title: 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.
authors: INSERM, U1048, I2MC, Université Toulouse III Paul-Sabatier, Centre Hospitalier Universitaire de Toulouse, Toulouse Cedex 4, France.
authors: Sophie
authors: S
authors: Dupuis-Coronas
authors: Frédéric
authors: F
authors: Lagarrigue
authors: Damien
authors: D
authors: Ramel
authors: Gaëtan
authors: G
authors: Chicanne
authors: Estelle
authors: E
authors: Saland
authors: Frédérique
authors: F
authors: Gaits-Iacovoni
authors: Bernard
authors: B
authors: Payrastre
authors: Hélène
authors: H
authors: Tronchère
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D020868:Gene Silencing; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; C107023:p80(NPM-ALK) protein; C492139:PIKFYVE protein, human; C116930:Pikfyve protein, mouse; D011505:Protein-Tyrosine Kinases; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse