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Gene Review

KITLG  -  KIT ligand

Homo sapiens

Synonyms: FPH2, KL-1, Kit ligand, Kitl, MGF, ...
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Disease relevance of KITLG

  • In skin samples containing lesions and in clinically normal skin from patients with mastocytosis, however, mast-cell growth factor was also found free in the dermis and in the extracellular spaces between keratinocytes, suggesting the presence of a soluble form of this protein [1].
  • The altered distribution of mast-cell growth factor in the skin of patients with cutaneous mastocytosis is consistent with abnormal production of the soluble form of this factor [1].
  • The demonstration that r-hSCF can promote both the hyperplasia and the functional activation of human mast cells and melanocytes in vivo has implications for our understanding of the role of endogenous SCF in health and disease [2].
  • Five subjects developed areas of persistent hyperpigmentation at r-hSCF injection sites; by light microscopy, these sites exhibited markedly increased epidermal melanization and increased numbers of melanocytes [2].
  • In this study we tested the mitogenic activity of recombinant human SCF on myeloid leukemia cells as well as the expression of its receptor [3].

Psychiatry related information on KITLG


High impact information on KITLG

  • After phosphorylation, the IKK phosphoacceptor sites on IkappaB serve as an essential part of a specific recognition site for E3RS(IkappaB/beta-TrCP), an SCF-type E3 ubiquitin ligase, thereby explaining how IKK controls IkappaB ubiquitination and degradation [6].
  • Finally, components of both the APC and the SCF E3 ubiquitin-ligase complex contain several conserved sequence motifs, including WD-40 repeats and cullin homology domains, which suggest that both complexes may use a similar mechanism for substrate ubiquitination [7].
  • Mechanism of lysine 48-linked ubiquitin-chain synthesis by the cullin-RING ubiquitin-ligase complex SCF-Cdc34 [8].
  • This finding has profound implications for understanding plant physiology and development and for defining new modes of regulation of SCF ubiquitin ligase complexes [9].
  • In this issue of Cell, Deffenbaugh et al. provide experimental support for a model in which the dynamic release of the ubiquitin-charged E2 Cdc34 from its primary binding site within the rigid cradle-like SCF E3 complex allows for unexpected spatial flexibility to assemble a polyubiquitin chain [10].

Chemical compound and disease context of KITLG


Biological context of KITLG

  • Stem cell factor (SCF), a key regulator of hematopoiesis, potently synergizes with a number of hematopoietic growth factors [16].
  • On the basis of these observations, a model for SCF small middle dotc-kit complex formation and dimerization is proposed [17].
  • In unilineage erythropoietic culture of CD34+ progenitors, short-term pretreatment of immature erythroid precursors with SCF results in protection from apoptosis induced by chemotherapeutic agents and restores normal proliferation and differentiation after removal of the cytotoxic stimulus [18].
  • Moreover, IL-9 acts synergistically with SCF for recruiting quiescent leukemic cells in cell cycle [19].
  • Among the 12 erythroid growth-promoting cytokines tested, stem cell factor (SCF) at a concentration of 50 ng/mL resulted in the most significant increase in cell proliferation and HbF content [20].

Anatomical context of KITLG


Associations of KITLG with chemical compounds

  • A 14-d course of r-hSCF significantly increased dermal mast cell density at sites distant to those injected with the cytokine and also increased both urinary levels of the major histamine metabolite, methyl-histamine, and serum levels of mast cell alpha-tryptase [2].
  • SCF mediates its biological effects by binding to and activating a receptor tyrosine kinase designated c-kit or SCF receptor [17].
  • In the presence of SCF, the number of ECFC was greatly expanded during this culture period, and total production of benzidine-positive cells plus hemoglobin synthesis were ultimately increased [23].
  • The ability of SCF to induce c-kit receptor dimerization was assessed by flow cytometric analysis of FRET between the donor fluorochrome FITC and the acceptor fluorochrome Cy3 [24].
  • This costimulatory effect of SCF was not mediated by increased STAT5 tyrosine or serine phosphorylation or increased STAT5 DNA binding [25].

