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

The common gamma-chain (gamma(c)) is a functional component of the IL-4R, yet cells lacking gamma(c) are able to respond to IL-4. This has led to the suggestion that a surrogate gamma'-chain, which can interact with the IL-4R alpha chain to mediate signaling, is expressed on cells lacking gamma(c). An alternative possibility is that in the absence of gamma(c), the IL-4R alpha chain is able to transduce signals by homodimerization. To test this latter possibility, a chimeric receptor containing the extracellular domain of c-kit (the stem cell factor (SCF) receptor) and the cytoplasmic and transmembrane domains of the IL-4R alpha chain was generated. Treatment of cells expressing the chimeric receptor kit/IL-4R alpha with SCF induces activation of the IL-4R alpha-associated kinase JAK-1 and the transcription factor STAT6. However, tyrosine phosphorylation of JAK-3, which associates with gamma(c), is not induced by SCF in these cells. SCF-mediated ligation of kit/IL-4R alpha is sufficient to elicit IL-4-specific gene expression, including up-regulation of CD23 and synthesis of germ-line epsilon transcripts. In the T cell line CTLL2, ligation of kit/IL-4R alpha induces cellular proliferation. Finally, in JAK-1-deficient HeLa cells, STAT6 activation by IL-4 is completely abolished. Together, these data demonstrate that the IL-4R alpha cytoplasmic domain is sufficient to activate JAK-1 and STAT6 and to induce expression of IL-4 target genes, thus identifying a mechanism by which IL-4 signaling can proceed in the absence of JAK-3 and gamma(c).
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PMID:The IL-4 receptor alpha-chain cytoplasmic domain is sufficient for activation of JAK-1 and STAT6 and the induction of IL-4-specific gene expression. 919 Sep 38

Rat gonocytes migrate to the basement membrane during the first postnatal week, a change in position crucial for their survival. These cells express the c-kit gene from the day of birth through Day 5 in vivo and develop the ability to migrate in Sertoli cell-gonocyte cocultures. In this study, we asked whether c-kit expression and synthesis of Kit protein are required for pseudopod production by gonocytes in vitro. To determine whether gonocyte migration in vitro is invariably accompanied by c-kit expression, we quantified percentages of gonocytes expressing c-kit with increasing time in vitro and correlated these data with pseudopod development by individual cells. We also determined the effect of exposure to Kit antibodies on gonocyte migration in vitro, and, conversely, asked whether addition of exogenous stem cell factor (SCF), the Kit ligand, stimulates pseudopod development. We found that 1) increasing numbers of gonocytes express c-kit with increasing time in vitro; 2) once these cells begin migrating in vitro, the appearance of a pseudopod on a gonocyte is absolutely correlated with kit expression by that cell; 3) incubating cocultures with Kit antibodies significantly reduces the number of cells with pseudopods, without any detectable decrease in numbers of gonocytes; and 4) addition of exogenous SCF to cocultures prepared on Day 5 results in a transient but significant increase in the percentage of gonocytes with pseudopods even though we found that Sertoli cells in the cultures produce endogenous SCF. Thus, our findings provide evidence to support a role for c-kit expression by neonatal gonocytes and, presumably, SCF expression by neonatal Sertoli cells in stimulating migration of these germ cells in vitro.
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PMID:Expression of the c-kit gene is critical for migration of neonatal rat gonocytes in vitro. 928 7

