Oncogenic tyrosine kinase of malignant hemopathy targets the centrosome.
Myeloproliferative disorders (MPD) are malignant diseases of hematopoietic progenitor cells. Many MPDs result from a chromosomal translocation that creates a fusion gene encoding a chimeric kinase. The fibroblast growth factor receptor 1 (FGFR1)-MPD is characterized by the fusion of the FGFR1 kinase with various partners, including FOP. We show here that both normal FOP and FOP-FGFR1 fusion kinase localize to the centrosome. The fusion kinase encounters substrates at the centrosome where it induces strong phosphorylation on tyrosine residues. Treatment with FGFR1 kinase inhibitor SU5402 abolishes FOP-FGFR1-induced centrosomal phosphorylation and suppresses the proliferative and survival potentials of FOP-FGFR1 Ba/F3 cells. We further show that FOP-FGFR1 allows cells to overcome G1 arrest. Therefore, the FOP-FGFR1 fusion kinase targets the centrosome, activates signaling pathways at this organelle, and sustains continuous entry in the cell cycle. This could represent a potential new mechanism of oncogenic transformation occurring specifically at the centrosome.
Delaval
Bénédicte
B
Laboratories of Molecular Oncology and Molecular Hematopoiesis, Marseille Cancer Institute, UMR599 Inserm and Institut Paoli-Calmettes, Marseilles, France.
Létard
Sébastien
S
Lelièvre
Hélène
H
Chevrier
Véronique
V
Daviet
Laurent
L
Dubreuil
Patrice
P
Birnbaum
Daniel
D
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D018385:Centrosome / Q000201:enzymology* / Q000378:metabolism; D016193:G1 Phase / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009196:Myeloproliferative Disorders / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D011758:Pyrroles / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D016196:S Phase / Q000502:physiology
C439709:FOP-FGFR1 fusion protein, human; D015514:Oncogene Proteins, Fusion; D011758:Pyrroles; D017468:Receptors, Fibroblast Growth Factor; C105686:SU 5402; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1