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

The molecular cloning for most of the hematopoietic growth factor receptors has been achieved over the past few years and revealed that they can by assigned to two discrete receptor families, namely the hematopoietic growth factor superfamily (HRS) and the receptor tyrosine kinase family (RTK). The members of the HRS, including granulocyte-macrophage colony-stimulating factor receptor (GM-CSF-R), interleukin 3 receptor (IL-3-R), granulocyte CSF receptor (G-CSF-R) and erythropoietin receptor (Epo-R), share a common binding domain and the absence of a tyrosine kinase domain in their cytoplasmic portion. In some cases (e.g., GM-CSF-R), the high-affinity receptor structure is obtained through the association of the low-affinity binding chain (alpha chain) with an accessory protein (beta chain). It is conceivable that this protein might also represent the common subunit shared by GM-CSF-R and by IL-3-R when they are co-expressed to form the putative GM-CSF-R/IL-3-R complex. Although tyrosine phosphorylation following ligand receptor activation seems to be a common event in the HRS, its role in the signal transduction mechanisms is unknown. Due to the structural analogies among the members of this family any new insight into one particular receptor member, such as its subunit structure and its signal transduction pathways, will be generalizable to the other family members. The subclass III of the RTK family, including the CSF-1-R and c-kit, is characterized by an additional insert into the kinase domain that recognizes and binds protein substrates. Ligand induced activation of the kinase domain and its signaling potential are mediated by receptor oligomerization which stabilizes interactions between adjacent cytoplasmic domains and leads to activation of kinase function by molecular interaction. Interestingly, the receptors included in this subclass are the products of well known cellular proto-oncogenes. A large variety of structural alteration found in receptor-derived oncogene products may lead to constitutive activation of receptor signals that, consequently, result in the subversion of the mechanisms controlling the cell growth.
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PMID:Hematopoietic growth factor receptors. 189 57

We have cloned and characterized a new member of the receptor tyrosine kinase family. The cDNA clone, isolated from a rat olfactory cDNA library, has considerable homology to the family of receptors that includes the colony-stimulating factor 1 receptor, the c-kit proto-oncogene, and the platelet-derived growth factor (PDGF) receptors. Analysis of DNA sequence homology, ligand-binding, and ligand-stimulated phosphorylation data suggests that this clone encodes the rat PDGF-A/B or alpha-receptor. Comparison of its sequence to those of other receptors allows us to postulate a mechanism for receptor dimerization and activation. The expression of the rat alpha-PDGF receptor in nonneuronal cells of the olfactory epithelium and in the olfactory bulb is consistent with a role for PDGF in glial cell generation.
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PMID:Isolation and characterization of the alpha platelet-derived growth factor receptor from rat olfactory epithelium. 215 69

Structural features of v-kit, the oncogene of HZ4 feline sarcoma virus, suggested that this gene arose by transduction and truncation of cellular sequences. Complementary DNA cloning of the human proto-oncogene coding for a receptor tyrosine kinase confirmed this possibility: c-kit encodes a transmembrane glycoprotein that is structurally related to the receptor for macrophage growth factor (CSF-1) and the receptor for platelet-derived growth factor. The c-kit gene is widely expressed as a single, 5-kb transcript, and it is localized to human chromosome 4 and to mouse chromosome 5. A c-kit peptide antibody permitted the identification of a 145,000 dalton c-kit gene product that is inserted in the cellular plasma membrane and is capable of self-phosphorylation on tyrosine residues in both human glioblastoma cells and transfected mouse fibroblasts. Our results suggest that p145c-kit functions as a cell surface receptor for an as yet unidentified ligand. Furthermore, carboxy- and amino-terminal truncations that occurred during the viral transduction process are likely to have generated the transformation potential of v-kit.
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PMID:Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. 244 37

The high-affinity receptor for IgE, Fc epsilon RI, represents the major cell surface structure through which mast cells express immunologically specific secretory function. By contrast, the stem cell factor receptor (SCFR), which is encoded by c-kit, is essential for normal mast cell development. The signaling pathways initiated by the stimulation of mast cells through the Fc epsilon RI, which lacks intrinsic kinase activity, and the SCFR, a member of the receptor tyrosine kinase family, generally have been regarded to be distinct. We report here that mouse mast cells stimulated either with SCF or with IgE and specific antigen exhibit a remarkably similar pattern of activation of mitogen-activated protein kinases (MAPK), 90 kDa-S6 kinases (pp90rsk), and pp70-S6 kinases (pp70-S6K). These results indicate that all three families of protein kinases are associated with the cell surface receptor-dependent activation of secretion, as well as proliferation, in mast cells. We also show that the immunosuppressant rapamycin, but not FK506, can inhibit both SCF-dependent pp70-S6 kinase activation and SCF-dependent proliferation in mouse mast cells, without suppressing IgE- and antigen-dependent mediator release. These findings suggest that the activation of pp70-S6 kinase represents an important link in the stimulation of cell proliferation by SCF. Our results also indicate that the intracellular signaling pathways initiated by stimulation of mast cells through the Fc epsilon RI or the SCFR exhibit more overlap than has previously been appreciated.
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PMID:Activation of MAP kinases, pp90rsk and pp70-S6 kinases in mouse mast cells by signaling through the c-kit receptor tyrosine kinase or Fc epsilon RI: rapamycin inhibits activation of pp70-S6 kinase and proliferation in mouse mast cells. 750 92

