Modulation of FLT3 signal transduction through cytoplasmic cysteine residues indicates the potential for redox regulation

Böhmer, Annette; Barz, Saskia; Schwab, Katjana; Kolbe, Ulrike; Gabel, Anke; Kirkpatrick, Joanna; Ohlenschläger, Oliver; Görlach, Matthias; Böhmer, Frank‐D.

doi:10.1016/j.redox.2019.101325

Cited by 15 publications

(19 citation statements)

References 57 publications

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“…Fms-like tyrosine kinase 3 is a member of the PDGFR (class III RTK) family containing disulfide bridges as well as free cysteines. By serine replacement of cytoplasmic cysteines evidence was found that oxidative modification of cysteine residues, e.g., by exogenous ROS, regulates the kinase activity of this clinically important oncoprotein (Bohmer et al, 2019).…”

Section: Kinases and Phosphatasesmentioning

confidence: 99%

Cysteines and Disulfide Bonds as Structure-Forming Units: Insights From Different Domains of Life and the Potential for Characterization by NMR

et al. 2020

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Disulfide bridges establish a fundamental element in the molecular architecture of proteins and peptides which are involved e.g., in basic biological processes or acting as toxins. NMR spectroscopy is one method to characterize the structure of bioactive compounds including cystine-containing molecules. Although the disulfide bridge itself is invisible in NMR, constraints obtained via the neighboring NMR-active nuclei allow to define the underlying conformation and thereby to resolve their functional background. In this mini-review we present shortly the impact of cysteine and disulfide bonds in the proteasome from different domains of life and give a condensed overview of recent NMR applications for the characterization of disulfide-bond containing biomolecules including advantages and limitations of the different approaches.

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Section: Kinases and Phosphatasesmentioning

confidence: 99%

Cysteines and Disulfide Bonds as Structure-Forming Units: Insights From Different Domains of Life and the Potential for Characterization by NMR

et al. 2020

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“…Structural characteristics of wild‐type FLT3‐dimer formation as consequence of FL binding have recently been elucidated . Interestingly, regardless of the sequence variety of JM domain, FLT3 ITD receptors form homodimers in absence of FL and, if co‐transfected with FLT3 WT, FLT3 WT/FLT3 ITD heterodimers . Thus, elongation mutations of the JM domain promote FLT3 ITD receptor dimerization and its subsequent phosphorylation and auto‐activation in the absence of the ligand …”

Section: Introductionmentioning

confidence: 99%

Wild‐type FLT3 and FLT3 ITD exhibit similar ligand‐induced internalization characteristics

Kellner

Keil

Schindler

et al. 2020

J Cellular Molecular Medi

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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 inhibitor treatment strongly promoted FLT3 ITD surface localization, and attenuated but did not abrogate FL-induced internalization. Experiments with the dynamin inhibitor dynasore suggest that active FLT3 as well as FLT3 ITD is largely endocytosed via clathrin-dependent endocytosis. Internalization of kinase-inactivated molecules occurred through a different yet unidentified mechanism. Our data demonstrate that FLT3 WT and constitutively active FLT3 ITD receptor follow, despite very different biogenesis kinetics, similar internalization and degradation routes. K E Y W O R D S degradation, Fms-like tyrosine kinase 3 internal tandem duplications, GFP hybrid genes, oncogene, plasma membrane, receptor endocytosis, receptor tyrosine kinase | 4669 KELLNER Et aL.

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“…A population of individuals is exposed to competitive selection that weeds out poor solutions. Recombination and mutation are used to create new solutions [15][16][17][18][19][20][21][22].…”

Section: Data Setmentioning

confidence: 99%

Theoretical Studies Aimed at Finding FLT3 Inhibitors and a Promising Compound and Molecular Pattern with Dual Aurora B/FLT3 Activity

et al. 2020

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FLT3 and dual Aurora B/FLT3 inhibitors have shown relevance in the search for promising new anticancer compounds, mainly for acute myeloid leukemia (AML). This study was designed to investigate the interactions between human FLT3 in the kinase domain with several indolin−2-one derivatives, structurally similar to Sunitinib. Molegro Virtual Docker (MVD) software was utilized in docking analyses. The predicted model of the training group, considering nineteen amino acid residues, performed in Chemoface, achieved an R2 of 0.82, suggesting that the binding conformations of the ligands with FLT3 are reasonable, and the data can be used to predict the interaction energy of other FLT3 inhibitors with similar molecular patterns. The MolDock Score for energy for compound 1 showed more stable interaction energy (–233.25 kcal mol−1) than the other inhibitors studied, while Sunitinib presented as one of the least stable (–160.94 kcal mol−1). Compounds IAF70, IAF72, IAF75, IAF80, IAF84, and IAF88 can be highlighted as promising derivatives for synthesis and biological evaluation against FLT3. Furthermore, IAF79 can be considered to be a promising dual Aurora B/FLT3 inhibitor, and its molecular pattern can be exploited synthetically to search for new indolin−2-one derivatives that may become drugs used in the treatment of cancers, including AML.

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Modulation of FLT3 signal transduction through cytoplasmic cysteine residues indicates the potential for redox regulation

Cited by 15 publications

References 57 publications

Cysteines and Disulfide Bonds as Structure-Forming Units: Insights From Different Domains of Life and the Potential for Characterization by NMR

Cysteines and Disulfide Bonds as Structure-Forming Units: Insights From Different Domains of Life and the Potential for Characterization by NMR

Wild‐type FLT3 and FLT3 ITD exhibit similar ligand‐induced internalization characteristics

Theoretical Studies Aimed at Finding FLT3 Inhibitors and a Promising Compound and Molecular Pattern with Dual Aurora B/FLT3 Activity

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