FLT3 signaling in disease

Stable Identifier
R-HSA-9682385
Type
Pathway
Species
Homo sapiens
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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).

Literature References
PubMed ID Title Journal Year
30651634 Targeting FLT3 mutations in AML: review of current knowledge and evidence

Daver, N, Schlenk, RF, Russell, NH, Levis, MJ

Leukemia 2019
31066629 FMS-like Tyrosine Kinase 3/FLT3: From Basic Science to Clinical Implications

Kazi, JU, Rönnstrand, L

Physiol. Rev. 2019
12969963 FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells

Zheng, R, Levis, M, Piloto, O, Brown, P, Baldwin, BR, Gorin, NC, Beran, M, Zhu, Z, Ludwig, D, Hicklin, D, Witte, L, Li, Y, Small, D

Blood 2004
29964125 Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases

Klug, LR, Kent, JD, Heinrich, MC

Pharmacol. Ther. 2018
30332834 Targeting Oncogenic Signaling in Mutant FLT3 Acute Myeloid Leukemia: The Path to Least Resistance

Staudt, D, Murray, HC, McLachlan, T, Alvaro, F, Enjeti, AK, Verrills, NM, Dun, MD

Int J Mol Sci 2018
Participants
Participant Of
Disease
Name Identifier Synonyms
cancer 162 malignant tumor, malignant neoplasm, primary cancer
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