期刊
JOURNAL OF CELL SCIENCE
卷 126, 期 20, 页码 4746-4755出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.131789
关键词
Oncogenic RTK; FLT3; FLT3 ITD; Leukemia; AML; Ras; Localization; Plasma membrane; Endomembrane
类别
资金
- Deutsche Forschungsgemeinschaft [BO 1043/7-1, RU 860/3-1]
- Deutsche Krebshilfe [108401 TP2]
FMS-like tyrosine kinase 3 with internal tandem duplication (FLT3 ITD) is an important oncoprotein in acute myeloid leukemia (AML). Owing to its constitutive kinase activity FLT3 ITD partially accumulates at endomembranes, a feature shared with other disease-associated, mutated receptor tyrosine kinases. Because Ras proteins also transit through endomembranes we have investigated the possible existence of an intracellular FLT3-ITD/Ras signaling pathway by comparing Ras signaling of FLT3 ITD with that of wild-type FLT3. Ligand stimulation activated both K- and N-Ras in cells expressing wild-type FLT3. Live-cell Ras-GTP imaging revealed ligand-induced Ras activation at the plasma membrane (PM). FLT3-ITD-dependent constitutive activation of K-Ras and N-Ras was also observed primarily at the PM, supporting the view that the PM-resident pool of FLT3 ITD engaged the Ras/Erk pathway in AML cells. Accordingly, specific interference with FLT3-ITD/Ras signaling at the PM using PM-restricted dominant negative K-RasS17N potently inhibited cell proliferation and promoted apoptosis. In conclusion, Ras signaling is crucial for FLT3-ITD-dependent cell transformation and FLT3 ITD addresses PM-bound Ras despite its pronounced mislocalization to endomembranes.
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