We studied the functional characteristics of subpopulations of cord blood-derived CD34+ cells expressing different levels of CD38 and c-kit antigens, using clonal cell culture and long-term culture with allogeneic bone marrow stromal cells or the MS-5 murine stromal cell line to assay long-term culture-initiating cells (LTC-IC) in each subpopulation. To investigate the capacity for replication, proliferation, and differentiation of each subpopulation of CD34+ cells, we also studied the correlation between LTC-IC and telomerase activity. After 5 weeks of coculture, LTC-IC accounted for one out of 32 CD34+CD38- cells and one out of 33 CD34+c-kit- cells. In contrast, the frequency of LTC-IC was low in their antigen-positive counterparts (one per 84 CD34+CD38+ cells, one per 90 CD34+c-kit(low) cells, and very low among CD34+c-kit(high) cells). It was noteworthy that some LTC-IC derived from CD34+CD38- as well as CD34+c-kit- cells generated colony-forming cells (CFCs) after up to 9 weeks of coculture. Telomerase activity was consistently low in CD34+CD38- and CD34+c-kit- cells compared to CD38+ or c-kit(high or low) cells, suggesting that CD34+CD38- or c-kit- cells are likely to be more quiescent. These results suggest that the CD34+CD38- and CD34+c-kit- cell populations are primitive stem/progenitor cells, and that the telomerase activity of these cells correlates with their proliferative capacity as well as their stage of differentiation.
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PMID:Human cord blood-derived primitive progenitors are enriched in CD34+c-kit- cells: correlation between long-term culture-initiating cells and telomerase expression. 959 71

To investigate the clinical role of the soluble form of c-kit receptor (s-kit) in patients with acute myeloid leukemia (AML), we determined the levels of serum s-kit and expression of c-kit antigens and mRNA in leukemic cells. The serum s-kit level was measured using ELISA assay in 30 AML patients and 20 normal controls. C-kit antigens of leukemic blasts were stained immunohistologically, and c-kit mRNA was detected by RT-PCR. The serum s-kit level in M1 and M2 were significantly increased (p<0.01) and that in M4 or M5 was significantly decreased (p<0.05) compared to that in the controls. In the comparisons among subtypes of FAB classification, M1 and M2 showed significantly higher levels than M4 or M5 (p<0.05 and p<0.01, respectively). Both expression of c-kit antigens and mRNA were observed in M0 (1/4), M1 (2/4) and M2 (6/8), but neither was observed in M4 or M5. The serum s-kit levels were correlated with the absolute number of AML blasts in peripheral blood (r=0.564, p<0.05). These results indicate that the serum s-kit level is related to the stage of differentiation of AML blasts in accordance with the expression of c-kit protein and mRNA in AML blasts, and is useful for assessment of leukemic cell burden.
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PMID:Serum soluble c-kit receptor and expression of c-kit protein and mRNA in acute myeloid leukemia. 965 58

We compared the effect of human flt3 ligand (FL) and stem cell factor (SCF) on cord blood (CB)-derived CD34+ cells expressing different levels of flt3 or c-kit tyrosine kinase (TK) receptor in clonal cell culture. The c-kit receptor was expressed by 58.5+/-16.7% of CB CD34+ cells (n=19), in which c-kit(high), c-kit(low) and c-kit cell populations could be identified. In contrast, the flt3 receptor (FR) was weakly expressed on 58.6+/-8.3% (n=9) of CB CD34+ cells. FL+erythropoietin (Epo) failed to support erythroid burst (BFU-E) formation by any subpopulation of CD34+ cells. However, SCF + Epo supported BFU-E and erythrocyte-containing mixed (CFU-mix) colony formation from all subpopulations. Interestingly, FL markedly augmented CFU-mix colony formation supported by interleukin (IL)-3 + Epo when CD34+c-kit(low) or CD34+FR+ cells were used as the target. On the other hand, SCF significantly enhanced CFU-mix colony formation supported by IL-3 + Epo when CD34+c-kit(high) or low and CD34+FR+ cells were used. The replating potential of CFU-mix supported by IL-3 + Epo+ FL was greater when CD34+c-kit(low) or CD34+FR+ cells were used. When the CD34+c-kit(low) cells were used, the number of lineages expressed in secondary cultures of CFU-mix colonies derived from primary cultures containing IL-3 + Epo + FL or SCF was significantly larger than when the primary cultures contained IL-3 + Epo. Furthermore, the number of long-term culture-initiating cells found in CD34+FR+ cells was larger than that in FR cells. CB-derived CD34+c-kit(low) cells represent a less mature population than c-kit(high) cells, as reported previously. Therefore, these results indicate that both FL and SCF can act on primitive multipotential progenitors. However, it is still uncertain whether CB-derived CD34+FR+ cells are less mature than CD34+FR- cells.
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PMID:Haematopoietic action of flt3 ligand on cord blood-derived CD34-positive cells expressing different levels of flt3 or c-kit tyrosine kinase receptor: comparison with stem cell factor. 965 59

