Oncogenic Tyrosine Kinase of Malignant Hemopathy Targets the Centrosome

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 G 1 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. (Cancer Res 2005; 65(16): 7231-40)

Centrosomal targeting of tyrosine kinase activity does not enhance oncogenicity in chronic myeloproliferative disorders

“…In previous studies, FOP-FGFR1 was shown to localize to the centrosome, whereas the centrosomal localization of CEP110-FGFR1 was rather equivocal. 8,27 In conclusion, the subcellular localization is variable among individual CMD chimeric fusion proteins. Centrosomal localization, therefore, does not appear to be necessary for the effects conferred by constitutive tyrosine kinase activation.…”

“…Similar findings have been reported for FOP-FGFR1 earlier. 27 However, phosphorylation of centrosomal substrates did not translate into a proliferative advantage of myeloid Ba/F3 cells, which are commonly used to assess growth factor-independent proliferation as a measure of oncogenic transformation. Specifically, as expected the original leukemic fusion proteins FIP1L1-PDGFRa and TEL-PDGFRb conferred IL-3-independent proliferation in this system.…”

“…The large number of centrosomally localized translocation partners has led to the hypothesis that centrosomal targeting of the tyrosine kinase contributes to the oncogenic potential of fusion kinases in CMD. 4,[26][27][28] Although the frequent fusion of tyrosine kinases to translocation partner proteins with a centrosomal localization in CMD is widely recognized, FOP-FGFR1 so far is the only chimeric fusion with a confirmed centrosomal localization. 27,29 FOP-FGFR1 has been shown to activate PI-3K, PLC-g, AKT and STAT pathways at the centrosome and to promote cell-cycle progression.…”

“…4,[26][27][28] Although the frequent fusion of tyrosine kinases to translocation partner proteins with a centrosomal localization in CMD is widely recognized, FOP-FGFR1 so far is the only chimeric fusion with a confirmed centrosomal localization. 27,29 FOP-FGFR1 has been shown to activate PI-3K, PLC-g, AKT and STAT pathways at the centrosome and to promote cell-cycle progression. 27,28 However, the functional role of centrosomal localization for the oncogenic potential of tyrosine kinases in CMD is still poorly understood.…”

“…27,29 FOP-FGFR1 has been shown to activate PI-3K, PLC-g, AKT and STAT pathways at the centrosome and to promote cell-cycle progression. 27,28 However, the functional role of centrosomal localization for the oncogenic potential of tyrosine kinases in CMD is still poorly understood. In this study, we therefore addressed this issue by artificially targeting tyrosine kinases to centrosomes by fusion with the centrosomal targeting domain of AKAP450 (PACT, Pericentrin-AKAP450 Centrosomal Targeting) 21,30 or the C-terminus of CEP164.…”