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

We have cloned and sequenced the human KIT proto-oncogene, which contains 21 exons and spans more than 34 kb of DNA on chromosome segment 4q12. We also establish physical linkage between the KIT gene and the related PDGFRA gene. The organization of the KIT gene is virtually identical to that of the homologous FMS gene, located on chromosome 5. Together, these data suggest that the KIT and PDGFRA genes on chromosome 4 and the FMS and PDGFRB genes on chromosome 5 arose by duplication of a common ancestral gene, followed by duplication of a chromosome.
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PMID:Organization and nucleotide sequence of the human KIT (mast/stem cell growth factor receptor) proto-oncogene. 127 99

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

c-fms and c-kit are structurally related tyrosine kinase receptors for colony-stimulating factor-1 (CSF-1) and for steel factor (SF), respectively. The level of c-fms mRNA, like c-kit mRNA, increases during the maturation of oocytes and is an abundant maternal message found in the unfertilized oocyte. Following fertilization, the level of both c-fms and c-kit oocyte mRNAs decreases rapidly until they are no longer detected by the early 2-cell stage. By the late 2-cell stage, both mRNAs are reexpressed, albeit at low levels. This low level of mRNA expression continues throughout preimplantation development. CSF-1 and SF transcripts are not detected in early preimplantation embryos, but are detected in cumulus cells, oviduct, and uterus, suggesting a paracrine action of these growth factors during the preimplantation period. The patterns of CSF-1/c-fms mRNA and SF/c-kit mRNA expression are consistent with the hypothesis that these two ligand/receptor systems may act in a compensatory or synergistic manner during preimplantation development.
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PMID:Expression of CSF-1/c-fms and SF/c-kit mRNA during preimplantation mouse development. 137 50

The recent identification of the mouse White spotting and Steel loci as genes encoding the c-kit receptor and its ligand, respectively, has shed light on the importance of this ligand and receptor in embryogenesis, melanogenesis and hematopoiesis. In order to determine if the c-kit proto-oncogene is involved in human disease, we isolated seven overlapping lambda recombinants, using a fetal brain cDNA, and characterized the normal human gene (KIT). The longest mapped transcript is 5230 bp, is alternatively spliced and includes 21 exons that span more than 70 kb of DNA. From the exon-intron structure, we have localized an alternative splice site to the 3' end of exon 9. The overall c-kit gene structure closely resembles that found in the CSF-1R gene (c-fms). This similarity includes a large first intron, the same number of exons containing translated sequence and very similar exon-intron boundaries. Using pulsed-field gel electrophoresis, we have linked KIT to the platelet-derived growth factor receptor A gene, with both residing on a 700-kb BssHI fragment. These data will allow investigation into the control of KIT expression and the potential to identify mutations or altered expression of this gene in human disease.
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PMID:Cloning and structural analysis of the human c-kit gene. 137 10

The murine Kit receptor gene on chromosome 5 has been found to be frequently involved in germline mutations and rearrangements, leading to a characteristic set of severe developmental defects, known as the W phenotype. Here we describe the structure of the murine c-kit gene, based on restriction analysis of genomic phage clones and sequence determination of exon-intron boundaries. The Kit-coding region is distributed over 21 exons, most of which have sizes that range between 100 and 200 base pairs. The 3' non-translated sequence and the 3' end of the coding region form a single large exon, which encompasses 2.3 kb and is flanked by polyadenylation signals. The entire region spans a genomic distance of at least 70 kb. Though the exonic demarcations of c-kit show remarkable similarity to those of the human c-fms gene (which encodes the highly related colony-stimulating factor 1 receptor), no correlation could be found between the sizes of introns that separate homologous exon pairs. The data suggest that evolutionary pressures were confined to the conservation of structures of coding exons, whereas flanking regions were subject to large changes, owing to insertions and deletions. Finally, the analysis of the Kit genomic structure reveals that the inherited mutations of the Kit gene that have been reported thus far occur at various dispersed positions within the gene. Hence, the entire gene appears to have as yet unknown features which cause it to be frequently subject to mutations in murine germline tissues.
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PMID:Structural organization of the murine c-kit proto-oncogene. 137 13

