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Gene Review

KIT  -  v-kit Hardy-Zuckerman 4 feline sarcoma...

Homo sapiens

Synonyms: C-Kit, CD117, Mast/stem cell growth factor receptor Kit, PBT, Piebald trait protein, ...
 
 
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Disease relevance of KIT

 

Psychiatry related information on KIT

  • Recently we reported the different frequencies of p53 and c-kit gene mutations among sinonasal NK/T cell lymphoma (NKTCL) in Korea, north China (Beijing), and Japan, suggesting some racial, environmental, or life-style differences as a possible cause of nasal tumorigenesis [6].
  • Six hundred adolescents and their therapists completed the Perceived Barriers to Treatment scale (PBT) at discharge from a brief substance abuse intervention [7].
 

High impact information on KIT

  • Primitive cells bearing Y chromosomes that expressed c-kit, MDR1, and Sca-1 were also investigated [8].
  • Three mutations in the MET gene are located in codons that are homologous to those in c-kit and RET, proto-oncogenes that are targets of naturally-occurring mutations [9].
  • However, by using a dimerization-inhibitory monoclonal antibody to the SCF receptor, we confined a putative dimerization site to the nonstandard fourth immunoglobulin-like domain of the receptor [10].
  • Mast-cell growth factor, the ligand for the product of the c-kit proto-oncogene, stimulates the proliferation of mast cells and increases the production of melanin by melanocytes [11].
  • We have previously reported the identification of a novel mast cell growth factor (MGF) that was shown to be a ligand for c-kit and is encoded by a gene that maps near the steel locus on mouse chromosome 10 [12].
 

Chemical compound and disease context of KIT

 

Biological context of KIT

  • Stable transfection of the mutant c-kit complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells, suggesting that the mutations contribute to tumor development [1].
  • The c-kit proto-oncogene encodes a receptor tyrosine kinase [17].
  • Sequencing of whole coding region of c-kit cDNA revealed that c-kit genes of HMC-1 cells were composed of a normal, wild-type allele and a mutant allele with two point mutations resulting in intracellular amino acid substitutions of Gly-560 for Val and Val-816 for Asp [17].
  • Amino acid sequences in the regions of the two mutations are completely conserved in all of mouse, rat, and human c-kit [17].
  • The nucleotide sequence of the c-kit cDNA predicts a 975 amino acid protein product with a calculated mol. wt of 109.001 kd [18].
 

Anatomical context of KIT

  • Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product [17].
  • In order to determine the causal role of these mutations in the constitutive activation, murine c-kit mutants encoding Gly-559 and/or Val-814, corresponding to human Gly-560 and/or Val-816, were constructed by site-directed mutagenesis and expressed in a human embryonic kidney cell line, 293T cells [17].
  • Finally, TNF-alpha downregulated c-kit cell-surface expression on CD34+ bone marrow cells, and this was predominantly a p55 TNF receptor-mediated event as well [19].
  • Fetal hemoglobin modulation during human erythropoiesis: stem cell factor has "late" effects related to the expression pattern of CD117 [20].
  • The stem cell factor (SCF) receptor, c-kit, is structurally related to these receptors and, although not expressed on mature peripheral blood cells, is expressed in leukemic blasts derived from 60% to 80% of acute myeloid leukemia (AML) patients [13].
 

Associations of KIT with chemical compounds

  • Sequencing of c-kit complementary DNA, which encodes a proto-oncogenic receptor tyrosine kinase (KIT), from five GISTs revealed mutations in the region between the transmembrane and tyrosine kinase domains [1].
  • In contrast, imatinib is ineffective, in vitro and in vivo, against the mastocytosis-associated c-kit D816V mutation [21].
  • While all 3 patients with the FIP1L1-PDGFRA rearrangement achieved a sustained complete response with imatinib mesylate therapy, the other two, both carrying the c-kit Asp816 to Val (Asp816Val) mutation, did not [22].
  • These studies indicate that SU5416 and SU6668 inhibit biologic functions of c-kit in addition to exhibiting antiangiogenic properties and suggest that the combination of these activities may provide a novel therapeutic approach for the treatment of AML [13].
  • In patient blasts, both SU5416 and SU6668 inhibited SCF-induced phosphorylation of c-kit and ERK1/2 and induced apoptosis [13].
 

Physical interactions of KIT

 

Enzymatic interactions of KIT

  • SCF alone tyrosine-phosphorylated several bands including the 145 kDa subunit of c-kit [26].
 

