Wild-type FLT3 and FLT3 ITD exhibit similar ligand-induced internalization characteristics.

Journal of Cellular and Molecular Medicine
Fabienne KellnerJörg P Müller

Abstract

Class III receptor tyrosine kinases control the development of hematopoietic stem cells. Constitutive activation of FLT3 by internal tandem duplications (ITD) in the juxtamembrane domain has been causally linked to acute myeloid leukaemia. Oncogenic FLT3 ITD is partially retained in compartments of the biosynthetic route and aberrantly activates STAT5, thereby promoting cellular transformation. The pool of FLT3 ITD molecules in the plasma membrane efficiently activates RAS and AKT, which is likewise essential for cell transformation. Little is known about features and mechanisms of FLT3 ligand (FL)-dependent internalization of surface-bound FLT3 or FLT3 ITD. We have addressed this issue by internalization experiments using human RS4-11 and MV4-11 cells with endogenous wild-type FLT3 or FLT3 ITD expression, respectively, and surface biotinylation. Further, FLT3 wild-type, or FLT3 ITD-GFP hybrid proteins were stably expressed and characterized in 32D cells, and internalization and stability were assessed by flow cytometry, imaging flow cytometry, and immunoblotting. FL-stimulated surface-exposed FLT3 WT or FLT3 ITD protein showed similar endocytosis and degradation characteristics. Kinase inactivation by mutation or FLT3 inhibito...Continue Reading

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Citations

Oct 3, 2020·Cancers·Jörg P Müller, Dirk Schmidt-Arras
Apr 4, 2021·Pharmacology & Therapeutics·Mohammed F AlmataniHouda Alachkar

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Methods Mentioned

BETA
ubiquitination
glycosylation
flow cytometry
FCS
GTPase
confocal microscopy

Software Mentioned

IDEAS
ZEN

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