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

The stem cell factor (SCF) is a polypeptide ligand that is essential for the development of germ cells, hematopoietic progenitor cells, and melanocyte precursors. It binds to a tyrosine kinase membrane receptor that is encoded by the c-kit proto-oncogene. We have constructed an expression vector that directs the synthesis of the entire extracellular ligand-binding domain of the Kit/SCF receptor. When expressed and amplified in Chinese hamster ovary cells, a secreted 90-kDa glycoprotein could be harvested from the growth medium of the cells in a soluble form. This extracellular portion of the Kit/SCF receptor, denoted Kit-X, was recognized by antibodies specific to the SCF receptor; and when injected into animals, it raised antibodies that were reactive with the complete membrane form of the receptor. Direct binding and covalent cross-linking of radiolabeled SCF showed that Kit-X fully retained high affinity ligand binding and also underwent efficient dimerization in the presence of the ligand. The capacity of Kit-X to act as an antagonist of SCF was assayed on cultured cells that overexpress the receptor. Simultaneous addition of SCF and Kit-X to these cells resulted in a stoichiometric inhibition of SCF binding and a consequent decrease in autophosphorylation of the SCF receptor on tyrosine residues. The inhibition extended to later SCF-mediated responses, including the association of the receptor with phosphatidylinositol 3'-kinase and coupling to the Raf1 protein kinase. These results indicate that the recombinant ectodomain of the Kit-SCF receptor can be used as a specific antagonist of SCF actions and may enable detailed molecular analysis of ligand-receptor interactions.
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PMID:A recombinant ectodomain of the receptor for the stem cell factor (SCF) retains ligand-induced receptor dimerization and antagonizes SCF-stimulated cellular responses. 137 32

Kit-ligand is a novel polypeptide growth factor which binds and activates the c-kit protooncogene, a receptor tyrosine kinase. We used the technique of reverse transcription-polymerase chain reaction to demonstrate the expression of this growth factor in human placenta. In situ hybridization showed that kit-ligand mRNA is expressed in cytotrophoblast and syncytiotrophoblast cells in the placenta, and in fetally derived extravillous trophoblast cells which have invaded the maternal endometrium. Five species of mRNA encoding variants of kit-ligand were identified by nested reverse transcription-polymerase chain reaction. Cloning and sequencing indicate that these variants arise by alternative splicing of the kit-ligand transcript. One of these species, KL486, uses a novel splice site in exon 8. There is a different pattern of expression of the variants in amnion, chorion, trophoblast, and placenta, indicating tissue-specific control of splicing.
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PMID:Expression of messenger RNA for kit-ligand in human placenta: localization by in situ hybridization and identification of alternatively spliced variants. 138 93

Primordial germ cells in the mouse are known to be derived from the epiblast. They can be identified histochemically, by their high alkaline phosphatase activity. At 8 d post coitum they have been observed within the embryonic part of the egg cylinder, at the posterior end of the primitive streak. Earlier, at 7.25 days post coitum, we have observed them embedded in the extra-embryonic mesoderm, as a tight clump. Germ cell counts over the 7-8 d period of gastrulation have been made. They are consistent with either of two models: (1) derivation of the germ cell lineage from a very small stem cell pool, followed by a constant rate of proliferation, and (2) derivation from a larger initial stem cell pool, followed by a period when germ cells are differentiating but not dividing. From their initial extra-embryonic location, germ cells spread into the mesoderm of the primitive streak, and the endoderm of the yolk sac and hind gut. Active locomotion is probably required for their passage up the dorsal mesentery and into the genital ridges. Mutant alleles at two loci, W (White-spotting) and Sl (Steel), drastically reduce the number of germ cells reaching the ridges. Since those that succeed in reaching the ridges suffer little if any delay, the defect is unlikely to be due to reduced powers of locomotion, but rather to a failure of proliferation or survival. W acts cell-autonomously: its gene product is the c-kit polypeptide, a transmembrane tyrosine kinase receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Development of primordial germ cells in the mouse. 153 Jan 50

Mutations at the mouse W/c-kit locus lead to intrinsic defects in stem cells of the melanocytic, hematopoietic, and germ cell lineages. W alleles vary in the overall severity of phenotype that they confer, and some alleles exhibit an independence of pleiotropic effects. To elucidate the molecular basis for these biological differences, we analyzed the c-kit locus and the c-kit-associated autophosphorylation activities in five different W mutants representative of a range of W phenotypes. Mast cell cultures derived from mice or embryos homozygous for each W allele were deficient in c-kit autophosphorylation activity, the extent of which paralleled the severity of phenotype conferred by a given W allele both in vivo and in an in vitro mast cell coculture assay. The mildly dominant, homozygous viable alleles W44 and W57 were found to express reduced levels of an apparently normal c-kit protein. In contrast, c-kit kinase defects conferred by the moderately dominant, homozygous viable alleles W41 or W55 or the homozygous lethal allele, W37, were attributed to single-point mutations within the kinase domain of the c-kit polypeptide, which result in point substitutions of amino acid residues highly conserved in the family of protein tyrosine kinases. The nature and location of these amino acid substitutions account for the relative severity of phenotypes conferred by these W alleles and demonstrate that the pleiotropic developmental defects associated with the W/c-kit locus arise as the result of dominant loss-of-function mutations in a transmembrane receptor tyrosine kinase.
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PMID:W mutant mice with mild or severe developmental defects contain distinct point mutations in the kinase domain of the c-kit receptor. 169 59

