles of receptor tyrosine kinase, phosphatidylinositol 3'-kinase, and protein kinase C. 752 1

Stem cell factor (CSF), also called c-kit ligand (KL) or mast cell growth factor (MGF) is a peptide growth factor/cytokine with broad activities, especially on hematopoiesis. Its physiological role is best understood through the naturally occurring steel and W mutations in the mouse. This cytokine has recently been made available because of molecular cloning and its expression in recombinant form SCF is produced by a variety of cells, especially fibroblast, and interacts with target cells in each of the hematopoietic lineages to stimulate proliferation and differentiation. It has been found that SCF is important for the survival, proliferation and differentiation of mast cells and that it influences all stages of their development. SCF activity is not restricted to hematopoiesis, as it plays an important role in the development of germ cells and melanocytes as well. Preclinical studies show that SCF can protect against lethal irradiation, elicit multilineage responses in peripheral blood and bone marrow cellularity and increase circulating peripheral blood progenitor cells in a dose-dependent manner. Recombinant human SCF has major clinical potential through its synergy with other factors, especially G-CSF, to enhance mobilization of stem cells in peripheral blood.
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PMID:[Stem cell factor]. 752 11

Autonomous, factor-independent growth and differentiation of malignant cells in preleukemic and leukemic disease states is a well-recognized phenomenon and is often associated with a poor prognosis. Mast cells are distinct hematopoietic cells and express a unique profile of antigens. Growth and differentiation of normal mast cells is dependent on mast cell growth factor (MGF), the ligand of the c-kit protooncogene product. In this study, we screened for mast cell-lineage involvement in 52 patients suffering from myeloid leukemias, myelodysplastic syndromes (MDS), systemic mastocytosis, or other diseases by probing for mast cell-related molecules (c-kit, tryptase, histamine, and MGF) and by analyzing kit ligand/MGF-independent growth of mast cells in long-term suspension culture. Of the 52 patients tested, 2 patients with refractory anemia with excess of blast cells in transformation and 1 patient suffering from chronic myeloid leukemia blast crisis (CML-BC) were diagnosed as mastocytic disease. These patients were characterized by complex chromosomal abnormalities, splenomegaly, high percentages of circulating metachromatic cells (5% to 25%), high levels of cellular tryptase (> 10 ng/10(5) peripheral blood mononuclear cells/mL) and a tryptase/histamine (ng:ng) ratio greater than 1. The metachromatic cells expressed the mast-cell-related surface antigen c-kit, but not basophil-related antigens (CD11b, CDw17). Furthermore, in these 3 patients, spontaneous, MGF-independent growth of mast cells along with spontaneous synthesis of tryptase was demonstrable in long-term culture. No autocrine production, paracrine production, or overproduction of MGF was found. The spontaneous growth of mast cells could neither be abbrogated by addition of monoclonal antibodies (MoAbs) to c-kit nor by MoAbs against MGF (< 5% inhibition), whereas factor (MGF)-dependent differentiation of mast cells in these patients could be abbrogated by MoAbs to c-kit or MoAbs to MGF (> 70% inhibition, P < .001). In addition, serum MGF levels in these patients were within the normal range and MGF could not be detected in cell-free culture supernatants. All 3 patients showed rapid progression of disease and had a survival time of less than 1 year. In conclusion, we describe a unique form of transformation in MDS and CML-BC characterized by mast cell lineage involvement and factor-independent differentiation of mast cells. This form of leukemic transformation has to be delineated from chronic myeloid leukemia with basophilia or basophil crisis, from primary mast cell leukemia, and from monocytic leukemias and myelodysplastic disorders associated with basophilia.
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PMID:Kit ligand/mast cell growth factor-independent differentiation of mast cells in myelodysplasia and chronic myeloid leukemic blast crisis. 752 72