The lymphokine interleukin-3 (IL-3) promotes the growth and survival of immature hematopoietic cells. Previous studies have shown that IL-3 induces rapid increases in protein-tyrosine kinase (PTK) activity in IL-3--dependent cells. Unlike some other hematopoietic growth factor receptors (eg, c-fms and c-kit), however, the known subunits of the IL-3 receptor (IL-3R) lack intrinsic kinase activity. Recently, it was reported that the IL-2R (whose p75 beta-subunit shares sequence homology with a known murine IL-3R subunit and a common beta-subunit of the human IL-3R and granulocyte-macrophage colony-stimulating factor [GM-CSF] receptors) can physically associate with and regulate the activity of the SRC-family PTK, p56-LCK. Because most IL-3--dependent cells contain p53/56-LYN, but not p56-LCK, we explored the effects of IL-3 on the activities of LYN and other SRC-like PTKs in two human leukemic cell lines, AML-193 and TALL-101, which are phenotypically myeloid, and whose in vitro growth is dependent on IL-3. These cells expressed four of the eight known SRC-family proto-oncogenes: lyn, fyn, yes, and hck. When these factor-dependent leukemic cell lines were deprived of lymphokine to achieve cellular quiescence and then restimulated with IL-3, rapid increases (detectable within 1 minute and maximal by 10 minutes) were observed in the activity of the p53/56-LYN kinase, as assessed by in vitro kinase assays. In contrast, no alteration in the activities of other SRC-family PTKs present in these cells was detected after restimulation with IL-3 under the same conditions. This effect of IL-3 reflected an increase in the specific activity of the LYN kinase, because levels of the 53-Kd and 56-Kd LYN proteins were unaltered by IL-3 stimulation, as assessed by immunoblotting. Furthermore, the magnitude of these inducible increases in LYN kinase activity was dependent on the concentration of IL-3, and correlated with IL-3--induced proliferation. The IL-3--induced upregulation of LYN kinase activity may be mediated by the 120-Kd common subunit of the human IL-3 and GM-CSF receptors, because GM-CSF also stimulated marked increases in the activity of the LYN kinase, whereas granulocyte-CSF (G-CSF) did not, despite inducing cellular proliferation. These observations provide the first example of an IL-3--regulable PTK, and strongly suggest that the p53/56-LYN kinase participates in early IL-3--initiated signalling events, at least in some human leukemic cell lines.
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PMID:Interleukin-3 regulates the activity of the LYN protein-tyrosine kinase in myeloid-committed leukemic cell lines. 163 19

Mutations at three loci in the mouse--W, Steel Sl), and microphthalmia (mi)--can lead to a deficiency in melanocytes and mast cells. As well, W and Sl mutants can be anemic and sterile, whereas mi mice are osteopetrotic due to a monocyte/macrophage defect. Recent data have shown that the c-kit receptor tyrosine kinase is the gene product of the W locus, whereas Sl encodes the ligand for this growth factor receptor. We show here that ectopic expression of c-fms, a gene that encodes a macrophage growth factor receptor that is closely related to the c-kit receptor, complements mutations at the W locus in an in vitro mast cell/fibroblast coculture system but is unable to reverse the inability of mi/mi mast cells to survive under these conditions. Furthermore, mast cells expressing the c-fms receptor survive on a monolayer of fibroblasts homozygous for the Sl mutation. These results suggest that ligand binding to the c-kit or c-fms receptor activates identical or overlapping signal transduction pathways. Furthermore, they suggest that mi encodes a protein necessary for transducing signals mediated by way of either the c-kit or c-fms receptor.
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PMID:The c-fms gene complements the mitogenic defect in mast cells derived from mutant W mice but not mi (microphthalmia) mice. 182 51

