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

Synonyms

 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).

RAS/RAF/ERK Pathway

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).

Summary

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.

References

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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