Developmental expression of the c-kit proto-oncogene, a receptor tyrosine kinase encoded by the W locus, was investigated by in situ hybridization in normal mouse embryos. Early after implantation transcripts were detectable only in the maternal placenta (6 1/2-7 1/2 days p.c.). Subsequently (8 1/2 days p.c.) numerous ectodermal (neural tube, sensory placodes) and endodermal (embryonic gut) derivatives expressed c-kit. Later transcripts were detected also in the blood islands of the yolk sac and in the embryonic liver, the main sites of embryonic hemopoiesis. Around midgestation, transcripts accumulated in the branchial pouches and also in primordial germ cells of the genital ridges. This complex pattern of expression remained characteristic also later in gestation, when c-kit was expressed in highly differentiated structures of the craniofacial area, in presumptive melanoblasts and in the CNS. In the adult ovary, maternal c-kit transcripts were detected. They were present in the oocytes of both immature and mature ovarian follicles, but not in the male germ line, where c-kit expression may be down regulated. Thus, c-kit activity is complex and appears in multiple tissues including those that also display defects in mutations at the W locus where c-kit is encoded. Correlation between W phenotypes and c-kit expression, as well as the regulation of the complex and multiple expression of polypeptide growth factors and receptors, is discussed.
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PMID:Developmental expression of c-kit, a proto-oncogene encoded by the W locus. 169 18

Mutations at the W locus in the mouse have pleiotropic effects on embryonic development and hematopoiesis. The characteristic phenotype of mutants at this locus, which includes white coat color, sterility, and anemia, can be attributed to the failure of stem cell populations to migrate and/or proliferate effectively during development. Mapping experiments suggest that the c-kit proto-oncogene, which encodes a putative tyrosine kinase receptor, is a candidate for the W locus. We show here that the c-kit gene is disrupted in two spontaneous mutant W alleles, W44 and Wx. Genomic DNA that encodes amino acids 240 to 342 of the c-kit polypeptide is disrupted in W44; the region encoding amino acids 342 to 791 is disrupted in Wx. W44 homozygotes exhibit a marked reduction in levels of c-kit mRNA. These results strongly support the identification of c-kit as the gene product of the W locus.
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PMID:The dominant-white spotting (W) locus of the mouse encodes the c-kit proto-oncogene. 245 42

Melanoma growth stimulatory activity (MGSA) is a mitogenic polypeptide secreted by Hs294T human melanoma cells. Comparison of the N-terminal sequences of the 13 and 16 kd MGSA species with the cDNA sequence revealed that the mature form of human MGSA is maximally 73 amino acids long. Expression of the cDNA in mammalian cells results in the secretion of this peptide with mitogenic activity. MGSA is structurally related to the platelet-derived beta-thromboglobulin and to several other polypeptides. These factors may constitute a family of growth factors. MGSA mRNA was detected in a variety of cell types. The level of MGSA mRNA in melanoma cells is strongly elevated by treatment with MGSA. MGSA is the gene product of a recently detected gene gro. The gene was mapped to chromosome 4 (region q13----q21). This same region also contains genes for two of the structurally related factors, for c-kit, a receptor for an as yet unidentified ligand, and for 'piebald trait', an inherited skin pigmentation disorder.
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PMID:Molecular characterization and chromosomal mapping of melanoma growth stimulatory activity, a growth factor structurally related to beta-thromboglobulin. 297 Sep 63

The growth and differentiation of neural precursor cells in the central nervous system (CNS) are regulated by their response to polypeptide growth factors which interact with specific transmembrane receptor tyrosine kinases (RTKs). We demonstrate that rat oligodendrocyte-type 2 astrocyte (O-2A) glial progenitor cells, precursors of the myelin-forming cells in the CNS, express the transmembrane RTK c-kit, the gene product of the murine dominant white spotting (W) locus and receptor for stem cell factor. Expression of c-kit transcripts and immunoreactive protein is lost when O-2A progenitors differentiate into post-mitotic oligodendrocytes. Analysis of developing rat brain revealed an increase in the expression of c-kit transcripts between postnatal days 10 and 12, a window of time preceding the emergence of oligodendrocytes and the onset of myelination in vivo. Expression of c-kit in vitro and in vivo suggests a role for this receptor and its ligand during oligodendrocyte development.
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PMID:Expression of the receptor tyrosine kinase c-kit in oligodendrocyte progenitor cells. 751

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

Murine erythroleukemia cells that lack endogenous p53 expression were transfected with a temperature-sensitive p53 allele. The temperature-sensitive p53 protein behaves as a mutant polypeptide at 37 degrees C and as a wild-type polypeptide at 32 degrees C. Three independent clones expressing the temperature-sensitive p53 protein were characterized with respect to p53-mediated G1 cell cycle arrest, apoptosis, and differentiation. Clone ts5.203 responded to p53 activation at 32 degrees C by undergoing G1 arrest, apoptosis, and differentiation. Apoptosis was seen in cells representative of all phases of the cell cycle and was not restricted to cells arrested in G1. The addition of a cytokine (erythropoietin, c-kit ligand, or interleukin-3) to the culture medium of ts5.203 cells blocked p53-mediated apoptosis and differentiation but not p53-mediated G1 arrest. These observations indicate that apoptosis and G1 arrest can be effectively uncoupled through the action of cytokines acting as survival factors and are consistent with the idea that apoptosis and G1 arrest represent separate functions of p53. Clones ts15.15 and tsCB3.4 responded to p53 activation at 32 degrees C by undergoing G1 arrest but not apoptosis. We demonstrate that tsCB3.4 secretes a factor with erythropoietin-like activity and that ts15.15 secretes a factor with interleukin-3 activity and suggest that autocrine secretion of these cytokines blocks p53-mediated apoptosis. These data provide a framework in which to understand the variable responses of cells to p53 overexpression.
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PMID:Cytokines inhibit p53-mediated apoptosis but not p53-mediated G1 arrest. 756 57


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