FGFR3–TACC3 cancer gene fusions cause mitotic defects by removal of endogenous TACC3 from the mitotic spindle

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.

Oncogenic driver FGFR3-TACC3 is dependent on membrane trafficking and ERK signaling

“…During interphase, the FGFR3-TACC3 fusion appears in vesicle-like structures, which is expected for a transmembrane protein and consistent with previous reports (Figure 1D ) [ 18 ]. However, the addition of the TACC3 domain does alter cellular localization, as FGFR3 WT displays both cytoplasmic and plasma membrane (PM) localization (Figure 1D ).…”

“…The presence of the C-terminal coiled-coil domain of TACC3 in the FGFR3-TACC3 fusion protein has been shown to be responsible for the localization of FGFR3-TACC3 to the nucleus and to mitotic spindle poles [ 7 , 17 ]. FGFR3-TACC3 has been reported to increase the rate of aneuploidy and chromosomal separation errors, due to the presence of FGFR3-TACC3 at the mitotic spindle and the absence of TACC3 WT (wild-type) at spindle microtubules [ 17 , 18 ]. These data suggest that a nuclear-localized FGFR3-TACC3 could significantly accelerate cancer progression.…”

“…However, the addition of the TACC3 domain does alter cellular localization, as FGFR3 WT displays both cytoplasmic and plasma membrane (PM) localization (Figure 1D ). While the presence of FGFR3-TACC3 may contribute to mitotic chromosomal segregation errors and aneuploidy [ 17 , 18 ], this may not be the initial oncogenic driver of cellular proliferation as reflected in focus formation.…”

“…It has been demonstrated that the involvement of TACC3 in the fusion protein FGFR3-TACC3 leads to an increased rate of aneuploidy and severe mitotic defects. Localization of FGFR3-TACC3 to the centrosome and mitotic spindle leads to chromosomal segregation errors and a reduction of TACC3 presence at the mitotic spindle [ 17 , 18 ]. FGFR3-TACC3 has also been found to co-localize with phospho-PIN4 to induce peroxisome biogenesis and protein synthesis [ 19 ].…”

Abelson-induced phosphorylation of TACC3 modulates its interaction with microtubules and affects its impact on axon outgrowth and guidance

“…Moreover, TACC3 in association with ch-TOG has been shown to localize to the mitotic spindles (Lee et al, 2001). However, the FGFR3-TACC3 fusion, which pulls TACC3 away from mitotic spindles and localizes to the spindle poles, causes mitotic defect,s which might explain the involvement of these proteins in tumor formation (Sarkar et al, 2017). From this perspective, it might be intriguing to investigate TACC domain tyrosine residues and TACC association with microtubules during cell division.…”