Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

FMS-Like Tyrosine Kinase-3

  • Julhash U. KaziEmail author
  • Sausan A. Moharram
  • Lars Rönnstrand
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101667


 CD135;  FLK2;  FLK-2;  STK1

Historical Background

Receptor tyrosine kinases are cell surface receptors that transduce signals mainly from extracellular stimuli leading to activation of numerous intracellular signaling cascades. The human genome encodes 58 receptor tyrosine kinases which can be subdivided into 20 different families (Lemmon and Schlessinger 2010). Within the 20 different families, the type III receptor tyrosine kinase family, also known as PDGFR family, consists of five receptor tyrosine kinases including PDGFRA, PDGFRB, KIT, CSF1R, and FLT3. The Fms-like tyrosine kinase 3 (FLT3) is a receptor for the dimeric FLT3 ligand (FL). The receptor was first described by two different groups in human and mouse (Matthews et al. 1991; Rosnet and Marchetto. 1991; Rosnet et al. 1991). In human, it was mapped to chromosome 13q12 and in mouse it was mapped to chromosome 5.

FLT3 Gene and Protein

The human FLT3 open reading frame (coding sequence) contains 2979 nucleotides and...
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  1. Beslu N, LaRose J, Casteran N, Birnbaum D, Lecocq E, Dubreuil P, et al. Phosphatidylinositol-3′ kinase is not required for mitogenesis or internalization of the Flt3/Flk2 receptor tyrosine kinase. J Biol Chem. 1996;271:20075–81.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Birg F, Courcoul M, Rosnet O, Bardin F, Pebusque MJ, Marchetto S, et al. Expression of the FMS/KIT-like gene FLT3 in human acute leukemias of the myeloid and lymphoid lineages. Blood. 1992;80:2584–93.PubMedPubMedCentralGoogle Scholar
  3. Carow CE, Levenstein M, Kaufmann SH, Chen J, Amin S, Rockwell P, et al. Expression of the hematopoietic growth factor receptor FLT3 (STK-1/Flk2) in human leukemias. Blood. 1996;87:1089–96.PubMedPubMedCentralGoogle Scholar
  4. Heiss E, Masson K, Sundberg C, Pedersen M, Sun J, Bengtsson S, et al. Identification of Y589 and Y599 in the juxtamembrane domain of Flt3 as ligand-induced autophosphorylation sites involved in binding of Src family kinases and the protein tyrosine phosphatase SHP2. Blood. 2006;108:1542–50.  https://doi.org/10.1182/blood-2005-07-008896.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Kazi JU, Rönnstrand L. FLT3 signals via the adapter protein Grb10 and overexpression of Grb10 leads to aberrant cell proliferation in acute myeloid leukemia. Mol Oncol. 2013a;7:402–18.  https://doi.org/10.1016/j.molonc.2012.11.003.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Kazi JU, Rönnstrand L. Suppressor of cytokine signaling 2 (SOCS2) associates with FLT3 and negatively regulates downstream signaling. Mol Oncol. 2013b;7:693–703.  https://doi.org/10.1016/j.molonc.2013.02.020.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Kazi JU, Sun J, Phung B, Zadjali F, Flores-Morales A, Rönnstrand L. Suppressor of cytokine signaling 6 (SOCS6) negatively regulates Flt3 signal transduction through direct binding to phosphorylated tyrosines 591 and 919 of Flt3. J Biol Chem. 2012;287:36509–17.  https://doi.org/10.1074/jbc.M112.376111.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141:1117–34.  https://doi.org/10.1016/j.cell.2010.06.011.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Mackarehtschian K, Hardin JD, Moore KA, Boast S, Goff SP, Lemischka IR. Targeted disruption of the flk2/flt3 gene leads to deficiencies in primitive hematopoietic progenitors. Immunity. 1995;3:147–61.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Masson K, Liu T, Khan R, Sun J, Rönnstrand L. A role of Gab2 association in Flt3 ITD mediated Stat5 phosphorylation and cell survival. Br J Haematol. 2009;146:193–202.  https://doi.org/10.1111/j.1365-2141.2009.07725.x.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Matthews W, Jordan CT, Wiegand GW, Pardoll D, Lemischka IR. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell. 1991;65:1143–52.  https://doi.org/10.1016/0092–8674(91)90010-V.CrossRefPubMedPubMedCentralGoogle Scholar
  12. McClanahan T, Culpepper J, Campbell D, Wagner J, Franz-Bacon K, Mattson J, et al. Biochemical and genetic characterization of multiple splice variants of the Flt3 ligand. Blood. 1996;88:3371–82.PubMedPubMedCentralGoogle Scholar
  13. Moharram SA, Chougule RA, Su X, Li T, Sun J, Zhao H, et al. Src-like adaptor protein 2 (SLAP2) binds to and inhibits FLT3 signaling. Oncotarget. 2016;  https://doi.org/10.18632/oncotarget.10760.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Oshikawa G, Nagao T, Wu N, Kurosu T, Miura O. c-Cbl and Cbl-b ligases mediate 17-allylaminodemethoxygeldanamycin-induced degradation of autophosphorylated Flt3 kinase with internal tandem duplication through the ubiquitin proteasome pathway. J Biol Chem. 2011;286:30263–73.  https://doi.org/10.1074/jbc.M111.232348.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Puissant A, Fenouille N, Alexe G, Pikman Y, Bassil CF, Mehta S, et al. SYK is a critical regulator of FLT3 in acute myeloid leukemia. Cancer Cell. 2014;25:226–42.  https://doi.org/10.1016/j.ccr.2014.01.022.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Rosnet O, Marchetto S. deLapeyriere O, Birnbaum D. Murine Flt3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family. Oncogene. 1991;6:1641–50.PubMedPubMedCentralGoogle Scholar
  17. Rosnet O, Mattei MG, Marchetto S, Birnbaum D. Isolation and chromosomal localization of a novel FMS-like tyrosine kinase gene. Genomics. 1991;9:380–5.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Rosnet O, Buhring HJ, Marchetto S, Rappold I, Lavagna C, Sainty D, et al. Human FLT3/FLK2 receptor tyrosine kinase is expressed at the surface of normal and malignant hematopoietic cells. Leukemia. 1996;10:238–48.PubMedPubMedCentralGoogle Scholar
  19. Zhang S, Broxmeyer HE. p85 subunit of PI3 kinase does not bind to human Flt3 receptor, but associates with SHP2, SHIP, and a tyrosine-phosphorylated 100-kDa protein in Flt3 ligand-stimulated hematopoietic cells. Biochem Biophys Res Commun. 1999;254:440–5.  https://doi.org/10.1006/bbrc.1998.9959.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Julhash U. Kazi
    • 1
    • 2
    Email author
  • Sausan A. Moharram
    • 1
  • Lars Rönnstrand
    • 1
  1. 1.Division of Translational Cancer Research, Department of Laboratory MedicineLund UniversityLundSweden
  2. 2.Laboratory of Computational BiochemistryKN Biomedical Research InstituteBarisalBangladesh