title: Oncogenic Gene Fusion FGFR3-TACC3 Is Regulated by Tyrosine Phosphorylation.
abstract: Fibroblast growth factor receptors (FGFR) 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 detection of FGFR translocations and fusion proteins. The research conducted in this article examines a frequently identified fusion protein between FGFR3 and transforming acidic coiled-coil containing protein 3 (TACC3), frequently identified in glioblastoma, lung cancer, bladder cancer, oral cancer, head and neck squamous cell carcinoma, gallbladder cancer, and cervical cancer. Using titanium dioxide-based phosphopeptide enrichment (TiO2)-liquid chromatography (LC)-high mass accuracy tandem mass spectrometry (MS/MS), it was demonstrated that the fused coiled-coil TACC3 domain results in constitutive phosphorylation of key activating FGFR3 tyrosine residues. The presence of the TACC coiled-coil domain leads to increased and altered levels of FGFR3 activation, fusion protein phosphorylation, MAPK pathway activation, nuclear localization, cellular transformation, and IL3-independent proliferation. Introduction of K508R FGFR3 kinase-dead mutation abrogates these effects, except for nuclear localization which is due solely to the TACC3 domain.
  
  
  
  These results demonstrate that FGFR3 kinase activity is essential for the oncogenic effects of the FGFR3-TACC3 fusion protein and could serve as a therapeutic target, but that phosphorylated tyrosine residues within the TACC3-derived portion are not critical for activity. Mol Cancer Res; 14(5); 458-69. ©2016 AACR.
authors: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California.
authors: Katelyn N
authors: KN
authors: Nelson
authors: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California.
authors: April N
authors: AN
authors: Meyer
authors: Université Joseph Fourier Grenoble, Grenoble, France.
authors: Asma
authors: A
authors: Siari
authors: Proteomics Facility, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors: Alexandre R
authors: AR
authors: Campos
authors: Proteomics Facility, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
authors: Khatereh
authors: K
authors: Motamedchaboki
authors: Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, California. Moores UCSD Cancer Center, University of California San Diego, La Jolla, California. ddonoghue@ucsd.edu.
authors: Daniel J
authors: DJ
authors: Donoghue
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002853:Chromatography, Liquid; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D000072417:Protein Domains; D040901:Proteomics / Q000379:methods*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism*; D053719:Tandem Mass Spectrometry; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D008869:Microtubule-Associated Proteins; D015514:Oncogene Proteins, Fusion; C120551:TACC3 protein, human; D014443:Tyrosine; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3