Abstract
Fibroblast growth factor receptor 3–transforming acidic coiled-coil containing protein 3 (FGFR3–TACC3; FT3) is a gene fusion resulting from rearrangement of chromosome 4 that has been identified in many cancers including those of the urinary bladder. Altered FGFR3 signalling in FT3-positive cells is thought to contribute to cancer progression. However, potential changes in TACC3 function in these cells have not been explored. TACC3 is a mitotic spindle protein required for accurate chromosome segregation. Errors in segregation lead to aneuploidy, which can contribute to cancer progression. Here we show that FT3-positive bladder cancer cells have lower levels of endogenous TACC3 on the mitotic spindle, and that this is sufficient to cause mitotic defects. FT3 is not localized to the mitotic spindle, and by virtue of its TACC domain, recruits endogenous TACC3 away from the spindle. Knockdown of the fusion gene or low-level overexpression of TACC3 partially rescues the chromosome segregation defects in FT3-positive bladder cancer cells. This function of FT3 is specific to TACC3 as inhibition of FGFR3 signalling does not rescue the TACC3 level on the spindle in these cancer cells. Models of FT3-mediated carcinogenesis should, therefore, include altered mitotic functions of TACC3 as well as altered FGFR3 signalling.
Highlights
Gene fusions are the result of structural chromosomal rearrangements and are considered driver mutations in cancer [1]
Bladder cancer is mainly associated with an activating point mutation in fibroblast growth factor receptor 3 (FGFR3) which has been found in more than 80% of cases of low-grade tumours; an FGF3 –transforming acidic coiled-coil containing protein 3 (FGFR3– TACC3; FT3) fusion gene has recently been identified in bladder cancer [3]
We found that FT3 does not localize to the mitotic spindle or centrosomes and is instead found in vesicular structures expected of a transmembrane protein
Summary
Gene fusions are the result of structural chromosomal rearrangements and are considered driver mutations in cancer [1]. Bladder cancer is mainly associated with an activating point mutation in fibroblast growth factor receptor 3 (FGFR3) which has been found in more than 80% of cases of low-grade tumours; an FGF3 –transforming acidic coiled-coil containing protein 3 (FGFR3– TACC3; FT3) fusion gene has recently been identified in bladder cancer [3]. FGFR is activated by FGF-heparin binding to monomeric FGFRs, resulting in dimerization and transphosphorylation in the cytoplasmic tyrosine kinase domain. This event leads to activation of several downstream signalling pathways including MAPK [6]. Aberrant activation of FGFR signalling has been implicated in cell proliferation and tumourigenesis [6]
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