Abstract
BackgroundThe 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.ResultsWe 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 Cγ1 (PLCγ1) at the centrosome. We show that this enzyme is recruited by FOP-FGFR1 at the centrosome during interphase.ConclusionThese 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.
Highlights
The t(6;8) translocation found in rare and agressive myeloproliferative disorders results in a chimeric gene encoding the FOP-FGFR1 fusion protein
The FOP-FGFR1 fusion protein, in which the N-terminal FOP protein-protein interaction sequence is fused to the tyrosine kinase region of FGFR1, is encoded by a chimeric gene that results from a translocation between chromosomal regions 8p12 and 6q27
FOP-FGFR1 fusion protein interacts with CAP350 at the centrosome To better understand the role of the fusion protein at the centrosome, we looked for centrosomal interacting proteins
Summary
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 Nterminal region of the centrosomal protein FOP and the tyrosine kinase of the FGFR1 receptor. Chromosomal rearrangements that affect FGFR1 induce an atypical myeloproliferative disorder (MPD), characterized by dual lympho and myeloproliferation and aggressive evolution In this MPD, the FGFR1 tyrosine kinase is fused to one of several partners, including BCR [2], CEP110 [3], ERVK [4], FOP (FGFR1 oncogene partner) [5], MYO18A [6], TIF1 [7] and ZNF198 [8]. FOP-FGFR1 binds and activates PLCγ1 [9]
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