Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Hardy-Zuckerman 4 feline sarcoma virus (HZ4-FeSV), isolated from a feline fibrosarcoma, is a replication defective acute transforming feline retrovirus that originated by transduction of feline c-kit sequences with feline leukemia virus (FeLV). The v-kit sequences of the HZ4-FeSV, a segment of 1106 nucleotides, correspond to sequences of the cytoplasmic domain of the c-kit receptor kinase. The HZ4-FeSV is known to encode an 80-kilodalton protein with FeLV gag and kit determinants. The P80gag-kit protein and its associated activities from HZ4-FeSV-transformed mink cells were characterized. The P80gag-kit protein was found to be myristoylated, suggesting a membrane association for this protein. In agreement with the predicted relationship with tyrosine kinases, by using the in vitro immune complex-kinase procedure, the P80gag-kit protein was shown to display a tyrosine-specific autophosphorylation activity. In vivo, the P80 protein was found to be phosphorylated on serine and threonine and to a lesser degree on tyrosine. In addition, potential in vivo protein substrates for tyrosine-specific phosphorylation mediated by the P80gag-kit kinase were identified in HZ4-FeSV-transformed cells.
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PMID:Tyrosine protein kinase activity of the HZ4-feline sarcoma virus P80gag-kit-transforming protein. 169 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 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

Mice carrying mutations at the W locus located on chromosome 5 are characterized by severe macrocytic anaemia, lack of hair pigmentation and sterility. Mutations at this locus appear to affect the proliferation and/or migration of cells during early embryogenesis and result in an intrinsic defect in the haematopoietic stem cell hierarchy. An understanding of the molecular basis of the complex and pleiotropic phenotype in W mutant mice would thus provide insights into the important developmental processes of gametogenesis, melanogenesis and haematopoiesis. Here we show that the mouse mutant W has a deletion of the c-kit proto-oncogene. Interspecific backcross analysis demonstrates that the W locus is very tightly linked to c-kit and that the two loci cannot be segregated at this level of analysis. c-kit is the cellular homologue of the oncogene v-kit of the HZ4 feline sarcoma virus and encodes a transmembrane protein tyrosine kinase receptor that is structurally similar to the receptors for colony-stimulating factor-1 (CSF-1) and platelet derived growth factor. The co-localization of c-kit with W provides a molecular entry into this important region of the mouse genome. In addition, these observations provide the first example of a germ-line mutation in a mammalian proto-oncogene and implicate the c-kit gene as a candidate for the W locus.
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PMID:The proto-oncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus. 245 11

The proto-oncogene c-kit encodes a transmembrane kinase which is related to the receptors for colony-stimulating factor type 1 and platelet-derived growth factor, as well as to the immunoglobulin superfamily. Antibodies specific for the kinase domain of the P80 gag-kit protein of the Hardy-Zuckerman 4 feline sarcoma virus were prepared. These kit-specific antibodies were used to identify and characterize the c-kit protein in cat brain tissue. The c-kit protein product displays an autophosphorylating activity in immune complex kinase assays, and, in turn, this activity was used to identify the c-kit protein in different tissues. In cat brain, a single 145-kilodalton (kDa) glycoprotein was detected. Its N-linked carbohydrates were found to be sensitive to digestion with the endoglycosidases (neuraminidase, endoglycosidase F, and endoglycosidase H), indicating hybrid and/or complex and high-mannose structures. A partial purification of the c-kit protein was achieved by wheat germ agglutinin affinity chromatography, and the autophosphorylating activity of the partially purified c-kit protein was characterized and found to be specific for tyrosine. The kit antibodies cross-react with the murine c-kit protein product, and variant c-kit proteins in different mouse tissues were identified, with sizes of about 145 kDa (brain), 160 kDa (spleen), and 150 kDa (testis).
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PMID:c-kit protein, a transmembrane kinase: identification in tissues and characterization. 246 68

A new acute transforming feline retrovirus, the Hardy-Zuckerman 4 feline sarcoma virus (HZ4-FeSV), has been isolated from a feline fibrosarcoma. The viral genome of HZ4-FeSV contains a new oncogene designated v-kit, has the structure 5' delta gag-kit-delta pol-delta env 3' and specifies a gag-kit polyprotein of relative molecular mass 80,000. The predicted kit amino-acid sequence displays partial homology with tyrosine-specific protein kinase oncogenes. HZ4-FeSV appears to have been generated by transduction of feline c-kit sequences with feline leukaemia virus.
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PMID:A new acute transforming feline retrovirus and relationship of its oncogene v-kit with the protein kinase gene family. 300 97