Physical interactions of KITLG

  • CUL7: A DOC domain-containing cullin selectively binds Skp1.Fbx29 to form an SCF-like complex [26].
  • Simultaneous addition of SCF and Kit-X to these cells resulted in a stoichiometric inhibition of SCF binding and a consequent decrease in autophosphorylation of the SCF receptor on tyrosine residues [27].
  • SCF interacted with a number of hematopoietic growth factors to stimulate colony growth and was particularly effective in stimulating the formation of mixed-cell colonies from CD34+ soybean agglutinin negative (SBA-) cells [28].
  • It is expressed by the primitive CD34 positive haemopoietic stem cells and interacts with the Kit ligand for signal transduction [29].
  • Discrete protein interactions with the Grb2/c-Cbl complex in SCF- and TPO-mediated myeloid cell proliferation [30].

Enzymatic interactions of KITLG

  • In addition, Btk is phosphorylated by SCF, which causes association of Btk with TRAIL-receptor1 [31].
  • SCF alone tyrosine-phosphorylated several bands including the 145 kDa subunit of c-kit [32].

Co-localisations of KITLG


Regulatory relationships of KITLG


Other interactions of KITLG

  • This study was designed to examine interactions between TNF-alpha and SCF [16].
  • Recombinant human stem cell factor (SCF) is homologous with recombinant rat SCF (rrSCF) and is a ligand for c-kit [39].
  • The kit ligand (KL), also termed stem cell factor (SCF), is a recently discovered hematopoietic growth factor that augments response of early progenitor cells to other growth factors and supports proliferation of continuous mast cell lines [21].
  • Thus, highly homogenous populations of SCF/Epo-dependent erythroid progenitors can be obtained in large cell numbers that are most suitable for further biochemical and molecular studies [40].
  • FL and SCF were equally effective in stimulating colony formation in combination with IL-3 [41].