Co-localisations of KIT

 

Regulatory relationships of KIT

 

Other interactions of KIT

  • The molecular weight of the c-kit receptor was determined by affinity cross-linking 125I-SCF to MB-02 cells [3].
  • Forty-six percent of patients had activating mutations of FLT3 (24.5%), c-kit (3%), or ras (21%) genes [33].
  • Because of the prominent role of CSF in the maintenance of normal erythropoiesis in vivo, we examined the effects of SCF on the Epo-inducible human erythroleukemia cell line MB-02, and characterized the c-kit receptor in these cells [3].
  • AML blasts may express VEGFR-2, c-kit, and FLT3 [34].
  • These promising results demonstrate that inhibition of the c-kit and/or PDGF receptors may represent an effective strategy for treating KS [4].
 

Analytical, diagnostic and therapeutic context of KIT

References

  1. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Hirota, S., Isozaki, K., Moriyama, Y., Hashimoto, K., Nishida, T., Ishiguro, S., Kawano, K., Hanada, M., Kurata, A., Takeda, M., Muhammad Tunio, G., Matsuzawa, Y., Kanakura, Y., Shinomura, Y., Kitamura, Y. Science (1998) [Pubmed]
  2. Effects of human stem cell factor (c-kit ligand) on proliferation of myeloid leukemia cells: heterogeneity in response and synergy with other hematopoietic growth factors. Pietsch, T., Kyas, U., Steffens, U., Yakisan, E., Hadam, M.R., Ludwig, W.D., Zsebo, K., Welte, K. Blood (1992) [Pubmed]
  3. Stem cell factor influences the proliferation and erythroid differentiation of the MB-02 human erythroleukemia cell line by binding to a high-affinity c-kit receptor. Broudy, V.C., Morgan, D.A., Lin, N., Zsebo, K.M., Jacobsen, F.W., Papayannopoulou, T. Blood (1993) [Pubmed]
  4. Imatinib-induced regression of AIDS-related Kaposi's sarcoma. Koon, H.B., Bubley, G.J., Pantanowitz, L., Masiello, D., Smith, B., Crosby, K., Proper, J., Weeden, W., Miller, T.E., Chatis, P., Egorin, M.J., Tahan, S.R., Dezube, B.J. J. Clin. Oncol. (2005) [Pubmed]
  5. Differential sensitivity to imatinib of 2 patients with metastatic sarcoma arising from dermatofibrosarcoma protuberans. Maki, R.G., Awan, R.A., Dixon, R.H., Jhanwar, S., Antonescu, C.R. Int. J. Cancer (2002) [Pubmed]
  6. Analysis of p53, K-ras, c-kit, and beta-catenin gene mutations in sinonasal NK/T cell lymphoma in northeast district of China. Hoshida, Y., Hongyo, T., Jia, X., He, Y., Hasui, K., Dong, Z., Luo, W.J., Ham, M.F., Nomura, T., Aozasa, K. Cancer Sci. (2003) [Pubmed]
  7. Adolescent and therapist perception of barriers to outpatient substance abuse treatment. Mensinger, J.L., Diamond, G.S., Kaminer, Y., Wintersteen, M.B. The American journal on addictions / American Academy of Psychiatrists in Alcoholism and Addictions (2006) [Pubmed]
  8. Chimerism of the transplanted heart. Quaini, F., Urbanek, K., Beltrami, A.P., Finato, N., Beltrami, C.A., Nadal-Ginard, B., Kajstura, J., Leri, A., Anversa, P. N. Engl. J. Med. (2002) [Pubmed]
  9. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Schmidt, L., Duh, F.M., Chen, F., Kishida, T., Glenn, G., Choyke, P., Scherer, S.W., Zhuang, Z., Lubensky, I., Dean, M., Allikmets, R., Chidambaram, A., Bergerheim, U.R., Feltis, J.T., Casadevall, C., Zamarron, A., Bernues, M., Richard, S., Lips, C.J., Walther, M.M., Tsui, L.C., Geil, L., Orcutt, M.L., Stackhouse, T., Lipan, J., Slife, L., Brauch, H., Decker, J., Niehans, G., Hughson, M.D., Moch, H., Storkel, S., Lerman, M.I., Linehan, W.M., Zbar, B. Nat. Genet. (1997) [Pubmed]
