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

The receptors for colony stimulating factor-1 (CSF-1), platelet derived growth factor and the c-kit protein tyrosine kinase (PTK) contain within their catalytic domains a stretch of 60-100 residues, largely unrelated in sequence, with no counterpart in other PTKs. Of the 64 amino acids within this kinase insert, 58 were deleted from the mouse CSF-1 receptor by oligonucleotide-directed mutagenesis. The mutant CSF-1 receptor was not markedly affected in its kinase activity, post-translational processing or its ability to induce autocrine transformation of NIH 3T3 mouse fibroblasts. Similarly, retention of kinase and transforming activities were observed following deletion of part or all of the kinase insert from the v-fms oncoprotein. The c- and v-fms kinase inserts were probed using monoclonal and polyclonal antibodies and were found to be highly antigenic. Two monoclonal antibodies raised to the v-fms cytoplasmic domain both recognized epitopes within the insert, and bound enzymatically active v-fms glycoproteins. These results indicate that the fms kinase insert is located on the surface of the protein and folds separately from the rest of the catalytic domain, but is not required for the biological activity of fms PTKs ectopically expressed in mouse fibroblasts. The insert may therefore play a specific function in cells such as monocytes and trophoblasts that normally express the CSF-1 receptor.
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PMID:The unique insert of cellular and viral fms protein tyrosine kinase domains is dispensable for enzymatic and transforming activities. 255 72

FDC-P1 haemopoietic cells were used to select mutations of c-fms that constitutively activate the receptor for macrophage-colony stimulating factor (M-CSF or CSF-1). One mutation changed Ser 929 to Gly within a Ser/Gly rich region of the C-terminal tail and a second changed a nearby, highly conserved Leu 926 for Pro. A third mutation (D802V) changed Asp 802 to Val within the alpha L12/beta 9 region of the tyrosine kinase domain, so supporting the crystallographic evidence that this region triggers kinase activation. A c-kit mutation exactly equivalent to D802V was previously identified in a leukamic cell line and was demonstrated here to be transforming. Surprisingly, although D802V potently transformed FDC-P1 cells, it could not induce Rat-2 fibroblast foci, even in the presence of M-CSF. It is suggested that the accelerated receptor degradation induced by D802V may account for its cell specific effect.
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PMID:Selection of activating mutations of c-fms in FDC-P1 cells. 747 56

The c-kit proto-oncogene encodes a tyrosine kinase receptor for stem cell factor and plays a critical role in the growth and differentiation of various types of cells including hematopoietic stem cells. To investigate the mechanisms of its transcriptional regulation, we isolated the 5' flanking region of the human c-kit gene and characterized its promoter activity in hematopoietic cells. Nucleotide sequence analysis revealed that the 1.2 kb 5' flanking region lacked a typical "TATA box," but had a relatively high G + C content and four potential Sp1-binding sites. Putative binding sites for AP-2, basic helix-loop-helix proteins, Ets-domain proteins, Myb and GATA-1 were also found. Primer extension and S1 nuclease protection analyses of hematopoietic cells indicated that the major transcription start sites are 62 bp and 58 bp upstream of the translation start site. Essentially the same start sites were detected in non-hematopoietic cells such as small cell lung carcinoma and glioblastoma: this single promoter in c-kit is different from the multiple promoter system of c-fms, a c-kit-related gene, in which at least two promoters are differently used in hematopoietic and non-hematopoietic cells. An analysis of the c-kit 5' flanking region using the bacterial chloramphenicol acetyltransferase gene (CAT assay) in human erythroleukemia HEL cells, which express the endogenous c-kit mRNA at high levels, showed that a region from -180 to -22 is important for the expression of the c-kit gene. In addition, a negative regulatory element(s) is suggested to be involved in the regulation of the c-kit gene expression in mammals.
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PMID:Characterization of the promoter region of the human c-kit proto-oncogene. 750 48

Ligand-induced dimerization is a key step in the activation of receptor tyrosine kinases, including the epidermal growth factor receptor, stem cell factor receptor (c-kit), and colony-stimulating factor 1 receptor (c-fms). The erythropoietin receptor (EPOR), a member of the cytokine receptor family, contains no kinase motif and its activation mechanism remains unclear. Here we show that chimeric receptors carrying the extracellular domain of the epidermal growth factor receptor or c-kit linked to the cytoplasmic domain of the EPOR, transmitted epidermal growth factor or stem cell factor-dependent proliferation signals in an interleukin 3-dependent cell line. The chimeric receptors as well as the wild-type EPOR also mediated the ligand-induced tyrosine phosphorylation of a set of similar proteins. Moreover, erythropoietin triggered mitogenic signals of chimeric receptors carrying the extracellular domain of the EPOR linked to the tyrosine kinase of c-fms. These data demonstrate the interchangeability of domains between two distinct receptor families and suggest that ligand-induced dimerization is a key step in activating the EPOR.
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PMID:Ligand-induced activation of chimeric receptors between the erythropoietin receptor and receptor tyrosine kinases. 750 12