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

Testicular cells composed mostly of germ cells and immature Sertoli cells from neonatal mice 2 and 5 days old were cultured to investigate germ-cell proliferation mediated by the c-kit receptor. The addition of antibody to block the interaction of the c-kit receptor with its ligand inhibited the proliferation of cultured spermatogonia from 5-day-old mice in a dose-dependent manner, but not from that of 2-day-old mice. The addition of anti-c-kit ACK2 monoclonal antibody also inhibited the proliferation of spermatogonia from 5-day-old mutant Sld/Sld mice but not of 5-day-old mutant Wv/Wv mice. The results indicate that c-kit-positive type A spermatogonia in the testes of 5-day-old mice require steel factor (kit ligand) for their proliferation, whereas self-renewal and differentiation of c-kit-negative primitive type A spermatogonia in the testes of 2-day-old mice do not.
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PMID:Switching of mouse spermatogonial proliferation from the c-kit receptor-independent type to the receptor-dependent type during differentiation. 752 77

Despite extensive research on the molecular mechanisms of signal transduction by growth factors and their oncogenic receptor tyrosine kinases, the physiological relevance of these pathways, especially in mammals, remains largely unknown. A unique exception is the Steel factor (SLF) and its c-kit-encoded receptor, because many natural germ line mutations of both the ligand and the receptor exist in mice. The protooncogene c-kit encodes a cell surface receptor that belongs to the immunoglobulin gene family and carries an intrinsic tyrosine kinase activity in its cytoplasmic portion. The precursor of the Kit ligand, SLF, is also a transmembrane protein that exists as a soluble factor as well as a cell surface protein. The interaction of Kit with SLF leads to receptor dimerization, kinase activation, and tyrosine phosphorylation of cytoplasmic proteins that contain Src homology 2 motifs. Various mutations in Kit and SLF result in a defective signaling pathway and underly the complex phenotypes of W and Sl mice, respectively. The early development of at least four cell lineages is affected. These are erythrocytes, melanocytes, germ cells, and mast cells. Correlation between the behavior of these lineages and specific mutations uncovered interesting physiological aspects of the mechanism of signal transduction by a polypeptide growth factor. These include the different degrees of severity of affected lineages, indications for distinct functions during early embryonic development and at late phases, the significance of synergy between a growth factor and lymphokines, the interaction between mutant and wild-type proteins in heterozygous animals, and the possibility that a surface-anchored ligand may act differently than a soluble factor. Predictably, the lessons learned with Kit and Sl mice will be widely relevant to other pairs of ligands and receptors that control the function of different cell lineages and physiological processes.
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PMID:Steel factor and c-kit protooncogene: genetic lessons in signal transduction. 753

Hematopoietic cell proliferation and differentiation is dependent in part on the interaction of hematopoietic stem and progenitor cells with cells making up the hematopoietic microenvironment (HM). Direct cell-cell interactions appear to be important in the hematopoietic microenvironment. One mechanism to accomplish such interactions is the expression of membrane-associated growth factors. Stem cell factor (SCF), the product of the steel gene in mice (also termed mast cell growth factor, c-kit ligand, or Steel factor), is a hematopoietic growth factor demonstrating substantial synergistic activity with a number of other cytokines on primitive hematopoietic stem and progenitor cells. Cloned SCF cDNA encode both a membrane-associated and a secreted growth factor. The physiologic relevance of these isoforms is unknown at present. In order to better understand the physiologic role of these SCF isoforms in normal hematopoiesis, we have established multiple stromal cell lines expressing each isoform. We have used these cell lines to study protein sequences that are required for appropriate post-translational processing of SCF protein in HM-derived stromal cell lines. These lines have also been used to study the interaction of membrane-associated and secreted SCF with murine and human hematopoietic cells. In addition, we have generated transgenic mice expressing each isoform of murine and human SCF. These transgenic mice will be used to study the function of each isoform in hematopoiesis in vivo.
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PMID:Analysis of steel factor (stem cell factor) isoforms in the hematopoietic microenvironment. 753 48


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