  10. The fourth immunoglobulin domain of the stem cell factor receptor couples ligand binding to signal transduction. Blechman, J.M., Lev, S., Barg, J., Eisenstein, M., Vaks, B., Vogel, Z., Givol, D., Yarden, Y. Cell (1995) [Pubmed]
  11. Altered metabolism of mast-cell growth factor (c-kit ligand) in cutaneous mastocytosis. Longley, B.J., Morganroth, G.S., Tyrrell, L., Ding, T.G., Anderson, D.M., Williams, D.E., Halaban, R. N. Engl. J. Med. (1993) [Pubmed]
  12. Molecular cloning of mast cell growth factor, a hematopoietin that is active in both membrane bound and soluble forms. Anderson, D.M., Lyman, S.D., Baird, A., Wignall, J.M., Eisenman, J., Rauch, C., March, C.J., Boswell, H.S., Gimpel, S.D., Cosman, D. Cell (1990) [Pubmed]
  13. The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts. Smolich, B.D., Yuen, H.A., West, K.A., Giles, F.J., Albitar, M., Cherrington, J.M. Blood (2001) [Pubmed]
  14. An activating mutation in the transmembrane domain of the granulocyte colony-stimulating factor receptor in patients with acute myeloid leukemia. Forbes, L.V., Gale, R.E., Pizzey, A., Pouwels, K., Nathwani, A., Linch, D.C. Oncogene (2002) [Pubmed]
  15. C-kit expression in pediatric solid tumors: a comparative immunohistochemical study. Smithey, B.E., Pappo, A.S., Hill, D.A. Am. J. Surg. Pathol. (2002) [Pubmed]
  16. c-kit protein (stem cell factor receptor) expression on cells with erythroid characteristics and on normal human bone marrow without the use of monoclonal antibodies. McGuckin, C.P., Uhr, M.R., Gordon-Smith, E.C. Exp. Hematol. (1995) [Pubmed]
  17. Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product. Furitsu, T., Tsujimura, T., Tono, T., Ikeda, H., Kitayama, H., Koshimizu, U., Sugahara, H., Butterfield, J.H., Ashman, L.K., Kanayama, Y. J. Clin. Invest. (1993) [Pubmed]
  18. 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. Qiu, F.H., Ray, P., Brown, K., Barker, P.E., Jhanwar, S., Ruddle, F.H., Besmer, P. EMBO J. (1988) [Pubmed]
  19. Tumor necrosis factor-alpha inhibits stem cell factor-induced proliferation of human bone marrow progenitor cells in vitro. Role of p55 and p75 tumor necrosis factor receptors. Rusten, L.S., Smeland, E.B., Jacobsen, F.W., Lien, E., Lesslauer, W., Loetscher, H., Dubois, C.M., Jacobsen, S.E. J. Clin. Invest. (1994) [Pubmed]
  20. Fetal hemoglobin modulation during human erythropoiesis: stem cell factor has "late" effects related to the expression pattern of CD117. Wojda, U., Leigh, K.R., Njoroge, J.M., Jackson, K.A., Natarajan, B., Stitely, M., Miller, J.L. Blood (2003) [Pubmed]
  21. Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders. Pardanani, A., Tefferi, A. Blood (2004) [Pubmed]
  22. CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy. Pardanani, A., Ketterling, R.P., Brockman, S.R., Flynn, H.C., Paternoster, S.F., Shearer, B.M., Reeder, T.L., Li, C.Y., Cross, N.C., Cools, J., Gilliland, D.G., Dewald, G.W., Tefferi, A. Blood (2003) [Pubmed]
  23. A recombinant ectodomain of the receptor for the stem cell factor (SCF) retains ligand-induced receptor dimerization and antagonizes SCF-stimulated cellular responses. Lev, S., Yarden, Y., Givol, D. J. Biol. Chem. (1992) [Pubmed]
  24. Steel factor induces tyrosine phosphorylation of CRKL and binding of CRKL to a complex containing c-kit, phosphatidylinositol 3-kinase, and p120(CBL). Sattler, M., Salgia, R., Shrikhande, G., Verma, S., Pisick, E., Prasad, K.V., Griffin, J.D. J. Biol. Chem. (1997) [Pubmed]
  25. Transforming growth factor beta 1 inhibits expression of the gene products for steel factor and its receptor (c-kit). Heinrich, M.C., Dooley, D.C., Keeble, W.W. Blood (1995) [Pubmed]