The protooncogene c-kit encodes a transmembrane receptor-type tyrosine kinase which belongs to the beta-PDGER/CSF-1 receptor tyrosine kinase family. The interaction between c-kit receptor and its corresponding ligand, stem cell factor (SCF), has been suggested to be involved in embryogenesis as well as carcinogenesis via the autocrine/paracrine system. In the present study, cancer cell lines and normal/benign/malignant tissues of the human female genital tract were examined for the expression of both c-kit and SCF by Northern blot and immunohistochemical analyses. Two of 16 cell lines showed mRNA expression of both c-kit and SCF, while 2 and 12 cell lines expressed c-kit and SCF, respectively. In tissues, several cases of malignant tumors, including three cervical cancers, one ovarian cancer, and one ovarian immature teratoma, expressed mRNA of both c-kit and SCF. In normal tissues, squamous epithelium expressed SCF immunohistochemically, while c-kit protein was detected only in melanocytes. Some tissues of malignant tumors, one squamous cell carcinoma of the cervix, two small cell carcinomas of the cervix, two serous adenocarcinomas of the ovary, and two immature teratomas of the ovary, expressed both c-kit and SCF proteins immunohistochemically. It is also notable that c-kit protein was expressed only in malignant germ cells of dysgerminomas, while SCF was expressed in the connective tissues surrounding germ cells. The present study suggests that the c-kit/SCF system may play an important role in the carcinogenesis of the female genital tract.
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PMID:Coexpression of the c-kit receptor and the stem cell factor in gynecological tumors. 751 96

To elucidate which cytokine receptors may be expressed by human glioblastoma and normal astrocytic cells, the presence of messenger ribonucleic acid (RNA) for a number of cytokine receptors was examined in 16 glioblastoma cell lines and adult and fetal astrocytes. A complementary deoxyribonucleic acid copy of total RNA was synthesized and amplified with specific primers using the polymerase chain reaction method. The receptors studied were interleukin (IL)-1 receptor type I (IL-1RI) and type II (IL-1RII), p75 and p55 tumor necrosis factor (TNF) receptors (p75TNFR and p55TNFR), interferon (IFN)-alpha/beta and -gamma receptors (IFN-alpha/beta R and IFN-gamma R), granulocyte-macrophage (GM) colony-stimulating factors receptor alpha subunit (GM-CSFR), G-CSF receptor (G-CSFR), M-CSF receptor (c-fms, M-CSFR), stem cell factor receptor (c-kit, SCFR), IL-6 receptor (IL-6R), and IL-8 receptor (IL-8R). Transcripts for IL-1RI, p55TNFR, IFN-alpha/beta R, and IFN-gamma R were present in all cell lines. The presence of IL-1RII, p75TNFR, GM-CSFR, M-CSFR, SCFR, IL-6R, and IL-8R was identified in 13, eight, seven, eight, 14, three, and one cell lines, respectively. Normal astrocytes were positive for IL-1RI, p75TNFR, p55TNFR, IFN-alpha/beta R, IFN-gamma R, M-CSFR, and SCFR, showing a similarity to glioblastoma cells. Expression of IL-1RII was observed in adult astrocytes but not in fetal astrocytes. Furthermore, gene expression was assessed in normal brain tissue and 11 glioblastoma tissue specimens. The normal brain tissue expressed IL-1RI, IL-1RII, IFN-alpha/beta R, M-CSFR, and SCFR. Of the 11 glioblastoma tissue specimens, IL-1RI was positive in 11, IL-1RII in 10, p75TNFR in nine, p55TNFR in nine, IFN-alpha/beta R in 10, IFN-gamma R in 10, GM-CSFR in two, G-CSFR in three, IL-8R in eight, and M-CSFR and SCFR in 11. These expressions were consistent with those in the cell lines, except for IL-8R. It is concluded that glioblastoma cells and normal astrocytes express a similar set of cytokine receptor genes in vitro and in vivo. Possible autocrine loops are suggested for IL-1 alpha/IL-1RI, TNF-alpha/p55TNFR, IFN-beta/IFN-alpha/beta R, M-CSF/M-CSFR, and SCF/SCFR in glioblastomas.
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PMID:Analysis of cytokine receptor messenger RNA expression in human glioblastoma cells and normal astrocytes by reverse-transcription polymerase chain reaction. 751 61