Analytical, diagnostic and therapeutic context of KITLG


  1. 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]
  2. Recombinant human stem cell factor (kit ligand) promotes human mast cell and melanocyte hyperplasia and functional activation in vivo. Costa, J.J., Demetri, G.D., Harrist, T.J., Dvorak, A.M., Hayes, D.F., Merica, E.A., Menchaca, D.M., Gringeri, A.J., Schwartz, L.B., Galli, S.J. J. Exp. Med. (1996) [Pubmed]
  3. 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]
  4. Atopic diseases and mediators. Ring, J. Int. Arch. Allergy Immunol. (1993) [Pubmed]
  5. Effects of activity on growth factor expression. Goldspink, G., Yang, S.Y. International journal of sport nutrition and exercise metabolism. (2001) [Pubmed]
  6. Phosphorylation meets ubiquitination: the control of NF-[kappa]B activity. Karin, M., Ben-Neriah, Y. Annu. Rev. Immunol. (2000) [Pubmed]
  7. The anaphase-promoting complex: new subunits and regulators. Page, A.M., Hieter, P. Annu. Rev. Biochem. (1999) [Pubmed]
  8. Mechanism of lysine 48-linked ubiquitin-chain synthesis by the cullin-RING ubiquitin-ligase complex SCF-Cdc34. Petroski, M.D., Deshaies, R.J. Cell (2005) [Pubmed]
  9. A new FronTIR in targeted protein degradation and plant development. Nemhauser, J.L., Chory, J. Cell (2005) [Pubmed]
  10. Dynamic release of Cdc34 from SCF. the hand that rocks the cradle. Wolf, D.A., Geyer, R. Cell (2003) [Pubmed]
  11. c-kit ligand stimulates tyrosine phosphorylation of a similar pattern of phosphotyrosyl proteins in primary primitive normal hematopoietic progenitors that are constitutively phosphorylated in comparable primitive progenitors in chronic phase chronic myelogenous leukemia. Wisniewski, D., Strife, A., Berman, E., Clarkson, B. Leukemia (1996) [Pubmed]
  12. Non-IgE-dependent activation of human lung- and cord blood-derived mast cells is induced by eosinophil major basic protein and modulated by the membrane form of stem cell factor. Piliponsky, A.M., Gleich, G.J., Nagler, A., Bar, I., Levi-Schaffer, F. Blood (2003) [Pubmed]
  13. The stem cell factor-c-kit system and mast cells in human pancreatic cancer. Esposito, I., Kleeff, J., Bischoff, S.C., Fischer, L., Collecchi, P., Iorio, M., Bevilacqua, G., Büchler, M.W., Friess, H. Lab. Invest. (2002) [Pubmed]
  14. 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]
  15. Imatinib mesylate causes hypopigmentation in the skin. Tsao, A.S., Kantarjian, H., Cortes, J., O'Brien, S., Talpaz, M. Cancer (2003) [Pubmed]
  16. 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]
  17. 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]
  18. Stem cell factor protects erythroid precursor cells from chemotherapeutic agents via up-regulation of BCL-2 family proteins. Zeuner, A., Pedini, F., Signore, M., Testa, U., Pelosi, E., Peschle, C., De Maria, R. Blood (2003) [Pubmed]
  19. Interleukin-9 stimulates the proliferation of human myeloid leukemic cells. Lemoli, R.M., Fortuna, A., Tafuri, A., Fogli, M., Amabile, M., Grande, A., Ricciardi, M.R., Petrucci, M.T., Bonsi, L., Bagnara, G., Visani, G., Martinelli, G., Ferrari, S., Tura, S. Blood (1996) [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. Effects of the stem cell factor, c-kit ligand, on human megakaryocytic cells. Avraham, H., Vannier, E., Cowley, S., Jiang, S.X., Chi, S., Dinarello, C.A., Zsebo, K.M., Groopman, J.E. Blood (1992) [Pubmed]
  22. 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]
  23. Stem cell factor retards differentiation of normal human erythroid progenitor cells while stimulating proliferation. Muta, K., Krantz, S.B., Bondurant, M.C., Dai, C.H. Blood (1995) [Pubmed]
  24. Analysis of c-kit receptor dimerization by fluorescence resonance energy transfer. Broudy, V.C., Lin, N.L., Bühring, H.J., Komatsu, N., Kavanagh, T.J. Blood (1998) [Pubmed]
  25. Stem cell factor enhances erythropoietin-mediated transactivation of signal transducer and activator of transcription 5 (STAT5) via the PKA/CREB pathway. Boer, A.K., Drayer, A.L., Vellenga, E. Exp. Hematol. (2003) [Pubmed]
