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Flt3  -  FMS-like tyrosine kinase 3

Mus musculus

Synonyms: B230315G04, CD135, FL cytokine receptor, FLK-2, FLT-3, ...
 
 
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Disease relevance of Flt3

 

High impact information on Flt3

 

Chemical compound and disease context of Flt3

 

Biological context of Flt3

  • Microchimerism, donor dendritic cells, and alloimmune reactivity in recipients of Flt3 ligand-mobilized hemopoietic cells: modulation by tacrolimus [11].
  • Fiz1, a novel zinc finger protein interacting with the receptor tyrosine kinase Flt3 [12].
  • The Flt3 gene possesses an open reading frame of 3000 nucleotides, and therefore appears to code for a protein of 1000 amino acids [13].
  • A new human gene encoding a putative receptor-type tyrosine kinase (RTK) was isolated by screening a placenta cDNA library with a mouse Flt3 probe [14].
  • Internal tandem duplication of Flt3 modulates chemotaxis and survival of hematopoietic cells by SDF1alpha but negatively regulates marrow homing in vivo [15].
 

Anatomical context of Flt3

  • Stimulation of Flt3 receptor tyrosine kinase through its cognate ligand expands early hematopoietic progenitor and dendritic cells (DCs) in humans and mice [16].
  • Here we show that common lymphoid and common myeloid progenitors, as well as steady state DCs in thymus, spleen, and epidermis, express Flt3 [16].
  • In the present study, we show that SU11657, a small multitargeted receptor tyrosine kinase inhibitor with Flt3 affinity, suppressed in vitro natural IFN-producing and DC development in Flt3L-supplemented mouse whole bone marrow cell cultures in a dose-dependant manner, while DC development in GM-CSF-supplemented cultures was not affected [17].
  • The receptor tyrosine kinase Flt3 has been shown to play a role in proliferation and survival of hematopoietic progenitor cells as well as differentiation of early B lymphoid progenitors [12].
  • The Flt3 transcript is 3.7 kb long, except in the testis, where two shorter post-meiotic transcripts are detected [13].
 

Associations of Flt3 with chemical compounds

  • Marrow sensitization to 5-fluorouracil using the ligands for Flt-3 and c-Kit [18].
  • An optimized analogue in this series, 75 (CT53518), inhibits Flt-3, betaPDGFR, and c-Kit receptor phosphorylation with IC(50) values of 50-200 nM, whereas 15-20-fold less potent activity against CSF-1R was observed [19].
 

Regulatory relationships of Flt3

  • Flt3 ligand regulates dendritic cell development from Flt3+ lymphoid and myeloid-committed progenitors to Flt3+ dendritic cells in vivo [16].
  • Flt3 isoforms containing ITD mutations (Flt3-ITD) induced factor-independent growth and resistance to radiation-induced apoptosis in 32D cells [20].
  • Progenipoietin (ProGP-4) is a chimeric molecule, exhibiting both Flt-3 and granulocyte-colony stimulating factor (G-CSF) receptor agonist activities [21].
  • In contrast, VEGF inhibited colony formation by more immature subsets of granulocyte-macrophage, erythroid and multipotential progenitor cells synergistically stimulated to proliferate with a colony stimulating factor and either steel factor or the ligand for the Flt-3 receptor tyrosine kinase [22].
 

Other interactions of Flt3

  • This led to the discovery that sTPOR synergizes with SF or Flt3/Flk2 ligand (FL) to support the formation of various types of hematopoietic colonies including multilineage colonies [23].
  • Flt3 ligand elicits a variety of effects on early hemopoietic progenitors by occupying its cognate receptor, Flt3, a member of the type III tyrosine kinase receptor family [24].
  • Two of seven clones had the capacity for M-CSF-dependent colony formation in semisolid medium, indicating that the cytoplasmic domain of Flt3 can transduce a proliferative signal [25].
  • 32D cells, expressing a constitutively active Flt3 variant with internal tandem duplication are greatly sensitized to radiation-induced apoptosis in the presence of D-64406 or D-65476 in the absence but not in the presence of IL-3 [1].
  • Herein, we evaluated whether a functional interaction between SDF1alpha/CXCR4 signaling and internal tandem duplication (ITD) of Flt3 regulates aberrant hematopoietic survival [15].
 

