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Mol Cancer. 2008 Apr 15;7:30. doi: 10.1186/1476-4598-7-30.

Myeloproliferative disorder FOP-FGFR1 fusion kinase recruits phosphoinositide-3 kinase and phospholipase Cgamma at the centrosome.

Author information

1
Centre de Recherche en Cancérologie de Marseille, Laboratoire d'Oncologie Moléculaire, UMR891 Inserm, Institut Paoli-Calmettes, Marseille, France. hlelievre2002@yahoo.fr

Abstract

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.

CONCLUSION:

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.

PMID:
18412956
PMCID:
PMC2373309
DOI:
10.1186/1476-4598-7-30
[Indexed for MEDLINE]
Free PMC Article

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