  26. CUL7: A DOC domain-containing cullin selectively binds Skp1.Fbx29 to form an SCF-like complex. Dias, D.C., Dolios, G., Wang, R., Pan, Z.Q. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  27. 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]
  28. Long-term generation of colony-forming cells in liquid culture of CD34+ cord blood cells in the presence of recombinant human stem cell factor. Migliaccio, G., Migliaccio, A.R., Druzin, M.L., Giardina, P.J., Zsebo, K.M., Adamson, J.W. Blood (1992) [Pubmed]
  29. Low frequency of c-kit expression and detection of an aberrant Kit message among Hong Kong Chinese myelogenous leukaemia patients. Chui, C.H., Lau, F.Y., Yau, K.S., Lee, F.C., Chan, L.C., Cheng, G. Cancer Lett. (1997) [Pubmed]
  30. Discrete protein interactions with the Grb2/c-Cbl complex in SCF- and TPO-mediated myeloid cell proliferation. Brizzi, M.F., Dentelli, P., Lanfrancone, L., Rosso, A., Pelicci, P.G., Pegoraro, L. Oncogene (1996) [Pubmed]
  31. Control of erythropoiesis by erythropoietin and stem cell factor: a novel role for Bruton's tyrosine kinase. von Lindern, M., Schmidt, U., Beug, H. Cell Cycle (2004) [Pubmed]
  32. 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]
  33. Stem cell factor/c-Kit interactions regulate human islet-epithelial cluster proliferation and differentiation. Li, J., Goodyer, C.G., Fellows, F., Wang, R. Int. J. Biochem. Cell Biol. (2006) [Pubmed]
  34. Cell-to-cell interaction of cytokine-dependent myeloblastic line constitutively expressing membrane-bound stem cell factor abrogates cytokine dependency partially through granulocyte-macrophage colony-stimulating factor production. Sasaki, K., Ikeda, K., Ogami, K., Takahara, J., Irino, S. Blood (1995) [Pubmed]
  35. Increased recruitment of hematopoietic progenitor cells underlies the ex vivo expansion potential of FLT3 ligand. Haylock, D.N., Horsfall, M.J., Dowse, T.L., Ramshaw, H.S., Niutta, S., Protopsaltis, S., Peng, L., Burrell, C., Rappold, I., Buhring, H.J., Simmons, P.J. Blood (1997) [Pubmed]
  36. The c-kit ligand stem cell factor and anti-IgE promote expression of monocyte chemoattractant protein-1 in human lung mast cells. Baghestanian, M., Hofbauer, R., Kiener, H.P., Bankl, H.C., Wimazal, F., Willheim, M., Scheiner, O., Füreder, W., Müller, M.R., Bevec, D., Lechner, K., Valent, P. Blood (1997) [Pubmed]
  37. Induction of the erythropoietin receptor gene and acquisition of responsiveness to erythropoietin by stem cell factor in HML/SE, a human leukemic cell line. Sato, T., Watanabe, S., Ishii, E., Tsuji, K., Nakahata, T. J. Biol. Chem. (1998) [Pubmed]
  38. Stem cell factor (c-kit ligand) enhances the interleukin-9-dependent proliferation of human CD34+ and CD34+CD33-DR- cells. Lemoli, R.M., Fortuna, A., Fogli, M., Motta, M.R., Rizzi, S., Benini, C., Tura, S. Exp. Hematol. (1994) [Pubmed]
  39. Recombinant human stem cell factor, a c-kit ligand, stimulates hematopoiesis in primates. Andrews, R.G., Knitter, G.H., Bartelmez, S.H., Langley, K.E., Farrar, D., Hendren, R.W., Appelbaum, F.R., Bernstein, I.D., Zsebo, K.M. Blood (1991) [Pubmed]
  40. Growth and differentiation of human stem cell factor/erythropoietin-dependent erythroid progenitor cells in vitro. Panzenböck, B., Bartunek, P., Mapara, M.Y., Zenke, M. Blood (1998) [Pubmed]
  41. The FLT3 ligand is a direct and potent stimulator of the growth of primitive and committed human CD34+ bone marrow progenitor cells in vitro. Rusten, L.S., Lyman, S.D., Veiby, O.P., Jacobsen, S.E. Blood (1996) [Pubmed]
  42. Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells. Majumdar, M.K., Thiede, M.A., Mosca, J.D., Moorman, M., Gerson, S.L. J. Cell. Physiol. (1998) [Pubmed]
  43. Interaction between stem cell factor and endothelin-1: effects on melanogenesis in human skin xenografts. Sriwiriyanont, P., Ohuchi, A., Hachiya, A., Visscher, M.O., Boissy, R.E. Lab. Invest. (2006) [Pubmed]
  44. C-kit positive porcine bone marrow progenitor cells identified and enriched using recombinant stem cell factor. Summerfield, A., Horn, M.P., Lozano, G., Carrasco, C.P., Atze, K., McCullough, K. J. Immunol. Methods (2003) [Pubmed]
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