Analytical, diagnostic and therapeutic context of Flt3

References

  1. Bis(1H-2-indolyl)-1-methanones as inhibitors of the hematopoietic tyrosine kinase Flt3. Teller, S., Krämer, D., Böhmer, S.A., Tse, K.F., Small, D., Mahboobi, S., Wallrapp, C., Beckers, T., Kratz-Albers, K., Schwäble, J., Serve, H., Böhmer, F.D. Leukemia (2002) [Pubmed]
  2. Perioperative immunomodulation with Flt3 kinase ligand or a whole tumor cell vaccine is associated with a reduction in lung metastasis formation after laparotomy in mice. Carter, J.J., Feingold, D.L., Oh, A., Kirman, I., Wildbrett, P., Stapleton, G., Asi, Z., Fowler, R., Bhagat, G., Huang, E.H., Fine, R.L., Whelan, R.L. Surgical innovation. (2006) [Pubmed]
  3. Combinational FLt3 ligand and granulocyte macrophage colony-stimulating factor treatment promotes enhanced tumor infiltration by dendritic cells and antitumor CD8(+) T-cell cross-priming but is ineffective as a therapy. Berhanu, A., Huang, J., Alber, S.M., Watkins, S.C., Storkus, W.J. Cancer Res. (2006) [Pubmed]
  4. Rapamycin inhibits IL-4--induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo. Hackstein, H., Taner, T., Zahorchak, A.F., Morelli, A.E., Logar, A.J., Gessner, A., Thomson, A.W. Blood (2003) [Pubmed]
  5. Flt3 in acute myelogenous leukemia: biology, prognosis, and therapeutic implications. Voutsadakis, I.A. Med. Oncol. (2003) [Pubmed]
  6. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Matthews, W., Jordan, C.T., Wiegand, G.W., Pardoll, D., Lemischka, I.R. Cell (1991) [Pubmed]
  7. Upregulation of Flt3 expression within the bone marrow Lin(-)Sca1(+)c-kit(+) stem cell compartment is accompanied by loss of self-renewal capacity. Adolfsson, J., Borge, O.J., Bryder, D., Theilgaard-Mönch, K., Astrand-Grundström, I., Sitnicka, E., Sasaki, Y., Jacobsen, S.E. Immunity (2001) [Pubmed]
  8. Early hematopoietic lineage restrictions directed by Ikaros. Yoshida, T., Yao-Ming Ng, S., Zuniga-Pflucker, J.C., Georgopoulos, K. Nat. Immunol. (2006) [Pubmed]
  9. Thymic stromal-derived lymphopoietin distinguishes fetal from adult B cell development. Vosshenrich, C.A., Cumano, A., Müller, W., Di Santo, J.P., Vieira, P. Nat. Immunol. (2003) [Pubmed]
  10. Effects of MLN518, a dual FLT3 and KIT inhibitor, on normal and malignant hematopoiesis. Griswold, I.J., Shen, L.J., La Rosée, P., Demehri, S., Heinrich, M.C., Braziel, R.M., McGreevey, L., Haley, A.D., Giese, N., Druker, B.J., Deininger, M.W. Blood (2004) [Pubmed]
  11. Microchimerism, donor dendritic cells, and alloimmune reactivity in recipients of Flt3 ligand-mobilized hemopoietic cells: modulation by tacrolimus. Morelli, A.E., Antonysamy, M.A., Takayama, T., Hackstein, H., Chen, Z., Qian, S., Zurowski, N.B., Thomson, A.W. J. Immunol. (2000) [Pubmed]
  12. Fiz1, a novel zinc finger protein interacting with the receptor tyrosine kinase Flt3. Wolf, I., Rohrschneider, L.R. J. Biol. Chem. (1999) [Pubmed]
  13. Murine Flt3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family. Rosnet, O., Marchetto, S., deLapeyriere, O., Birnbaum, D. Oncogene (1991) [Pubmed]
  14. Chromosomal localization of FLT4, a novel receptor-type tyrosine kinase gene. Galland, F., Karamysheva, A., Mattei, M.G., Rosnet, O., Marchetto, S., Birnbaum, D. Genomics (1992) [Pubmed]
  15. Internal tandem duplication of Flt3 modulates chemotaxis and survival of hematopoietic cells by SDF1alpha but negatively regulates marrow homing in vivo. Fukuda, S., Pelus, L.M. Exp. Hematol. (2006) [Pubmed]
