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

The proto-oncogene c-Kit, a transmembrane receptor tyrosine kinase, is an important regulator of cell growth whose constitutively active oncogenic counterpart, v-kit, induces sarcomas in cats. Mutations in murine c-kit that reduce the receptor tyrosine kinase activity cause deficiencies in the migration and proliferation of melanoblasts, hematopoietic stem cells, and primordial germ cells. We therefore investigated whether c-Kit regulates normal human melanocyte proliferation and plays a role in melanomas. We show that normal human melanocytes respond to mast cell growth factor (MGF), the Kit-ligand that stimulates phosphorylation of tyrosyl residues in c-Kit and induces sequential phosphorylation of tyrosyl residues in several other proteins. One of the phosphorylated intermediates in the signal transduction pathway was identified as an early response kinase (mitogen-activated protein [MAP] kinase). Dephosphorylation of a prominent 180-kDa protein suggests that MGF also activates a phosphotyrosine phosphatase. In contrast, MGF did not induce proliferation, the cascade of protein phosphorylations, or MAP kinase activation in the majority of cells cultured from primary nodular and metastatic melanomas that grow independently of exogenous factors. In the five out of eight human melanoma lines expressing c-kit mRNAs, c-Kit was not constitutively activated. Therefore, although c-Kit-kinase is a potent growth regulator of normal human melanocytes, its activity is not positively associated with malignant transformation.
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PMID:c-Kit-kinase induces a cascade of protein tyrosine phosphorylation in normal human melanocytes in response to mast cell growth factor and stimulates mitogen-activated protein kinase but is down-regulated in melanomas. 137 24

Normal human melanocyte proliferation and differentiation is dependent on stimulation of one of three growth factor/receptor systems. They are fibroblast growth factor (FGF), hepatocyte growth factor (HGF), and mast cell growth factor (MGF), which activate the FGF receptor, c-Met, and c-Kit, respectively, known to be receptor tyrosine kinases. In contrast, human melanoma cells from primary nodular and metastatic lesions grow autonomously partially because of inappropriate production of basic FGF (bFGF) and continuous activation of the bFGF-receptor kinase. Activation of transmembrane receptor tyrosine kinases in melanocytes stimulates not only proliferation but also the expression of pigmentation. Melanoma cells constitutively express several tyrosyl-phosphorylated proteins that in normal melanocytes are stimulated in response to growth factors. This high level of phosphorylation was not due to either the presence of constitutively active Kit kinase and Met kinase nor to the absence of any of several known protein tyrosine phosphatases. Because bFGF by itself does not transform melanocytes to melanomas, there must be additional cooperating factors that confer the malignant phenotype to pigment cells.
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PMID:Growth factors, receptor kinases, and protein tyrosine phosphatases in normal and malignant melanocytes. 144 4

The mature cells in the haemopoietic system arise as the result of the extensive developmental and proliferative capacity of pluripotential stem cells. In order to understand the molecular basis for these developmental processes, it will be necessary to identify and characterize the cellular genes that control early steps in haemopoiesis. Mutations at the mouse W locus on chromosome 5 lead to pleiotropic developmental defects, including sterility, coat colour abnormalities, severe macrocytic anaemia and mast cell deficiency. The defects in all these lineages are cell autonomous and intrinsic, suggesting that the W locus encodes a gene product required directly for cellular differentiation. In an attempt to understand this classical mouse developmental mutation, we have demonstrated that the c-kit proto-oncogene, which encodes a transmembrane receptor tyrosine kinase, is very closely linked to W. Several further observations are consistent with the idea that W and c-kit are allelic: first, c-kit is expressed in those cell populations affected by W mutations; second, the expression of c-kit transcripts can be affected by mutations at the W locus; third, the tyrosine kinase activity associated with the protein encoded by c-kit is functionally impaired in mast cells derived from mutant W/Wv mice; and fourth, rearrangements within the c-kit gene have been reported in two W mutant alleles. These observations suggest that the dominant phenotype associated with W mutations results from loss-of-function alterations that affect the receptor tyrosine kinase encoded by c-kit. The demonstration that the W locus encodes a transmembrane growth factor receptor provides a molecular basis for understanding the intrinsic haemopoietic defect in W mutant mice and the role that this cellular proto-oncogene plays in haemopoiesis and other developmental processes.
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PMID:The mouse W/c-kit locus. 169 Jun 23

