FMS-Like Tyrosine Kinase-3
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
Signaling Downstream of FLT3
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.
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