The NPM-ALK oncogene interacts, activates and uses PIKfyve to increase invasiveness.

Abstract : NPM-ALK is a chimeric tyrosine kinase detected in most anaplastic large cell lymphomas which results from the reciprocal translocation t(2,5)(p23;q35) that fuses the N-terminal domain of nucleophosmin (NPM) to the catalytic domain of the ALK receptor. The constitutive activity of the kinase is responsible for its oncogenicity through the stimulation of several downstream signaling pathways leading to cell proliferation, migration and survival. We previously demonstrated that the high level of phosphatidylinositol 5-phosphate (PtdIns5P) measured in NPM-ALK expressing cells is controlled by the phosphoinositide kinase PIKfyve, a lipid kinase known for its role in vesicular trafficking. Here, we show that PIKfyve associates with NPM-ALK and that the interaction involves the 181-300 region of the oncogene. Moreover, we demonstrate that the tyrosine kinase activity of the oncogene controls PIKfyve lipid kinase activity, but is dispensable for the formation of the complex. Silencing or inhibition of PIKfyve, by using siRNA or the PIKfyve inhibitor YM201636, have no effect on NPM-ALK-mediated proliferation and migration, but strongly reduce invasive capacities of NPM-ALK expressing cells and their capacity to degrade the extracellular matrix. Accordingly, immunofluorescence studies confirm a perturbation of MMP-9 localization at the cell surface and defect in maturation. Altogether, these results suggest a role for PIKfyve in NPM-ALK mediated invasion.
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Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2011, epub ahead of print. 〈10.1074/jbc.M111.227512〉
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Soumis le : vendredi 19 août 2011 - 13:53:24
Dernière modification le : jeudi 9 novembre 2017 - 09:38:02

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Sophie Dupuis-Coronas, Frederic Lagarrigue, Damien Ramel, Gaetan Chicanne, Estelle Saland, et al.. The NPM-ALK oncogene interacts, activates and uses PIKfyve to increase invasiveness.. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2011, epub ahead of print. 〈10.1074/jbc.M111.227512〉. 〈inserm-00615475〉

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