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The nucleophosmin-anaplastic lymphoma kinase oncogene interacts, activates, and uses the kinase PIKfyve to increase invasiveness.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2011 Sep 16; Vol. 286 (37), pp. 32105-14. Date of Electronic Publication: 2011 Jul 07. - Publication Year :
- 2011
-
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.
- Subjects :
- Animals
Cell Line, Tumor
Cell Movement
Gene Silencing
Humans
Matrix Metalloproteinase 9 genetics
Matrix Metalloproteinase 9 metabolism
Mice
NIH 3T3 Cells
Neoplasm Invasiveness
Oncogene Proteins, Fusion genetics
Phosphatidylinositol 3-Kinases genetics
Protein-Tyrosine Kinases genetics
Cell Proliferation
Oncogene Proteins, Fusion metabolism
Phosphatidylinositol 3-Kinases metabolism
Protein-Tyrosine Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 286
- Issue :
- 37
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 21737449
- Full Text :
- https://doi.org/10.1074/jbc.M111.227512