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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Products of the ras gene family, termed p21ras, are GTP-binding proteins that have been implicated in signal transduction via receptors encoding tyrosine kinase domains. Recent findings have defined a superfamily of hemopoietin receptors that includes receptors for a number of interleukins and colony-stimulating factors. The intracellular portions of these receptors show only restricted homologies, have no tyrosine kinase domain, and provide no clues to the mode of signal transduction. However, in most cases the factors stimulate tyrosine phosphorylation. We demonstrate here that ligand-induced activation of the interleukin (IL)-2, IL-3, IL-5, and granulocyte-macrophage colony-stimulating factor receptors resulted in activation of p21ras in various hemopoietic cell lines. The only cytokine tested that binds to a hemopoietin receptor and that did not activate p21ras was IL-4. Activation of p21ras was also observed in response to Steel factor, which stimulates the endogenous tyrosine kinase activity of the c-kit receptor, as well as with phorbol esters, which activate protein kinase C. Experiments with protein kinase inhibitors implicated tyrosine kinase activity, but not protein kinase C activity, as the upstream signal in p21ras activation via these growth factor receptors. Attempts to demonstrate tyrosine phosphorylation of the p21ras GTPase-activating protein (GAP) were negative, suggesting that phosphorylation of GAP may not be the major mechanism for regulation of p21ras activity by tyrosine kinases.
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PMID:p21ras activation via hemopoietin receptors and c-kit requires tyrosine kinase activity but not tyrosine phosphorylation of p21ras GTPase-activating protein. 137 79

Human mast cell growth factor (MGF, a c-kit ligand) and colony stimulating factors (Epo, GM-CSF, G-CSF, IL-3) were assessed in the absence or presence of serum for stimulation in semi-solid medium of single CD34 , CD34 HLA-DR+, or CD34 HLA-DR+CD33- cells sorted per microtiter well. The % of wells containing CFU-GM and erythroid containing (BFU-E and CFU-GEMM) colonies increased in proportion to the number of cytokines added. In the presence of serum, 1, to 4 cytokine combinations resulted in respective increases in cloning efficiencies of 10 to 21.0, 19.5 to 31.5, 35.8 to 42.9, and 46.3 to 60.0%. MGF had little effect by itself, but did act in combination with CSFs to enhance numbers and size of the colonies from isolated single cells. High cloning efficiencies were also obtained in the absence of serum when multiple cytokines were used. The results demonstrate that MGF and CSFs can act directly on the proliferation of single hematopoietic progenitor cells in the absence of accessory cells and serum.
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PMID:Influence of combinations of cytokines on proliferation of isolated single cell-sorted human bone marrow hematopoietic progenitor cells in the absence and presence of serum. 137 67

More gene products that influence hematopoiesis continue to become available. As a result, is now possible to carry out both in vivo and in vitro studies with purified erythropoietin, various colony stimulating factors and 11 interleukins. The identification and availability of the ligand for the c-kit gene product has had a profound influence in the past year.
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PMID:The use of colony stimulating factors in combination. 137 91

Recently, a novel growth factor has been cloned that has growth promoting activities on a wide variety of hematopoietic cell lineages. This factor has been referred to as mast cell growth factor, stem cell factor, or kit ligand, and will be referred to here as steel factor. Steel factor stimulates the growth of cells via its interaction with the c-kit proto-oncogene, which is a tyrosine kinase receptor that is expressed on the surface of a number of different cell types. In addition to its effects on hematopoiesis, this factor also plays a role in the development of melanocytes and germ cells. The discovery of this growth factor provided the final piece of the puzzle to explain the molecular defects associated with several well known genetic mutations in mice, and has opened the door to understanding the role of this factor in development. Similar genetic defects may exist in humans as well. The aim of this paper is to review the biological structure and activities of this new growth factor, and to discuss its potential applications in clinical medicine.
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PMID:Biological activities and potential therapeutic uses of steel factor. A new growth factor active on multiple hematopoietic lineages. 137 88

The proto-oncogene c-Kit, a transmembrane receptor tyrosine kinase, is an important regulator of cell growth whose constitutively active oncogenic counterpart, v-kit, induces sarcomas in cats. Mutations in murine c-kit that reduce the receptor tyrosine kinase activity cause deficiencies in the migration and proliferation of melanoblasts, hematopoietic stem cells, and primordial germ cells. We therefore investigated whether c-Kit regulates normal human melanocyte proliferation and plays a role in melanomas. We show that normal human melanocytes respond to mast cell growth factor (MGF), the Kit-ligand that stimulates phosphorylation of tyrosyl residues in c-Kit and induces sequential phosphorylation of tyrosyl residues in several other proteins. One of the phosphorylated intermediates in the signal transduction pathway was identified as an early response kinase (mitogen-activated protein [MAP] kinase). Dephosphorylation of a prominent 180-kDa protein suggests that MGF also activates a phosphotyrosine phosphatase. In contrast, MGF did not induce proliferation, the cascade of protein phosphorylations, or MAP kinase activation in the majority of cells cultured from primary nodular and metastatic melanomas that grow independently of exogenous factors. In the five out of eight human melanoma lines expressing c-kit mRNAs, c-Kit was not constitutively activated. Therefore, although c-Kit-kinase is a potent growth regulator of normal human melanocytes, its activity is not positively associated with malignant transformation.
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PMID:c-Kit-kinase induces a cascade of protein tyrosine phosphorylation in normal human melanocytes in response to mast cell growth factor and stimulates mitogen-activated protein kinase but is down-regulated in melanomas. 137 24

Expression of mRNA for c-kit receptors and their ligands was examined in the cerebellum of mice by in situ hybridization technique. The c-kit receptors were expressed in the molecular layer of the cerebellum and the ligands for the c-kit receptors were detected at the boundary of molecular and granular layers. The expression of the c-kit ligands was not detectable in the cerebellum of lurcher (Lc/+) mutant mice that lack Purkinje cells, indicating the cells expressing the c-kit ligands were Purkinje cells. The cells expressing c-kit receptors decreased but were present in the cerebellum of Lc/+ mice. The c-kit mRNA-positive cells appeared to represent basket cells and stellate cells from their appearance and location. Since neurons in the molecular layer construct suppressive neurojunctions with Purkinje cells, the present result suggests that c-kit receptors and their ligands may play an important role for the construction of their junctions.
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PMID:Spatial expression of genes encoding c-kit receptors and their ligands in mouse cerebellum as revealed by in situ hybridization. 137 40

It is now established that the subclasses of mast cells (MC) that reside in mucosal and serosal environments can be distinguished from one another in terms of their expression of specific secretory granule-localized proteases and proteoglycans. Further, the hematopoietic- and connective tissue-derived cytokines that regulate expression of the genes that encode these constituents of the granule can now be identified using recently developed gene-specific probes and recombinant cytokines. When bone marrow-derived MC (BMMC) were developed with recombinant interleukin 3 (rIL-3) and maintained with this cytokine in the absence or presence of recombinant c-kit ligand (rKL), they remained safranin-, produced almost no 35S-labeled heparin proteoglycans, and contained greater levels of mouse MC protease (MMCP) -5 mRNA and mast cell carboxypeptidase A (MC-CPA) mRNA than MMCP-6 mRNA. They did not contain MMCP-4 or -2 mRNA, genes expressed late in the differentiation of progenitor cells into serosal and mucosal MCs, respectively. In contrast, BMMC developed with rKL alone or by sequential culture in medium containing rIL-3 followed by rKL expressed high levels of MMCP-4 and -6 mRNA, as well as the transcripts that encode MMCP-5 and MC-CPA. Although rKL-developed BMMC were safranin+ and produced substantial amounts of 35S-labeled heparin proteoglycans, they contained only minimal amounts of histamine and MC-CPA enzymatic activity relative to serosal MC. These are the first studies to characterize the transcriptional granule phenotype of a population of BMMC derived using any recombinant cytokine, to demonstrate a dissociation between histochemical staining and granule maturation, and to demonstrate antagonistic regulation of late expressed protease genes by a cytokine.
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PMID:Differential expression of secretory granule proteases in mouse mast cells exposed to interleukin 3 and c-kit ligand. 137 40

The c-kit proto-oncogene encodes a transmembrane tyrosine kinase receptor. It belongs to receptor tyrosine kinase subclass III, which also includes the colony-stimulating factor I receptor (c-fms), platelet-derived growth factor receptors A and B (PDGFRA and PDGFRB), as well as FLT1 and FLT3/FLK2. c-kit and PDGFRA, c-fms and PDGFRB, FLT1 and FLT3/FLK2 are grouped by pair in three clusters in man on chromosome 4 band q11-q13, chromosome 5 band q31-q33 and chromosome 13 band q12 respectively. Here, we report the genomic organization of the human c-kit gene, which is composed of 21 small coding exons, distributed over 80 kb. Comparison of the c-kit and c-fms oncogenes shows that they share identified exon/intron boundaries in their two kinase domains, as well as a similar exon/intron organization in the extracytoplasmic domain. Comparison with the kinase domains of tyrosine kinase genes not belonging to subclass III suggests that the exon/intron organization of c-kit and c-fms is a characteristic feature of subclass III. The genomic similarities between c-kit and c-fms, in conjunction with the location in pairs on different chromosomes of the subclass III genes, has led us to hypothesize that cis and trans duplications gave rise to this group of genes.
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PMID:Genomic organization of the human c-kit gene: evolution of the receptor tyrosine kinase subclass III. 137 82

An evaluation of the effectiveness of a genetically engineered recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF)/interleukin 3 (IL-3) fusion protein (FP) as a means of delivering cytokine combinations to megakaryocyte (MK) progenitor cells was performed, utilizing a serum-depleted clonal assay system and a long-term bone marrow culture system. The effects of the FP, alone and in combination with a variety of other cytokines, on the primitive MK progenitor cell, the megakaryocyte burst-forming unit (BFU-MK), and the more differentiated megakaryocyte colony-forming unit (CFU-MK) were assessed. Subpopulations of bone marrow cells (CD34+ DR- for BFU-MK and CD34+ DR+ for CFU-MK) served as sources of these two classes of MK progenitor cells. The FP was equivalent to a combination of optimal concentrations of GM-CSF and IL-3 in promoting both the number and size of BFU-MK-derived colonies. The GM-CSF/IL-3 combination, however, promoted the formation of far greater CFU-MK-derived colonies than did the FP alone. The size of MK colonies formed in the presence of the FP or GM-CSF/IL-3 was similar. The ability of the FP to stimulate BFU-MK- but not CFU-MK-derived colony formation was also further augmented by the addition of interleukin 1 alpha (IL-1 alpha). The addition of c-kit ligand (KL) increased both FP-stimulated CFU-MK- and BFU-MK-derived colony numbers but only BFU-MK-derived colony size. In addition, the FP alone sustained long-term megakaryocytopoiesis in vitro to a level equivalent to that of the GM-CSF/IL-3 combination and was superior in this regard to either GM-CSF or IL-3 alone. These data indicate that FP is capable of supporting various stages of human megakaryocytopoiesis. We conclude that such genetically engineered molecules as the FP may prove to be effective means of pharmacologically delivering the biological effects of specific cytokine combinations.
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PMID:Recombinant GM-CSF/IL-3 fusion protein: its effect on in vitro human megakaryocytopoiesis. 137 90

Previously, we have shown that conditioned medium from a subpopulation of human marrow stromal cells (CFU-RF) contain an activity able to stimulate the growth of macroscopic epo-dependent erythroid colonies. The ligand for the product of the c-kit proto-oncogene (also known as stem cell factor or SCF), among other activities, has been reported to have similar effects on erythroid colony growth. We have also presented data showing that SCF together with phytohemagglutinin-stimulated leukocyte conditioned medium can stimulate erythroid colony growth in the presence of antibodies to erythropoietin. Using the human SCF cDNA probe (K. Zsebo, Amgen Inc.) we now show that cells derived from CFU-RF colonies express SCF but not c-kit. Human umbilical vein endothelial cells were also found to express SCF and this expression was increased by addition of monocyte supernatant, IL-1 beta or thrombin. Cells of the human erythroleukemia cell line HEL were found to express c-kit but not SCF. Neither c-kit nor SCF mRNA were detected in phytohemagglutinin-stimulated lymphocytes. Together, these data support the view that the behaviour of proliferating erythroid stem cells in the marrow, which may express c-kit, could be regulated by membrane-bound SCF present on surrounding stromal cells.
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PMID:Expression of stem cell factor and c-kit mRNA in cultured endothelial cells, monocytes and cloned human bone marrow stromal cells (CFU-RF). 137 91


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