  26. Analysis of synergism between stem cell factor and granulocyte-macrophage colony-stimulating factor on human megakaryoblastic cells: an increase in tyrosine phosphorylation of 145 kDa subunit of c-kit in two-factor combination. Kamijo, T., Koike, K., Takeuchi, K., Higuchi, T., Sawai, N., Kikuchi, T., Tsumura, H., Akiyama, H., Koike, T., Ishii, E., Komiyama, A. Leuk. Res. (1997) [Pubmed]
  27. Distribution of Ca2+-activated K channels, SK2 and SK3, in the normal and Hirschsprung's disease bowel. Piotrowska, A.P., Solari, V., Puri, P. J. Pediatr. Surg. (2003) [Pubmed]
  28. Crystal structure of human stem cell factor: implication for stem cell factor receptor dimerization and activation. Zhang, Z., Zhang, R., Joachimiak, A., Schlessinger, J., Kong, X.P. Proc. Natl. Acad. Sci. U.S.A. (2000) [Pubmed]
  29. Characterization of hemopoietic cell populations from human cord blood expressing c-kit. Reisbach, G., Bartke, I., Kempkes, B., Kostka, G., Ellwart, J., Birner, A., Thalmeier, K., Mailhammer, R., Bornkamm, G.W., Ullrich, A. Exp. Hematol. (1993) [Pubmed]
  30. Hematopoietic tissues, as a playground of receptor tyrosine kinases of the PDGF-receptor family. Yoshida, H., Takakura, N., Hirashima, M., Kataoka, H., Tsuchida, K., Nishikawa, S., Nishikawa, S. Dev. Comp. Immunol. (1998) [Pubmed]
  31. Granulocyte-macrophage colony-stimulating factor (GM-CSF) reduces the density of stem cell factor receptors (c-kit oncogene product) on a GM-CSF-dependent human myeloid cell line. Oez, S., Hofmann-Wackersreuther, G., Birkmann, J., Smetak, M., Welte, K., Gallmeier, W.M. Eur. Cytokine Netw. (1993) [Pubmed]
  32. Human FLT3 ligand acts on myeloid as well as multipotential progenitors derived from purified CD34+ blood progenitors expressing different levels of c-kit protein. Sonoda, Y., Kimura, T., Sakabe, H., Tanimukai, S., Ohmizono, Y., Nakagawa, S., Yokota, S., Lyman, S.D., Abe, T. Eur. J. Haematol. (1997) [Pubmed]
  33. Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia. Meshinchi, S., Stirewalt, D.L., Alonzo, T.A., Zhang, Q., Sweetser, D.A., Woods, W.G., Bernstein, I.D., Arceci, R.J., Radich, J.P. Blood (2003) [Pubmed]
  34. SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. Giles, F.J., Stopeck, A.T., Silverman, L.R., Lancet, J.E., Cooper, M.A., Hannah, A.L., Cherrington, J.M., O'Farrell, A.M., Yuen, H.A., Louie, S.G., Hong, W., Cortes, J.E., Verstovsek, S., Albitar, M., O'Brien, S.M., Kantarjian, H.M., Karp, J.E. Blood (2003) [Pubmed]
  35. Gastrointestinal stromal tumours (GISTs) negative for KIT (CD117 antigen) immunoreactivity. Debiec-Rychter, M., Wasag, B., Stul, M., De Wever, I., Van Oosterom, A., Hagemeijer, A., Sciot, R. J. Pathol. (2004) [Pubmed]
  36. Mechanisms underlying the dysfunction of melanocytes in vitiligo epidermis: role of SCF/KIT protein interactions and the downstream effector, MITF-M. Kitamura, R., Tsukamoto, K., Harada, K., Shimizu, A., Shimada, S., Kobayashi, T., Imokawa, G. J. Pathol. (2004) [Pubmed]
  37. Mast cell growth factor (c-kit ligand) restores growth of multipotent progenitors in myelodysplastic syndrome. Glinsmann-Gibson, B., Spier, C., Baier, M., Taetle, R., Broudy, V.C., List, A.F. Leukemia (1994) [Pubmed]
  38. Expression and mutational analysis of tyrosine kinase receptors c-kit, PDGFRalpha, and PDGFRbeta in ovarian cancers. Wilczynski, S.P., Chen, Y.Y., Chen, W., Howell, S.B., Shively, J.E., Alberts, D.S. Hum. Pathol. (2005) [Pubmed]
 
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