Oncogenic tyrosine kinase of malignant hemopathy targets the centrosome

Bénédicte Delaval; Sébastien Létard; Hélène Lelièvre; Véronique Chevrier; Laurent Daviet; Patrice Dubreuil; Daniel Birnbaum

doi:10.1158/0008-5472.CAN-04-4167

Oncogenic tyrosine kinase of malignant hemopathy targets the centrosome

Cancer Res. 2005 Aug 15;65(16):7231-40. doi: 10.1158/0008-5472.CAN-04-4167.

Authors

Bénédicte Delaval¹, Sébastien Létard, Hélène Lelièvre, Véronique Chevrier, Laurent Daviet, Patrice Dubreuil, Daniel Birnbaum

Affiliation

¹ Laboratories of Molecular Oncology and Molecular Hematopoiesis, Marseille Cancer Institute, UMR599 Inserm and Institut Paoli-Calmettes, Marseilles, France.

PMID: 16103074
DOI: 10.1158/0008-5472.CAN-04-4167

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Cycle / physiology
Cell Growth Processes / physiology
Centrosome / enzymology*
Centrosome / metabolism
G1 Phase / physiology
Hematopoietic Stem Cells / enzymology*
Hematopoietic Stem Cells / metabolism
Hematopoietic Stem Cells / pathology
Mice
Myeloproliferative Disorders / enzymology*
Myeloproliferative Disorders / metabolism
Myeloproliferative Disorders / pathology
Oncogene Proteins, Fusion / metabolism
Oncogene Proteins, Fusion / physiology*
Phosphorylation
Pyrroles / pharmacology
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 1
Receptors, Fibroblast Growth Factor / antagonists & inhibitors
Receptors, Fibroblast Growth Factor / metabolism
Receptors, Fibroblast Growth Factor / physiology*
S Phase / physiology

Substances

FOP-FGFR1 fusion protein, human
Oncogene Proteins, Fusion
Pyrroles
Receptors, Fibroblast Growth Factor
SU 5402
Fgfr1 protein, mouse
Receptor Protein-Tyrosine Kinases
Receptor, Fibroblast Growth Factor, Type 1