  16. Flt3 ligand regulates dendritic cell development from Flt3+ lymphoid and myeloid-committed progenitors to Flt3+ dendritic cells in vivo. Karsunky, H., Merad, M., Cozzio, A., Weissman, I.L., Manz, M.G. J. Exp. Med. (2003) [Pubmed]
  17. Inhibition of natural type I IFN-producing and dendritic cell development by a small molecule receptor tyrosine kinase inhibitor with Flt3 affinity. Tussiwand, R., Onai, N., Mazzucchelli, L., Manz, M.G. J. Immunol. (2005) [Pubmed]
  18. Marrow sensitization to 5-fluorouracil using the ligands for Flt-3 and c-Kit. Jin, L., Neff, T., Blau, C.A. Exp. Hematol. (1999) [Pubmed]
  19. Identification of orally active, potent, and selective 4-piperazinylquinazolines as antagonists of the platelet-derived growth factor receptor tyrosine kinase family. Pandey, A., Volkots, D.L., Seroogy, J.M., Rose, J.W., Yu, J.C., Lambing, J.L., Hutchaleelaha, A., Hollenbach, S.J., Abe, K., Giese, N.A., Scarborough, R.M. J. Med. Chem. (2002) [Pubmed]
  20. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Mizuki, M., Fenski, R., Halfter, H., Matsumura, I., Schmidt, R., Müller, C., Grüning, W., Kratz-Albers, K., Serve, S., Steur, C., Büchner, T., Kienast, J., Kanakura, Y., Berdel, W.E., Serve, H. Blood (2000) [Pubmed]
  21. Progenipoietin-generated dendritic cells exhibit anti-tumor efficacy in a therapeutic murine tumor model. Björck, P., Lie, W.R., Woulfe, S.L., Klein, B.K., Olson, W., Storkus, W.J. Int. J. Cancer (2002) [Pubmed]
  22. Myeloid progenitor cell regulatory effects of vascular endothelial cell growth factor. Broxmeyer, H.E., Cooper, S., Li, Z.H., Lu, L., Song, H.Y., Kwon, B.S., Warren, R.E., Donner, D.B. Int. J. Hematol. (1995) [Pubmed]
  23. Soluble thrombopoietin receptor (Mpl) and granulocyte colony-stimulating factor receptor directly stimulate proliferation of primitive hematopoietic progenitors of mice in synergy with steel factor or the ligand for Flt3/Flk2. Ku, H., Hirayama, F., Kato, T., Miyazaki, H., Aritomi, M., Ota, Y., D'Andrea, A.D., Lyman, S.D., Ogawa, M. Blood (1996) [Pubmed]
  24. Flt3 ligand can promote survival and macrophage development without proliferation in myeloid progenitor cells. Nicholls, S.E., Winter, S., Mottram, R., Miyan, J.A., Whetton, A.D. Exp. Hematol. (1999) [Pubmed]
  25. Fms-like tyrosine kinase 3 catalytic domain can transduce a proliferative signal in FDC-P1 cells that is qualitatively similar to the signal delivered by c-Fms. Rossner, M.T., McArthur, G.A., Allen, J.D., Metcalf, D. Cell Growth Differ. (1994) [Pubmed]
  26. Expression of Flt3 tyrosine kinase receptor gene in mouse hematopoietic and nervous tissues. deLapeyrière, O., Naquet, P., Planche, J., Marchetto, S., Rottapel, R., Gambarelli, D., Rosnet, O., Birnbaum, D. Differentiation (1995) [Pubmed]
  27. Identification of Flt3 internal tandem duplications downstream targets by high-throughput immunoblotting protein array system. Takahashi, S. Am. J. Hematol. (2006) [Pubmed]
  28. Normal donor bone marrow is superior to Flt3 ligand-mobilized bone marrow in prolonging heart allograft survival when combined with anti-CD40L (CD154). Hackstein, H., Wang, Z., Morelli, A.E., Kaneko, K., Takayama, T., Colvin, B.L., Bein, G., Thomson, A.W. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. (2002) [Pubmed]
  29. Emerging Flt3 kinase inhibitors in the treatment of leukaemia. Tickenbrock, L., Müller-Tidow, C., Berdel, W.E., Serve, H. Expert opinion on emerging drugs. (2006) [Pubmed]
 
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