Anchoring of FLT3 in the endoplasmic reticulum alters signaling quality

Schmidt-Arras, Dirk; Böhmer, Sylvia‐Annette; Koch, Siegfried; Müller, Jörg P.; Blei, Lutz; Cornils, Hauke; Bauer, Reinhard; Korasikha, Sridhar; Thiede, Christian; Böhmer, Frank‐D.

doi:10.1182/blood-2007-10-121426

Cited by 87 publications

(111 citation statements)

References 34 publications

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“…Yet another factor that could contribute to the differences in phosphorylation sites seen in these experiments is the subcellular localization of the receptor. It is known that the FLT3-ITD, in contrast to wild-type FLT3 and FLT3-D835Y is trapped in the endoplasmic reticulum and does not reach the cell surface to any appreaciable extent [47]. Thus, the signal transduction molecules (including kinases and phosphatases) it encounters is likely to be different from those at the cell surface, and this could contribute to the differences in phosphorylation seen in the different forms of the receptor.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic Flt3 receptors display different specificity and kinetics of autophosphorylation

Razumovskaya¹,

Masson²,

Khan

et al. 2009

Experimental Hematology

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Objective. Fms-like tyrosine kinase-3 (FLT3), a growth factor receptor normally expressed in hematopoietic progenitor cells, has been shown to have an important role in the development of acute myeloid leukemia c due to activating mutations. FLT3 mutations are found in approximately one third of AML patients and correlate with a poor prognosis, thus making the FLT3 receptor a potential therapeutic target. The aim of the investigation is to analyze the kinetics and specificity of FLT3 autophosphorylation in wild-type FLT3 as well as in the oncogenic FLT3 mutants.Methods. We have used Ba/F3 cells stably expressing either wild-type, ITD or D835Y mutants of FLT3 in order to compare the site selectivity of tyrosine phosphorylation sites. By the use of a panel of phosphospecific antibodies directed against potential tyrosine phosphorylation sites in FLT3, we identified several novel phosphorylation sites in FLT3 and studied the kinetics and specificity of ligand-induced phosphorylation in living cells.Results. Eight phosphorylated tyrosines (pY589, pY591, pY599, pY726, pY768, pY793, pY842 and pY955) were investigated and shown to be differentially phosphorylated in the wild-type versus the mutated receptors. Furthermore, we show that tyrosines 726, 793 and 842 are novel phosphorylation sites of FLT3 in intact cells. Conclusion.In this study, we have looked at the site-specific phosphorylation in the wild-type FLT3 in comparison to the mutants found in AML. We observed not only quantitative changes but more importantly, qualitative differences in the phosphorylation patterns of the wild-type and the mutated FLT3 receptors, which might contribute to the understanding of the mechanisms by which FLT3 contributes to AML in patients with mutations in FLT3.

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Section: Discussionmentioning

confidence: 99%

Oncogenic Flt3 receptors display different specificity and kinetics of autophosphorylation

Razumovskaya¹,

Masson²,

Khan

et al. 2009

Experimental Hematology

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“…In contrast, arguing against this scenario are studies that express ITD and AL mutations in the same cell type and yet more aggressive transforming properties are observed for the ITD mutant Grundler et al, 2005). Clear differences in activation of downstream signaling pathways Schmidt-Arras et al, 2009) and in transcription profiles Lu et al, 2007) between the two classes of mutations have been reported. A switch in substrate specificity can account for these observations.…”

Section: Differences In Oncogenic Flt3 Signalingmentioning

confidence: 99%

Differential signaling of Flt3 activating mutations in acute myeloid leukemia: a working model

Chan

2011

Protein Cell

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Receptor tyrosine kinases couple a wide variety of extracellular cues to cellular responses. The class III subfamily comprises the platelet-derived growth factor receptor, c-Kit, Flt3 and c-Fms, all of which relay cell proliferation signals upon ligand binding. Accordingly, mutations in these proteins that confer ligand-independent activation are found in a subset of cancers. These mutations cluster in the juxtamembrane (JM) and catalytic tyrosine kinase domain (TKD) regions. In the case of acute myeloid leukemia (AML), the juxtamembrane (named ITD for internal tandem duplication) and TKD Flt3 mutants differ in their spectra of clinical outcomes. Although the mechanism of aberrant activation has been largely elucidated by biochemical and structural analyses of mutant kinases, the differences in disease presentation cannot be attributed to a change in substrate specificity or signaling strength of the catalytic domain. This review discusses the latest literature and presents a working model of differential Flt3 signaling based on mis-localized juxtamembrane autophosphorylation, to account for the disease variation. This will have bearing on therapeutic approaches in a complex disease such as AML, for which no efficacious drug yet exists.

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“…Constitutive activity of FLT3-ITD activates down-stream pro-survival signaling pathways including PI3K/AKT, STAT5 (whereby STAT5 activation is independent of JAK kinase activation [49]) and RAF/MEK/ERK, which are known to promote survival, proliferation and transformation [50][51][52]. Recent findings have identified that in order for PI3K/AKT and RAF/MEK/ERK pro-survival pathways to be activated they must be located down-stream of FLT3-ITD at the plasma membrane and STAT5 is located down-stream of FLT3-ITD at the ER [45,53].…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

NOX-driven ROS formation in cell transformation of FLT3-ITD-positive AML

Jayavelu

Moloney

Böhmer

et al. 2016

Experimental Hematology

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Anchoring of FLT3 in the endoplasmic reticulum alters signaling quality

Cited by 87 publications

References 34 publications

Oncogenic Flt3 receptors display different specificity and kinetics of autophosphorylation

Oncogenic Flt3 receptors display different specificity and kinetics of autophosphorylation

Differential signaling of Flt3 activating mutations in acute myeloid leukemia: a working model

NOX-driven ROS formation in cell transformation of FLT3-ITD-positive AML

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