Mutations at either W or mi (microphthalmia) loci in the mouse can lead to a deficiency in melanocytes and mast cells. In addition, W mutants can be anemic and sterile, whereas mi mice are osteopetrotic because of a monocyte/macrophage/osteoclast defect. Since c-kit receptor tyrosine kinase is the gene product of the W locus and mi mutation has been suggested to affect the transduction of signals from the c-kit and c-fms receptors, we here examined the effect of mi mutation on fertility. Testes and ovaries from mi/mi mice were histologically normal, and the pattern of c-kit protein expression was not different from that of +/+ mice. Homozygous mutant crosses (mi/mi x mi/mi) were fertile, but inversion of the uterus occurred in 86% of the deliveries. In some cases, the placenta was found still attached to the inverted uterus after delivery. Decidual cells were present and expressed c-kit protein normally in the placenta of mi/mi mice. The inversion was also observed in mi/mi females mated to +/+ males. No uterine inversion was noted when +/mi females were crossed with mi/mi or +/mi males, suggesting that the genotype of the mother but not of the father or fetus is important for the pathogenesis. The numbers and body weights of mi/mi newborns were less than those of +/mi littermates. Mast cells were absent, but c-kit-positive cells were present, in the uterine muscle layers of pregnant mi/mi mice.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:High incidence of uterine inversion in mast cell-deficient osteopetrotic mutant mice of mi/mi genotype. 751 99

Three receptor molecules, belonging to the class III of receptor tyrosine kinases, namely the receptors for colony-stimulating factor 1, CSF1R (product of the FMS proto-oncogene) and Steel factor, SLFR (product of the KIT proto-oncogene), as well as the recently identified FLT3/FLK2 gene product, appear to play distinct roles in normal hematopoietic differentiation. Their potential role in leukemic hematopoiesis has been approached by expression studies in hematopoietic malignancies, especially in acute leukemias of the myeloid and lymphoid lineages. We present here a review of available data, and discuss the possible significance and potential applications of these results.
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PMID:The expression of FMS, KIT and FLT3 in hematopoietic malignancies. 751 7

The generation of murine mast cells is supported by several cytokines, and mast cell lines are frequently established in long-term cultures of normal murine marrow cells. In contrast, growth of human mast cells was initially dependent on coculture with murine fibroblasts. The growth factor produced by murine fibroblasts and required to observe differentiation of human mast cells is attributable in part to stem cell factor (SCF). However, other factors are likely involved. We have previously shown that the combination of SCF and interleukin-3 (IL-3) efficiently sustains proliferation and differentiation of colony-forming cells (CFCs) from pre-CFC enriched from human umbilical cord blood by CD34+ selection. With periodic medium changes and the addition of fresh growth factors, five consecutive cultures of different cord blood samples gave rise to differentiated cells and CFCs for more than 2 months. Although differentiated cells continued to be generated for more than 5 months, CFCs were no longer detectable by day 50 of culture. The cells have the morphology of immature mast cells, are Toluidine blue positive, are karyotypically normal, are CD33+, CD34-, CD45+, c-kit-, and c-fms-, and die in the absence of either SCF or IL-3. These cells do not form colonies in semisolid culture and are propagated in liquid culture stimulated with SCF and IL-3 at a seeding concentration of no less than 10(4) cells/mL. At refeedings, the cultures contain a high number (> 50%) of dead cells and have a doubling time ranging from 5 to 12 days. This suggests that subsets of the cell population die because of a requirement for a growth factor other than SCF or IL-3. These results indicate that the combination of cord blood progenitor and stem cells, plus a cocktail of growth factors including SCF and IL-3, is capable with high efficiency of giving rise in serum-deprived culture to human mast cells that behave like factor-dependent cell lines. These cells may represent a useful tool for studies of human mast cell differentiation and leukemia.
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PMID:Long-term generation of human mast cells in serum-free cultures of CD34+ cord blood cells stimulated with stem cell factor and interleukin-3. 752 46

A number of growth factors have been described that affect the hematopoietic system. Among this group are Steel factor (also known as mast cell growth factor, stem cell factor and kit ligand), and the more recently described flt3 ligand. These factors have been shown to function by binding to and activating the c-kit and flt3 tyrosine kinase receptors, respectively. Both of these factors stimulate the growth of mouse and human hematopoietic progenitor cells. These factors therefore differ from such later acting hematopoietic factors as colony-stimulating factor (CSF)-1, which regulates the growth, survival and differentiation of monocytic cells through the c-fms tyrosine kinase receptor. Like Steel factor, the flt3 ligand has little biological activity on its own, but synergizes well with a number of other colony stimulating factors and interleukins. One major difference between the two factors appears to be their effect on mast cells. Steel factor stimulates both the proliferation and activation of mast cells, while preliminary data with the flt3 ligand suggests that it has no effect on mast cells. Although the flt3 ligand and Steel factor each act on early hematopoietic cells, differences in their activities suggest that they are not redundant and are both required for normal hematopoiesis.
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PMID:The flt3 ligand: a hematopoietic stem cell factor whose activities are distinct from steel factor. 753 49


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