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Oncogenic Potential of Fibroblast Growth Factor Receptor Translocations

  • Author(s): Nelson, Katelyn
  • Advisor(s): Donoghue, Daniel J
  • et al.
Abstract

Fibroblast Growth Factor Receptors (FGFRs) are critical for cell proliferation and differentiation. Mutation and/or translocation of FGFRs lead to aberrant signaling that often results in developmental syndromes or cancer growth. As sequencing of human tumors becomes more frequent, so does the emergence of FGFR translocations and fusion proteins. The research conducted in this work will focus on a frequently identified fusion protein between FGFR3 and transforming acidic coiled-coil containing protein 3 (TACC3). Through titanium dioxide-based phosphopeptide enrichment (TiO2)-liquid chromatography (LC)-high mass accuracy tandem mass spectrometry (MS/MS), it is apparent that the fused coiled-coil TACC3 domain results in constitutive phosphorylation of key activating FGFR3 tyrosine residues. Fusion of FGFR3 and TACC3 also results in MAPK pathway activation, nuclear localization, and cell transformation. Introduction of K508R FGFR3 kinase dead mutation abrogates these effects, except for nuclear localization which is due solely to the TACC3 domain. FGFR3-TACC3 also produces IL-3 independent growth and cell proliferation. Taken together, these results suggest that FGFR3 kinase activity is essential for the oncogenic effects of the FGFR3-TACC3 fusion protein and could serve as a therapeutic target.

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