The cytokine stem cell factor (SCF) synergizes with IL-7 to enhance the proliferation of thymocytes. We therefore investigated the role of the SCF receptor, the protooncogene c-kit, in the pathogenesis of pediatric T-lineage malignancies. Expression and regulation of c-kit in cells from children with non-Hodgkin's lymphoma (T-NHL) or acute lymphoblastic leukemia (T-ALL) and the proliferative effect of SCF on these cells were examined in seven cell lines and 21 biopsy tumor cell preparations. Inducibility of c-kit receptors by SCF, IL-1beta, IL-2, IL-7, TGF-beta, TNF-alpha, PMA or calcium ionophore A23187 was studied by flow cytometry (FCM). C-kit receptors were detected in three out of seven T-lymphoblastic cell lines and in nine out of 21 biopsy tumor cell preparations. Upregulation of c-kit could be induced by cultivation, and to a higher extent by cultivation and addition of IL-1beta, TNF-alpha, TGF-beta or A23187. Downregulation of c-kit occurred in the presence of SCF or PMA. SCF caused a downregulation of c-kit receptors in eight of nine, and a proliferative response in three of 11 c-kit-positive T-lymphoblastic cell preparations. We conclude that c-kit is able to transduce a growth stimulatory signal in some T-lymphoblastic cells and that its expression may not be detectable in a resting metabolic or proliferative state.
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PMID:Expression and regulation of c-kit receptor and response to stem cell factor in childhood malignant T-lymphoblastic cells. 969 76

Microinjection of a truncated form of the c-kit tyrosine kinase present in mouse spermatozoa (tr-kit) activates mouse eggs parthenogenetically, and tr-kit- induced egg activation is inhibited by preincubation with an inhibitor of phospholipase C (PLC) (Sette, C., A. Bevilacqua, A. Bianchini, F. Mangia, R. Geremia, and P. Rossi. 1997. Development [Camb.]. 124:2267-2274). Co-injection of glutathione-S-transferase (GST) fusion proteins containing the src-homology (SH) domains of the gamma1 isoform of PLC (PLCgamma1) competitively inhibits tr-kit- induced egg activation. A GST fusion protein containing the SH3 domain of PLCgamma1 inhibits egg activation as efficiently as the whole SH region, while a GST fusion protein containing the two SH2 domains is much less effective. A GST fusion protein containing the SH3 domain of the Grb2 adaptor protein does not inhibit tr-kit-induced egg activation, showing that the effect of the SH3 domain of PLCgamma1 is specific. Tr-kit-induced egg activation is also suppressed by co-injection of antibodies raised against the PLCgamma1 SH domains, but not against the PLCgamma1 COOH-terminal region. In transfected COS cells, coexpression of PLCgamma1 and tr-kit increases diacylglycerol and inositol phosphate production, and the phosphotyrosine content of PLCgamma1 with respect to cells expressing PLCgamma1 alone. These data indicate that tr-kit activates PLCgamma1, and that the SH3 domain of PLCgamma1 is essential for tr-kit-induced egg activation.
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PMID:Involvement of phospholipase Cgamma1 in mouse egg activation induced by a truncated form of the C-kit tyrosine kinase present in spermatozoa. 972 17

Mast cells express the receptor tyrosine kinase kit/stem cell factor receptor (SCFR) which is encoded by the proto-oncogene c-kit. Ligation of SCFR induces its dimerization and activation of its intrinsic tyrosine kinase activity leading to activation of Raf-1, phospholipases, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinases. However, little is known about the downstream signals initiated by SCFR ligation except for activation of extracellular signal-regulated kinases. The murine mast cell line, MC/9, synthesizes and secretes TNF-alpha following the aggregation of high affinity Fc receptors for IgE (Fc epsilonRI). Ligation of SCFR or Fc epsilonRI on MC/9 cells resulted in the activation of all three MAP kinase family members, extracellular signal-regulated kinases, c-Jun amino-terminal kinase (JNK), and p38. Stem cell factor (SCF)-induced activation of JNK and p38 was insensitive to wortmannin, cyclosporin A, and FK506 whereas activation of these kinases through Fc epsilonRI was sensitive to these drugs. Coligation of SCFR augmented Fc epsilonRI-mediated activation of MAP kinases, especially JNK activation, and SCF augmented Fc epsilonRI-mediated TNF-alpha production in MC/9 cells, although SCF alone did not induce TNF-alpha production. This augmentation by SCF was regulated at the level of transcription, at least in part, since the promoter activity of TNF-alpha was enhanced following addition of SCF. These results demonstrate that SCF can augment Fc epsilonRI-mediated JNK activation and cytokine gene transcription but via pathways that are regulated differently than the ones activated through Fc epsilonRI.
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PMID:Stem cell factor augments Fc epsilon RI-mediated TNF-alpha production and stimulates MAP kinases via a different pathway in MC/9 mast cells. 975 85

Mastocytosis represents a mast cell proliferative disease that generally runs a benign clinical course, with spontaneous remissions mostly by puberty in childhood-onset disease, although rare forms, particularly in adult-onset disease, can be associated with (pre)malignant hematologic disorders and very rarely present as mast cell leukemia or malignant mastocytosis. Reasons for this divergent clinical behavior of childhood- versus adult-onset disease are unknown. Recently, two activating mutations in the intracellular domain of the proto-oncogene c-kit, which encodes a tyrosine kinase receptor for the mast cell growth factor stem cell factor, have been detected in the human leukemic mast cell line HMC-1. We have therefore studied lesional skin biopsies from patients with adult- and childhood-onset indolent mastocytosis for the presence of these codon 560 and 816 mutations. C-kit coding DNA sequences were amplified and analyzed by mutation-specific restriction analyses, and mutated polymerase chain reaction products were additionally cloned and sequenced. The codon 816 mutation was found in all six samples from adult patients, but not in any of the 11 specimens from children. In addition, the codon 560 mutation could be demonstrated for the first time in indolent mastocytosis, namely in two of four specimens from adult patients, but not in those from two children. These data thus provide a possible explanation for the divergent clinical behavior of adult- versus childhood-onset indolent mastocytosis, with the first being associated with an activating mutation, possibly as part of a neoplastic process, and the latter representing most likely a reactive process of an as yet unknown pathogenesis.
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PMID:Identification of activating c-kit mutations in adult-, but not in childhood-onset indolent mastocytosis: a possible explanation for divergent clinical behavior. 985 47

We show a dramatic downregulation of the stem cell factor (SCF) receptor in different hematopoietic cell lines by murine stroma. Growth of the human erythroid/macrophage progenitor cell line TF-1 is dependent on granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3). However, TF-1 cells clone and proliferate equally well on stroma. Independent stroma-dependent TF-1 clones (TF-1S) were generated on MS-5 stroma. Growth of TF-1S and TF-1 cells on stroma still requires interaction between c-kit (SCF receptor) and its ligand SCF, because antibodies against c-kit inhibit growth to less than 2%. Surprisingly, c-kit receptor expression (RNA and protein) was downregulated by 2 to 3 orders of magnitude in TF-1S and TF-1 cells grown on stroma. This stroma-dependent regulation of the kit receptor in TF-1 was also observed on exposure to kit ligand-negative stroma, thus indicating the need for heterologous receptor ligand interaction. Removal of stroma induced upregulation by 2 to 4 orders of magnitude. Downregulation and upregulation of c-kit expression could also be shown for the megakaryocytic progenitor cell line M-07e and was comparable to that of TF-1, indicating that stroma-dependent regulation of c-kit is a general mechanism. Downregulation may be an economic way to compensate for the increased sensitivity of the c-kit/ligand interaction on stroma. The stroma-dependent c-kit regulation most likely occurs at the transcriptional level, because mechanisms, such as splicing, attenuation, differential promoter usage, or mRNA stability, could be excluded.
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PMID:Downregulation of c-kit (stem cell factor receptor) in transformed hematopoietic precursor cells by stroma cells. 988 16


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