The c-kit receptor tyrosine kinase is highly expressed by about 10% of the neurons in the dorsal root ganglia (DRGs) of mouse embryos. We investigated the in vitro effect of stem cell factor (SCF), the ligand for c-kit receptor, on DRGs. Recombinant murine SCF (rmSCF) induced the outgrowth of c-kit-positive neurites from DRGs of normal (+/+) embryos. The effect of SCF was dose dependent and completely abolished by anti-c-kit ACK2 monoclonal antibody (mAb). Some neurites whose outgrowth was induced by nerve growth factor (NGF) were c-kit-positive, but anti-NGF mAb did not inhibit the rmSCF-induced neurite outgrowth. rmSCF did not induce neurite outgrowth from DRGs of W/W embryos that did not express c-kit receptors on the cell surface and of W42/W42 mutant embryos that expressed c-kit receptors without tyrosine kinase activity. rmSCF also had a trophic effect on c-kit-positive neurons in the culture of dissociated DRG cells. Most c-kit-positive neurons appeared to respond to NGF as well, and the SCF-responsive subpopulation represented about 10% of NGF-responsive neurons. rmSCF did not support the survival of DRG neurons from embryos of W/W and W42/W42 genotypes. These results suggest that the stimulus through the c-kit receptor tyrosine kinase has an important role in development of the peripheral nervous system.
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PMID:Stem cell factor induces outgrowth of c-kit-positive neurites and supports the survival of c-kit-positive neurons in dorsal root ganglia of mouse embryos. 750 40

The W locus of mice encodes the c-kit receptor tyrosine kinase. Recently, we characterized a novel mutant allele, Wn, and demonstrated that the c-kit protein synthesized in Wn/Wn cultured mast cells (CMC) was reduced in size and not expressed on their surface (Tsujimura et al., 1993). In this study, we further examined biochemical nature of the mutant form of c-kit protein, by using Wn/Wn CMC and 293T cells transfected with Wn-type c-kit cDNA (c-kitWn). The c-kit product synthesized in Wn/Wn CMC was truncated almost all cytoplasmic domain and was less glycosylated. In c-kitWn-transected cells, both glycosylation and extracellular expression of c-kit protein was also impaired, however, no truncation was detected. These results indicate that Wn-mutant form of c-kit product is insufficient in maturation, which is associated with impairments in the transport to the plasma membrane, and retention of the mutant protein in endoplasmic reticulum is suggested. This is the first demonstration of the c-kit mutation affecting posttranslational processing its product.
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PMID:Wn mutation of c-kit receptor affects its post-translational processing and extracellular expression. 750

Stem cell factor (SCF) and its receptor (SCFR), a member of the receptor tyrosine kinase III family that is encoded by the c-kit gene, critically regulate several complex biological programs including hematopoiesis, mast cell development, cutaneous pigmentation, and gametogenesis. We show herein that mouse mast cells die rapidly after the withdrawal of SCF in vivo or in vitro, and provide morphological evidence that such mast cells undergo programmed cell death or apoptosis. We also show that when in vitro-derived mouse mast cells maintained in SCF are removed from SCF-containing medium for only 5 or 6 hours, the cells' genomic DNA exhibits the ladder-like pattern of oligonucleosome-sized fragments typical of apoptosis. These findings demonstrate that SCF can regulate the survival of a cellular lineage which expresses the SCFR by suppressing apoptosis. They also identify a mechanism that can result in striking and rapid reductions in the size of tissue mast cell populations without histological evidence of the concomitant induction of a significant inflammatory response.
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PMID:The c-kit ligand, stem cell factor, promotes mast cell survival by suppressing apoptosis. 750 84

The Ws mutant allele of rats represents a 12-base deletion at the tyrosine kinase domain of the c-kit gene. Although homozygous Ws/Ws rats were deficient in both connective tissue-type mast cells (CTMC) and mucosal-type mast cells (MMC), mast cells did develop when bone marrow cells of Ws/Ws rats were cultured in the presence of concanavalin A-stimulated spleen cell conditioned medium (ConA-SCM). Although the proliferative response of rat cultured mast cells (RCMC) derived from Ws/Ws rats to ConA-SCM was comparable to that of RCMC derived from control normal (+/+) rats, the proliferative response of Ws/Ws RCMC to rat recombinant stem cell factor (rrSCF; a ligand for the c-kit receptor tyrosine kinase) was much lower than that of +/+ RCMC. However, a slight c-kit kinase activity was detectable in Ws/Ws RCMC, and the proliferation of Ws/Ws RCMC was accelerated when rrSCF was added to ConA-SCM. Because CTMC contain rat mast cell protease-I (RMCP-I) and MMC contain RMCP-II, the phenotype of +/+ and Ws/Ws RCMC in various culture conditions was evaluated by immunohistochemistry of RMCPs. Both +/+ and Ws/Ws RCMC showed the MMC-like phenotype (RMCP-I-/II+) when they were cultured with ConA-SCM alone. Most +/+ RCMC and about half of Ws/Ws RCMC acquired a novel protease (RMCP-I+/II+) phenotype when they were cultured with rrSCF alone. However, because the number of Ws/Ws RCMC dropped to one-tenth in the medium containing rrSCF alone, the absolute number of Ws/Ws RCMC with the RMCP-I+/II+ phenotype did not increase significantly. The effect of rrSCF in inducing the novel phenotype was suppressed when ConA-SCM was added to rrSCF. In contrast, +/+ and Ws/Ws RCMC cocultured with +/+ fibroblasts showed the RMCP-I+/II+ phenotype even in the presence of ConA-SCM. Moreover, a fibroblast cell line derived from SI/SI mouse embryos that did not produce SCF did not support the survival of both +/+ and Ws/Ws RCMC but did induce the RMCP-I+/II+ phenotype in about half of +/+ and Ws/Ws RCMC when their survival was supported by the addition of ConA-SCM. The normal signal transduction through the c-kit receptor did not appear to be prerequisite for the acquisition of the RMCP-I+/II+ phenotype.
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PMID:Characterization of cultured mast cells derived from Ws/Ws mast cell-deficient rats with a small deletion at tyrosine kinase domain of c-kit. 750 12

The receptor tyrosine kinase c-kit is thought to mediate its diverse effects on different cell lineages by association and activation of distinct second messenger systems. One of the immediate events after binding of the kit ligand to the receptor is its association with the 85-kDa subunit (p85) of the phosphatidylinositol (PI) 3-kinase and the activation of the enzyme. In the present study, we examined the association and activation of PI 3-kinase with mutant forms of the c-kit receptor transiently expressed in COS-1 cells. To define the binding site of p85 we substituted the putative tyrosine phosphorylation sites in the kinase insert region of the c-kit receptor by phenylalanine (YF702, YF719, YF728, and YF745, respectively). The results indicate that, upon stimulation of cells with kit ligand, 1) the wild-type c-kit protein was readily autophosphorylated and autophosphorylation was not diminished significantly with any of the mutant proteins; 2) p85 and PI 3-kinase activity associated with wild-type c-Kit protein as well as with the mutant proteins YF702, YF728, and YF745. Ligand-induced association of p85 and PI 3-kinase activity were abolished with the YF719 c-Kit protein, and this was not due to different levels of expression of p85 or c-kit; and 3) c-kit receptor-bound p85 was not phosphorylated on tyrosine residues. These results indicate that tyrosine 719 within the 719YMDM motif in the kinase insert plays an important role in binding of p85 and that its phosphorylation is a prerequisite for binding of p85 and the subsequent activation of PI 3-kinase.
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PMID:Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit-associated PI 3-kinase activity in COS-1 cells. 750 96

Three monoclonal antibodies (MAbs) to the human c-kit receptor tyrosine kinase (P145c-kit), derived in independent laboratories, have been extensively used in studies of c-kit expression and the role of its ligand, steel factor (SLF), in hemopoiesis and mast cell differentiation and function. In this study, the relationship between the epitopes they identify, and their effects on SLF binding, receptor internalization, and signal transduction are compared. Epitope mapping studies carried out on the high P145c-kit-expressing cell line HEL-DR showed that SR-1 identifies an epitope independent of those bound by YB5.B8 and 17F11, while the latter two antibodies bound to distinct but interacting epitopes. SR-1 potently blocked the binding of SLF to P145c-kit on these cells and also on cells of the factor-dependent line MO7e. In contrast, YB5.B8 and 17F11 had minimal effects on ligand binding. Conversely, SLF partially blocked the binding of SR-1 and YB5.B8 to cells, while binding of 17F11 was actually enhanced by SLf on some target cells. Preincubation of HEL-DR and MO7e cells with MAbs prior to exposure to SLF revealed that 17F11 itself brought about partial down-regulation of P145c-kit and did not inhibit SLF-mediated down-regulation. SR-1 caused minimal down-regulation and inhibited SLF-mediated receptor internalization. YB5.B8 had minimal effects on either cell line in this assay. To determine whether the antibodies had any agonist activity, they were compared with SLF for their ability to bring about receptor phosphorylation in intact MO7e cells. All three antibodies induced detectable tyrosine phosphorylation with 17F11 being the most effective, while YB5.B8 was the least effective. Finally, the ability of the antibodies to influence the proliferation of the MO7e cells was examined. As expected, SR-1 potently inhibited the proliferative response to SLF, while 17F11 weakly inhibited and YB5.B8 had negligible effect. In the absence of SLF both 17F11 and YB5.B8 displayed very weak but reproducible agonist activity.
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PMID:Epitope mapping and functional studies with three monoclonal antibodies to the c-kit receptor tyrosine kinase, YB5.B8, 17F11, and SR-1. 751 Feb 97


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