Homozygous mutant rats at the newly found white spotting (Ws) locus were anemic and deficient in mast cells and melanocytes. Because the phenotype of Ws/Ws rats resembled the phenotype of mice possessing a double-gene dose of mutant alleles at the W locus and because the c-kit gene was mapped at the W locus of mice, we characterized the c-kit gene of Ws/Ws rats. The authentic sequence of the rat c-kit cDNA was determined by using a cDNA library prepared from the hippocampus of Sprague-Dawley rats. The c-kit cDNA of Ws/Ws and normal (+/+) control rats was obtained by reverse transcriptase modification of the polymerase chain reaction. When compared with the authentic sequence, a deletion of 12 bases was found in the c-kit cDNA of Ws/Ws rats. This change was shown to be a result of the deletion of the genomic DNA. Four amino acids encoded by the deleted 12 bases (ie, Val-Lys-Gly-Asn) were located at two amino acids downstream from the tyrosine autophosphorylation site in the c-kit kinase and were conserved not only in mouse and human c-kit kinases but also in mouse and human c-fms kinases (ie, receptors of colony-stimulating factor-1). Taken together, the Ws/Ws rat is the first characterized mutant of the c-kit gene in an animal species other than the mouse.
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PMID:Characterization of Ws mutant allele of rats: a 12-base deletion in tyrosine kinase domain of c-kit gene. 191 77

A new human gene encoding a receptor-type tyrosine kinase was isolated by a weak cross-hybridization with v-ros oncogene. A cDNA of about 7.7 kb carried a 4.2 kb open reading frame, and the predicted amino acid sequence of 1338 residues contained extracellular, transmembrane and tyrosine kinase domains. Although its extracellular domain is approximately 220 amino acids longer than those of the products of the fms family, i.e. c-fms, c-kit and platelet-derived growth factor receptor genes, the overall structure including cysteine motifs in its extracellular domain and a long peptide insertion in its tyrosine kinase domain indicates that this new gene is closely related to the fms family. Consequently, the gene was designated as flt (fms-like tyrosine kinase) gene. The expression of the flt gene was strongly suppressed in most of the tumor cell lines examined so far, whereas this mRNA was expressed in a variety of normal tissues of adult rat.
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PMID:Nucleotide sequence and expression of a novel human receptor-type tyrosine kinase gene (flt) closely related to the fms family. 215 38

The protein kinase domains of v-kit, the oncogene of the acute transforming feline retrovirus HZ4-FeSV (HZ4-feline sarcoma virus), CSF-1R (macrophage colony stimulating factor receptor) and PDGFR (platelet derived growth factor receptor) display extensive homology. Because of the close structural relationship of v-kit, CSF-1R and PDGFR we predicted that c-kit would encode a protein kinase transmembrane receptor (Besmer et al., 1986a; Yarden et al., 1986). We have now determined the primary structure of murine c-kit from a DNA clone isolated from a brain cDNA library. The nucleotide sequence of the c-kit cDNA predicts a 975 amino acid protein product with a calculated mol. wt of 109.001 kd. It contains an N-terminal signal peptide, a transmembrane domain (residues 519-543) and in the C-terminal half the v-kit homologous sequences (residues 558-925). c-kit therefore contains the features which are characteristic of a transmembrane receptor kinase. Comparison of c-kit, CSF-1R and PDGFR revealed a unique structural relationship of these receptor kinases suggesting a common evolutionary origin. The outer cellular domain of c-kit was shown to be related to the immunoglobulin superfamily. The sites of expression of c-kit in normal tissue predict a function in the brain and in hematopoietic cells. N-terminal sequences which include the extracellular domain and the transmembrane domain as well as 50 amino acids from the C-terminus of c-kit are deleted in v-kit. These structural alterations are likely determinants of the oncogenic activation of v-kit.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Primary structure of c-kit: relationship with the CSF-1/PDGF receptor kinase family--oncogenic activation of v-kit involves deletion of extracellular domain and C terminus. 245 20


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