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The nucleophosmin-anaplastic lymphoma kinase oncogene interacts, activates, and uses the kinase PIKfyve to increase invasiveness.

ABSTRACT: NPM-ALK is a chimeric tyrosine kinase detected in most anaplastic large cell lymphomas that 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 anaplastic lymphoma kinase (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 demonstrated previously that the high level of phosphatidylinositol 5-phosphate 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 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 matrix metalloproteinase 9 localization at the cell surface and defect in maturation. Altogether, these results suggest a role for PIKfyve in NPM-ALK-mediated invasion.

SUBMITTER: Dupuis-Coronas S

PROVIDER: S-EPMC3173219 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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The nucleophosmin-anaplastic lymphoma kinase oncogene interacts, activates, and uses the kinase PIKfyve to increase invasiveness.

Dupuis-Coronas Sophie S Lagarrigue Frédéric F Ramel Damien D Chicanne Gaëtan G Saland Estelle E Gaits-Iacovoni Frédérique F Payrastre Bernard B Tronchère Hélène H

The Journal of biological chemistry 20110707 37

NPM-ALK is a chimeric tyrosine kinase detected in most anaplastic large cell lymphomas that 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 anaplastic lymphoma kinase (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 demonstrated previo ...[more]

PMID: 21737449

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Project description:The oncogenic fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), found exclusively in a subset of ALK-positive anaplastic large cell lymphoma, promotes tumorigenesis by exerting its constitutively active tyrosine kinase activity. Thus, characterization of the NPM-ALK-induced changes in the phosphoproteome will likely provide insights into the biology of this oncoprotein. To achieve this goal, we used a strategy of combining sequential affinity purification of phosphopeptides and LC/MS. GP293 cells transfected with either NPM-ALK or an NPM-ALK mutant with decreased tyrosine kinase activity (negative control) were used. We identified 506 phosphoproteins detectable in NPM-ALK-expressing cells but not in the negative control. Bioinformatics analysis revealed that these phosphoproteins carry a wide diversity of biological functions, some of which have not been described in association with NPM-ALK, such as the tumor necrosis factor (TNF)/Fas/tumor necrosis factor-related apoptosis-induced ligand (TRAIL) signaling pathway and the ubiquitin proteasome degradation pathway. In particular, modulations of the TNF/Fas/TRAIL pathway by NPM-ALK were supported by our antibody microarray data. Further validation of the TNF/Fas/TRAIL pathway was performed in ALK(+) anaplastic large cell lymphoma (ALCL) cell lines with knockdown of NPM-ALK using short interference RNA, resulting in the loss of the tyrosine phosphorylation of tumor necrosis factor receptor-associated protein 1 (TRAP1) and receptor-interacting protein 1, two crucial TNF signaling molecules. Functional analyses revealed that knockdown of TRAP1 facilitated cell death induced by TRAIL or doxorubicin in ALK(+) ALCL cells. This suggests that down-regulation of TRAP1 in combination with TRAIL or doxorubicin might be a potential novel therapeutic strategy for ALK(+) ALCL. These findings demonstrated that our strategy allowed the identification of novel proteins downstream of NPM-ALK that contribute to the maintenance of neoplastic phenotype and holds great potential for future studies of cellular tyrosine kinases in normal states and diseases.

Dataset Information

The nucleophosmin-anaplastic lymphoma kinase oncogene interacts, activates, and uses the kinase PIKfyve to increase invasiveness.

Publications

The nucleophosmin-anaplastic lymphoma kinase oncogene interacts, activates, and uses the kinase PIKfyve to increase invasiveness.

Similar Datasets

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