FLT3 is a type III receptor tyrosine kinase (RTK). The extracellular domain consists of 5 immunoglobulin (Ig) domains that contribute to dimerization and ligand binding. The intracellular region has a juxtamembrane domain that plays a role in autoinhibiting the receptor in the absence of ligand, and a bi-lobed kinase region with an activation loop and the catalytic cleft (reviewed in Klug et al, 2018). Signaling through FLT3 occurs after ligand-induced dimerization and transautophosphorylation, and promotes signaling through the MAP kinase, PI3K and STAT5 pathways, among others. FLT3 signaling promotes cellular proliferation and differentiation and contributes to haematopoeisis. FLT3 is mutated in up to 30% of acute myeloid leukemias. ~25% of the FLT3 mutations in AML cases occur as internal tandem duplications (ITDs) either in the juxtamembrane domain region encoded by exon 14 or the tyrosine kinase domain (TKD), while ~7-10% of AML cases contain FLT3 missense mutations in the TKD (reviewed in Klug et al, 2018; Daver et al, 2019). These mutations all support ligand-independent activation of the receptor and result in constitutive activation and signaling (Zheng et al, 2004; reviewed in Klug et al, 2018; Kazi and Roonstrand, 2019). In rare cases, the FLT3 locus is also subject to translocations that generate constitutively active fusion proteins (reviewed in Kazi and Roonstrand, 2019). Oncogenic FLT3 activity can be targeted with tyrosine kinase inhibitors, although resistance often arises due to secondary mutations or activation of bypass pathways (reviewed in Staudt et al, 2018; Daver et al, 2019).
Schlenk, RF, Levis, MJ, Daver, N, Russell, NH
Heinrich, MC, Kent, JD, Klug, LR
Staudt, D, Murray, HC, Alvaro, F, Dun, MD, Enjeti, AK, McLachlan, T, Verrills, NM
Kazi, JU, Rönnstrand, L
Levis, M, Gorin, NC, Hicklin, D, Ludwig, D, Piloto, O, Small, D, Witte, L, Zheng, R, Li, Y, Zhu, Z, Beran, M, Baldwin, BR, Brown, P
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