当前位置： SCI文献检索 > ONCOGENE期刊下所有文献 > Identification and characterization of a BRAF fusion oncoprotein with retained autoinhibitory domains.

Identification and characterization of a BRAF fusion oncoprotein with retained autoinhibitory domains.

Abstract：

: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.

journal_name

Oncogene

journal_title

Oncogene

authors

Weinberg F,Griffin R,Fröhlich M,Heining C,Braun S,Spohr C,Iconomou M,Hollek V,Röring M,Horak P,Kreutzfeldt S,Warsow G,Hutter B,Uhrig S,Neumann O,Reuss D,Heiland DH,von Kalle C,Weichert W,Stenzinger A,Brors B,Gli

doi

10.1038/s41388-019-1021-1

subject

Has Abstract

pub_date

2020-01-01 00:00:00

pages

814-832

issue

eissn

0950-9232

issn

1476-5594

pii

10.1038/s41388-019-1021-1

journal_volume

pub_type

杂志文章

在线工具

Identification and characterization of a BRAF fusion oncoprotein with retained autoinhibitory domains.