Identification and characterization of a BRAF fusion oncoprotein with retained autoinhibitory domains
Fusion proteins involving the BRAF serine/threonine kinase occur in many cancers. The oncogenic potential of BRAF fusions has been attributed to the loss of critical N-terminal domains that mediate BRAF autoinhibition. We used whole-exome and RNA sequencing in a patient with glioblastoma multiforme...
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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
2020
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| In: |
Oncogene
Year: 2020, Jahrgang: 39, Heft: 4, Pages: 814-832 |
| ISSN: | 1476-5594 |
| DOI: | 10.1038/s41388-019-1021-1 |
| Online-Zugang: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41388-019-1021-1 Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41388-019-1021-1 
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| Verfasserangaben: | Florian Weinberg, Ricarda Griffin, Martina Fröhlich, Christoph Heining, Sandra Braun, Corinna Spohr, Mary Iconomou, Viola Hollek, Michael Röring, Peter Horak, Simon Kreutzfeldt, Gregor Warsow, Barbara Hutter, Sebastian Uhrig, Olaf Neumann, David Reuss, Dieter Henrik Heiland, Christof von Kalle, Wilko Weichert, Albrecht Stenzinger, Benedikt Brors, Hanno Glimm, Stefan Fröhling, Tilman Brummer |
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| 245 | 1 | 0 | |a Identification and characterization of a BRAF fusion oncoprotein with retained autoinhibitory domains |c Florian Weinberg, Ricarda Griffin, Martina Fröhlich, Christoph Heining, Sandra Braun, Corinna Spohr, Mary Iconomou, Viola Hollek, Michael Röring, Peter Horak, Simon Kreutzfeldt, Gregor Warsow, Barbara Hutter, Sebastian Uhrig, Olaf Neumann, David Reuss, Dieter Henrik Heiland, Christof von Kalle, Wilko Weichert, Albrecht Stenzinger, Benedikt Brors, Hanno Glimm, Stefan Fröhling, Tilman Brummer |
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| 520 | |a Fusion proteins involving the BRAF serine/threonine kinase occur in many cancers. The oncogenic potential of BRAF fusions has been attributed to the loss of critical N-terminal domains that mediate BRAF autoinhibition. We used whole-exome and RNA sequencing in a patient with glioblastoma multiforme to identify a rearrangement between TTYH3, encoding a membrane-resident, calcium-activated chloride channel, and BRAF intron 1, resulting in a TTYH3-BRAF fusion protein that retained all features essential for BRAF autoinhibition. Accordingly, the BRAF moiety of the fusion protein alone, which represents full-length BRAF without the amino acids encoded by exon 1 (BRAFΔE1), did not induce MEK/ERK phosphorylation or transformation. Likewise, neither the TTYH3 moiety of the fusion protein nor full-length TTYH3 provoked ERK pathway activity or transformation. In contrast, TTYH3-BRAF displayed increased MEK phosphorylation potential and transforming activity, which were caused by TTYH3-mediated tethering of near-full-length BRAF to the (endo)membrane system. Consistent with this mechanism, a synthetic approach, in which BRAFΔE1 was tethered to the membrane by fusing it to the cytoplasmic tail of CD8 also induced transformation. Furthermore, we demonstrate that TTYH3-BRAF signals largely independent of a functional RAS binding domain, but requires an intact BRAF dimer interface and activation loop phosphorylation sites. Cells expressing TTYH3-BRAF exhibited increased MEK/ERK signaling, which was blocked by clinically achievable concentrations of sorafenib, trametinib, and the paradox breaker PLX8394. These data provide the first example of a fully autoinhibited BRAF protein whose oncogenic potential is dictated by a distinct fusion partner and not by a structural change in BRAF itself. | ||
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