Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

FMS-Like Tyrosine Kinase-3

  • Julhash U. Kazi
  • 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 encodes a protein of 993 amino acids. The receptor shows as two bands (130 kDa and 160 kDa) in Western blotting due to differences in posttranslational modifications such as glycosylation. FLT3 knockout mice have been generated. FLT3 deficient mice are fertile and viable but display hematological defects (Mackarehtschian et al. 1995). Under normal physiological conditions, the gene is expressed in placenta, in various adult tissues including gonads and brain, and in hematopoietic cells (Rosnet and Marchetto 1991). Expression is detected in early hematopoietic cells of both myeloid and lymphoid lineages, but expression was found to be lost in mature blood cells such as B- and T-lymphocytes, monocytes, and granulocytes (Birg et al. 1992; Carow et al. 1996; McClanahan et al. 1996; Rosnet et al. 1996). Besides normal tissues, expression of FLT3 has also been described in hematopoietic malignancies including acute myeloid leukemia (AML). In AML, more than 30% patients carry an oncogenic mutation of FLT3. The most common mutations in FLT3 is the so-called internal tandem duplications (ITDs) that occur mainly in the juxtamembrane domain and less frequently in the kinase domain. The other type of mutations includes point mutations in the kinase domain. Like other type III receptor, tyrosine kinases FLT3 has an extracellular domain consisting of five immunoglobulin-like domains (Fig. 1). This domain acts as a binding site for the dimeric ligand FL. The intracellular domain of FLT3 contains a short juxtamembrane domain immediately after the transmembrane domain, and a protein tyrosine kinase domain divided into two parts by a short kinase insert followed by a short carboxyterminal tail.
FMS-Like Tyrosine Kinase-3, Fig. 1

Schematic representation of FLT3: FLT3 consists of an extracellular ligand binding domain with five immunoglobulin-like domains, a transmembrane domain, a juxtamembrane domain, and a tyrosine kinase domain with a short kinase insert and a short carboxyterminal tail. The most common FLT3 mutations in FLT3 (FLT3-ITD) occur in or nearby the juxtamembrane domain

Signaling Downstream of FLT3

Wild-type FLT3 needs its ligand, FL, for activation. FL exists as a non-covalent homodimer and can be found as a soluble form as well as a membrane-bound form. Dimerized ligands bind to two FLT3 monomers thereby inducing dimerization of the receptors. Receptor dimerization induces trans phosphorylation of specific tyrosine residues, resulting in stabilization of the active conformation of FLT3. Phosphorylation on tyrosine residues creates docking sites for SH2 domain-containing proteins. Depending on interacting proteins and the cellular context, FLT3 activates different signaling cascades including PI3K/AKT, RAS/RAF/ERK, and RAS/RAF/p38 signaling (Fig. 2). FLT3 signaling is tightly regulated by interacting proteins. Different classes of proteins such as kinases, phosphatases, ubiquitin ligases, and adaptor proteins are involved in regulation of FLT3 downstream signaling. Kinases, for example SRC and SYK, potentiate signals from FLT3 (Heiss et al. 2006; Puissant et al. 2014). On the other hand, adaptor proteins and ubiquitin ligases such as CBL (Oshikawa et al. 2011), SOCS6 (Kazi et al. 2012), SOCS2 (Kazi and Rönnstrand 2013b), and SLAP2 (Moharram et al. 2016) negatively regulate FLT3 signaling mainly through ubiquitination-mediated degradation of the receptor. Wild-type and oncogenic FLT3 mutants activate the same downstream signaling cascades, but in addition, FLT3-ITD also activates the STAT5 signaling pathway.
FMS-Like Tyrosine Kinase-3, Fig. 2

FLT3 downstream signaling: Ligand binding to the wild-type receptor results in dimerization and phosphorylation on several tyrosine residues. Tyrosine phosphorylation creates docking sites for SH2 domain-containing proteins and thereby activating downstream signaling cascades

PI3K/AKT Pathway

The phosphoinositide 3 kinase (PI3K)/AKT pathway is an important regulator of cell proliferation, survival, and metabolism. PI3Ks are a group of lipid kinases and the members of class I PI3Ks phosphorylate phosphatidylinositol-4,5-bisphosphate (PIP2) and convert it to phosphatidylinositol-3,4,5-trisphosphate (PIP3). The class IA PI3Ks have been extensively studied with respect to the type III receptor tyrosine kinase pathways. The members of class IA PI3Ks are heterodimers of a regulatory domain (p85α, p85β, or p55γ) and a catalytic domain (p110α, p110β, or p110γ). The regulatory domain contains SH2 domains which are involved in association of phosphotyrosine residues. The regulatory subunit p85 associates with murine FLT3 through the phosphorylated Y958 residue in the C-terminal tail (Beslu et al. 1996). However, the corresponding residue is absent in human FLT3, and therefore p85 does not directly bind to FLT3 but forms complex with other FLT3 binding proteins such as SHP2, SHIP, GAB1, GAB2, and GRB10 (Zhang and Broxmeyer 1999; Kazi and Rönnstrand 2013a).


Mitogen-activated protein kinase (MAPK) pathways are involved in cell survival, proliferation, differentiation, and migration. Pathways can be activated in response to the extracellular stimuli such as growth factors, cytokines, and stress. Activation of FLT3 in turn activates downstream signaling cascades, resulting in phosphorylation-dependent activation of ERK and p38. Several FLT3 interacting proteins, such as GRB2, GAB2, SRC, and SHP2, are known to be involved in these processes (Heiss et al. 2006; Masson et al. 2009).


Since FLT3 is one of the genes with the highest frequency of mutation in AML, FLT3 became an attractive target for AML treatment. Several FLT3 inhibitors have been tested and showed promising results in combination with chemotherapy. Major problems with FLT3 targeted therapy are the development of resistant disease. Thus, understanding of the FLT3 downstream signaling will provide an alternative approach to develop therapies for the treatment of AML patients carrying FLT3 mutations.


  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.PubMedCrossRefGoogle 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.PubMedGoogle 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.PubMedGoogle 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. doi: 10.1182/blood-2005-07-008896.PubMedCrossRefGoogle 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. doi: 10.1016/j.molonc.2012.11.003.PubMedCrossRefGoogle 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. doi: 10.1016/j.molonc.2013.02.020.PubMedPubMedCentralCrossRefGoogle 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. doi: 10.1074/jbc.M112.376111.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141:1117–34. doi: 10.1016/j.cell.2010.06.011.PubMedPubMedCentralCrossRefGoogle 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.PubMedCrossRefGoogle 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. doi: 10.1111/j.1365-2141.2009.07725.x.PubMedCrossRefGoogle 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. doi: 10.1016/0092–8674(91)90010-V.PubMedCrossRefGoogle 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.PubMedGoogle 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; doi: 10.18632/oncotarget.10760.Google 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. doi: 10.1074/jbc.M111.232348.PubMedPubMedCentralCrossRefGoogle 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. doi: 10.1016/j.ccr.2014.01.022.PubMedPubMedCentralCrossRefGoogle 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.PubMedGoogle 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.PubMedCrossRefGoogle 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.PubMedGoogle 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. doi: 10.1006/bbrc.1998.9959.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Julhash U. Kazi
    • 1
    • 2
  • 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