Myeloproliferative disorder FOP-FGFR1 fusion kinase recruits phosphoinositide-3 kinase and phospholipase Cgamma at the centrosome.
BACKGROUND
The t(6;8) translocation found in rare and agressive myeloproliferative disorders results in a chimeric gene encoding the FOP-FGFR1 fusion protein. This protein comprises the N-terminal region of the centrosomal protein FOP and the tyrosine kinase of the FGFR1 receptor. FOP-FGFR1 is localized at the centrosome where it exerts a constitutive kinase activity.


RESULTS
We show that FOP-FGFR1 interacts with the large centrosomal protein CAP350 and that CAP350 is necessary for FOP-FGFR1 localisation at centrosome. FOP-FGFR1 activates the phosphoinositide-3 kinase (PI3K) pathway. We show that p85 interacts with tyrosine 475 of FOP-FGFR1, which is located in a YXXM consensus binding sequence for an SH2 domain of p85. This interaction is in part responsible for PI3K activation. Ba/F3 cells that express FOP-FGFR1 mutated at tyrosine 475 have reduced proliferative ability. Treatment with PI3K pathway inhibitors induces death of FOP-FGFR1 expressing cells. FOP-FGFR1 also recruits phospholipase Cgamma1 (PLCgamma1) at the centrosome. We show that this enzyme is recruited by FOP-FGFR1 at the centrosome during interphase.


CONCLUSIONS
These results delineate a particular type of oncogenic mechanism by which an ectopic kinase recruits its substrates at the centrosome whence unappropriate signaling induces continuous cell growth and MPD.
Lelièvre
Hélène
H
Centre de Recherche en Cancérologie de Marseille, Laboratoire d'Oncologie Moléculaire, UMR891 Inserm, Institut Paoli-Calmettes, Marseille, France. hlelievre2002@yahoo.fr
Chevrier
Véronique
V
Tassin
Anne-Marie
AM
Birnbaum
Daniel
D
D000818:Animals; D019556:COS Cells; D049109:Cell Proliferation; D002470:Cell Survival; D018385:Centrosome / Q000201:enzymology*; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D007399:Interphase; D008868:Microtubule Proteins / Q000378:metabolism; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D017468:Receptors, Fibroblast Growth Factor / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D008868:Microtubule Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases; D051966:Phospholipase C gamma; D017468:Receptors, Fibroblast Growth Factor; C509238:CEP350 protein, human; C439709:FOP-FGFR1 fusion protein, human