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

The c-kit proto-oncogene encodes a transmembrane receptor with a tyrosine kinase internal domain. C-kit has been mapped to the W locus in the mouse, and the gene encoding the ligand has been shown to be the product of the murine SI locus. Previous genetic studies have shown that the murine W and SI loci play important roles in the normal function of hemopoietic stem cells. As these stem cells have been identified as the origins of abnormal clones in acute myeloblastic leukemia (AML), a study was begun of c-kit in AML. By Northern blot analysis, it was shown that all of 21 blast populations from AML patients were kit expression positive, but some AML cell lines did not transcribe detectable c-kit mRNA. This study is now extended to the responses of freshly obtained AML cells and cell lines to the ligand, mast-cell growth factor (MGF). In culture, fresh cells usually responded to added ligand with increases in both self-renewal and terminal divisions. The most obvious effects were seen when MGF was combined with either IL-3 or G-CSF. The response of cell lines to MGF mirrored their expression of c-kit; expression positive lines responded in culture with patterns similar to those seen for fresh cells. C-kit expression negative cells did not respond to MGF. RNA prepared from the cells giving rise to one such line, OCI/AML-5, was available for study. mRNA for c-kit could not be detected in this RNA sample by Northern blot analysis or the polymerase chain reaction. Thus the heterogeneity found in AML blast populations extends to the involvement of c-kit and its ligand in growth regulation, although blast populations without this regulatory apparatus appear to be rare.
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PMID:Mast cell growth factor, a ligand for the receptor encoded by c-kit, affects the growth in culture of the blast cells of acute myeloblastic leukemia. 171 40

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

The product of the proto-oncogene c-kit is a transmembrane receptor protein that plays an important role in the regulation of normal and neoplastic hematopoiesis via the interaction with its specific ligand termed stem cell factor. To examine whether c-kit product is possibly involved in the pathogenesis of human lymphomas, we analyzed the expression of the c-kit protein in neoplastic cells from a variety of lymphoid tumors by immunostaining of lymph node frozen sections with the 17F11 antibody, detecting an extracellular epitope of the c-kit receptor, and of c-kit RNA by Northern blot hybridization. Of 24 nonHodgkin's lymphomas (NHL) of B- and T-cell phenotype, none expressed immunodetectable c-kit protein that was also not evidenced in lymphoid cells of reactive lymph nodes and normal tonsils. In contrast, c-kit protein was expressed by Reed-Sternberg cells and their mononuclear variants from 11 of 21 Hodgkin's disease (HD) cases, and in tumor cells from 11 of 16 cases of CD30+ anaplastic large cell lymphoma (ALCL). c-kit specific mRNA was also detected in lymph node tissues from HD and ALCL cases but not in neoplastic tissues from NHL other than ALCL. In addition, c-kit/CD30+ tumor cells were evidenced by flow cytometry in a patient displaying massive bone marrow involvement by ALCL. With the exclusion of lymphocyte predominance cases of HD that resulted c-kit expression and the other histologic subtypes of HD or the immunologic phenotype of tumor cells (B, T, nonB-nonT) in both HD and ALCL. The highly restricted expression of the c-kit product among human lymphomas to HD and ALCL provides a further biologic link between these two closely related lymphoma entities.
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PMID:Expression of the c-kit receptor in human lymphomas is restricted to Hodgkin's disease and CD30+ anaplastic large cell lymphomas. 1465 71

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

The mast cell growth factor (MGF) affects migration, proliferation and differentiation of erythroid and myeloid progenitor cells by binding to a transmembrane receptor tyrosine kinase encoded by the c-Kit proto-oncogene. By using MGF-dependent human myeloid cell lines (M-07e and TF-1), here we show that a Kit-related 100 kDa protein is associated with the cell but it undergoes release into the medium upon treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C. Immunological analysis with a series of antibodies to Kit indicated that the released protein (p100Kit) contains the whole glycosylated extracellular portion of the transmembrane Kit protein (p145Kit). The secreted protein retained the ability to specifically bind MGF. Moreover, p100Kit was able to block the mitogenic effect of MGF on cultured M-07e cells, suggesting that the soluble protein may function as a physiological antagonist of MGF.
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PMID:Protein kinase C-dependent release of a functional whole extracellular domain of the mast cell growth factor (MGF) receptor by MGF-dependent human myeloid cells. 751 83

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


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