Peer-Reviewed Journal Details
Mandatory Fields
Corcoran, A,Cotter, TG
2013
January
Free Radical Research
FLT3-driven redox-modulation of Ezrin regulates leukaemic cell migration
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Optional Fields
AML ROS Src Ezrin/Radixin/Moesin FLT3-ITD ACUTE MYELOID-LEUKEMIA INTERNAL TANDEM DUPLICATION EZRIN/RADIXIN/MOESIN ERM PROTEINS EPIDERMAL-GROWTH-FACTOR OXYGEN SPECIES ROS F-ACTIN BINDING TYROSINE KINASE OXIDATIVE STRESS NUCLEOCYTOPLASMIC TRAFFICKING EPITHELIAL-CELLS
47
20
34
The concept of reactive oxygen species (ROS) being produced via the activation of specific oncogenes provides a basis for generating genomic instability and pro-survival signalling in tumour cells. The purpose of this study was to identify downstream targets of NADPH oxidase (Nox)-derived ROS signalling in acute myeloid leukaemia cells, by performing a proteomic analysis utilizing two-dimensional phosphotyrosine immunoblotting. The majority of the targets identified were cytoskeletal-associated proteins including Ezrin, a known regulator of the cytoskeleton, which was examined further. The study demonstrated that inhibition of Nox enzymes, using diphenyleneiodonium chloride in the acute myeloid leukaemia cell line MOLM-13, resulted in a decrease in Ezrin tyrosine phosphorylation and also triggered a shift in Ezrin sub-cellular localization as detected by immunofluorescence. The change in Ezrin localization coincided with altered cell morphology, observed using scanning electron microscopy and a decreased ability to migrate through a polycarbonate transwell membrane. Similar effects were observed upon inhibition of the oncogenic receptor tyrosine kinase FLT3 using the staurosporine derivate PKC412, implicating a role for FLT3 as an upstream regulator of Ezrin. Our results indicate that FLT3 drives production of ROS by Nox, which stimulates changes in Ezrin tyrosine phosphorylation and localization via redox regulation of Src. Furthermore, inhibition of FLT3 signalling leads to alterations in MOLM-13 cell morphology and has a significant influence on cell motility.
DOI 10.3109/10715762.2012.733385
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