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

Katelyn N. Nelson,Clark G. Wang,April N. Meyer,Daniel J. Donoghue

doi:10.18632/oncotarget.26142

Katelyn N. Nelson, Clark G. Wang + Show 2 more

Open Access

https://doi.org/10.18632/oncotarget.26142

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Journal: Oncotarget	Publication Date: Sep 28, 2018
Citations: 25	License type: cc-by

Affiliation: University of California, San Diego

Abstract

Fusion proteins resulting from chromosomal translocations have been identified as oncogenic drivers in many cancers, allowing them to serve as potential drug targets in clinical practice. The genes encoding FGFRs, Fibroblast Growth Factor Receptors, are commonly involved in such translocations, with the FGFR3-TACC3 fusion protein frequently identified in many cancers, including glioblastoma, cervical cancer, bladder cancer, nasopharyngeal carcinoma, and lung adenocarcinoma among others. FGFR3-TACC3 retains the entire extracellular domain and most of the kinase domain of FGFR3, with its C-terminal domain fused to TACC3. We examine here the effects of targeting FGFR3-TACC3 to different subcellular localizations by appending either a nuclear localization signal (NLS) or a myristylation signal, or by deletion of the normal signal sequence. We demonstrate that the oncogenic effects of FGFR3-TACC3 require either entrance to the secretory pathway or plasma membrane localization, leading to overactivation of canonical MAPK/ERK pathways. We also examined the effects of different translocation breakpoints in FGFR3-TACC3, comparing fusion at TACC3 exon 11 with fusion at exon 8. Transformation resulting from FGFR3-TACC3 was not affected by association with the canonical TACC3-interacting proteins Aurora-A, clathrin, and ch-TOG. We have shown that kinase inhibitors for MEK (Trametinib) and FGFR (BGJ398) are effective in blocking cell transformation and MAPK pathway upregulation. The development of personalized medicines will be essential in treating patients who harbor oncogenic drivers such as FGFR3-TACC3.

Highlights

Oncogenic driver mutations have taken a front seat in the world of cancer research
NIH3T3 cells transfected with both the nuclear- and cytoplasmic-targeted populations of the fusion protein (NLS-fibroblast growth factor receptor 3 (FGFR3)-transforming acidic coiled-coil containing protein 3 (TACC3) and nuclear localization signal (NLS)*FGFR3-TACC3) did not produce any cell transformation, indicating that equal distribution between these two populations does not contribute to oncogenicity, as seen with another fusion protein NPM-ALK [25]
We have determined the cellular location of FGFR3TACC3 required to initiate cell transformation and overactivation of the canonical MAPK pathway

Summary

Introduction

Oncogenic driver mutations have taken a front seat in the world of cancer research. These mutations are often chromosomal rearrangements resulting in fusion proteins [1]. A recently identified fusion protein is FGFR3-TACC3, which has been discovered in glioblastoma, lung cancer, bladder cancer, oral cancer, head and neck squamous cell carcinoma, gallbladder cancer, and cervical cancer [2,3,4] This fusion protein is formed by tandem duplication on chromosome 4 resulting in a fusion of the fibroblast growth factor receptor 3 (FGFR3) gene with transforming acidic coiled-coil containing protein 3 (TACC3) gene [5]. FGFRs are activated by binding of fibroblast growth factor (FGF) ligands and heparin sulfate proteoglycans (HSPG) to the extracellular Ig-like domains [6] This induces FGFR dimerization and activation by trans-autophosphorylation of tyrosine residues in the kinase domain activation loop. In FGFR3-TACC3, the coiled-coil domain of TACC3 allows for autophosphorylation and activation of FGFR3 without the need for ligand binding [7]

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