The transforming gene of the Hardy-Zuckerman-4 strain of feline sarcoma virus, v-kit, arose by transduction of the cellular c-kit gene, which encodes the receptor tyrosine kinase (RTK) p145c-kit. To gain insight into the molecular basis of the v-kit transforming potential, we characterized the feline c-kit by cDNA cloning. Comparison of the feline v-kit and c-kit sequences revealed, in addition to deletions of the extracellular and transmembrane domains, three additional mutations in the v-kit oncogene product: deletion of tyrosine-569 and valine-570, the exchange of aspartate at position 761 to glycine, and replacement of the C-terminal 50 amino acids by five unrelated residues. Examinations of individual v-kit mutations in the context of chimeric receptors yielded inhibitory effects for some mutants on both autophosphorylation and substrate phosphorylation functions. In contrast, deletion of tyrosine-569 and valine-570 significantly enhanced transforming and mitogenic activities of p145c-kit, while the other mutations had no significant effects. Conservation in subclass III RTKs and the identification of the corresponding residue in beta PDGF-R, Y579, as a binding site for src family tyrosine kinases suggests an important role for Y568 in kit signal regulation and the definition of its oncogenic potential. Repositioning of Y571 by an inframe two codon deletion may be the crucial alteration resulting in enhancement of v-kit oncogenic activity.
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PMID:Oncogenic activation of v-kit involves deletion of a putative tyrosine-substrate interaction site. 753 Aug 27

A somatic mutation in the X-linked phosphatidylinositol glycan class A (PIGA) gene causes the loss of glycosyl phosphatidylinositol (GPI)-linked proteins on blood cells from patients with paroxysmal nocturnal hemoglobinuria. Because all blood cell lineages may be affected it is thought that the mutation occurs in a hematopoietic stem cell. In transgenic mice, germline transmission of an inactive Piga gene is embryonic lethal. To inactivate the murine Piga gene in early hematopoiesis we therefore chose conditional gene inactivation using the Cre/loxP system. We expressed Cre recombinase under the transcription regulatory sequences of the human c-fes gene. FES-Cre inactivated PIGA in hematopoietic cells of mice carrying a floxed Piga allele (LF mice). PIGA(-) cells were found in all hematopoietic lineages of definitive but not primitive hematopoiesis. Their proportions were low in newborn mice but subsequently increased continuously to produce for the first time mice that have almost exclusively PIGA(-) blood cells. The loss of GPI-linked proteins occurred mainly in c-kit(+)CD34(+)Lin(-) progenitor cells before the CFU-GEMM stage. Using bone marrow reconstitution experiments with purified PIGA(-) cells we demonstrate that LF mice have long-term bone marrow repopulating cells that lack GPI-linked proteins, indicating that recombination of the floxed Piga allele occurs in the hematopoietic stem cell.
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PMID:FES-Cre targets phosphatidylinositol glycan class A (PIGA) inactivation to hematopoietic stem cells in the bone marrow. 1153 27

Protein phosphorylation on serine/threonine or tyrosine residues represents a significant regulatory mechanism in signal transduction during spermatogenesis, oogenesis, and fertilization. There are several families of tyrosine protein kinases operating during spermatogenesis: the Src family of tyrosine protein kinases; the Fujinami poultry sarcoma/feline sarcoma (Fps/Fes) and Fes-related protein (Fer) subfamily of non-receptor proteins; and c-kit, the transmembrane tyrosine kinase receptor that belongs to the family of the PDGF receptor. A remarkable characteristic is the coexistence of full-length and truncated tyrosine kinases in testis. Most of the truncated forms are present during spermiogenesis. Examples include the truncated forms of Src tyrosine kinase hematopoietic cell kinase (Hck), FerT, and tr-kit. A feature of FerT and tr-kit is the kinase domain that ensures the functional properties of the truncated protein. FerT, a regulator of actin assembly/disassembly mediated by cortactin phosphorylation, is present in the acroplaxome, a cytoskeletal plate containing an F-actin network and linking the acrosome to the spermatid nuclear envelope. This finding suggests that Fer kinase represents one of the tyrosine protein kinases that may contribute to spermatid head shaping. The c-kit ligand, stem cell factor (SCF), which induces c-kit dimerization and autophosphorylation, exists as both membrane-associated and soluble. Although tyrosine protein kinases are prominent in spermatogenesis, a remarkable observation is the paucity of phenotypic alterations in spermatogenic cells in male mice targeted with Fer kinase-inactivating mutation. It is possible that the redundant functions of the tyrosine protein kinase pool present during spermatogenesis may explain the limited phenotypes of single mutant mice. The production of compound and viable mutant mice, lacking the expression of two or more tyrosine kinases, may shed light on this intriguing issue.
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PMID:Tyrosine protein kinases and spermatogenesis: truncation matters. 1643 22