2020
DOI: 10.1074/jbc.ra119.011536
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Analyses of the oncogenic BRAFD594G variant reveal a kinase-independent function of BRAF in activating MAPK signaling

Abstract: Class 3 mutations in B-Raf proto-oncogene, Ser/Thr kinase (BRAF), that result in kinase-impaired or kinase-dead BRAF have the highest mutation frequency in BRAF gene in lung adenocarcinoma. Several studies have reported that kinase-dead BRAF variants amplify mitogen-activated protein kinase (MAPK) signaling by dimerizing with and activating WT C-Raf proto-oncogene, Ser/Thr kinase (CRAF). However, the structural and functional principles underlying their activation remain elusive. Herein, using cell biology and… Show more

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Cited by 23 publications
(20 citation statements)
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“…Of note, some variants act as inactivating mutations but still give rise to overlapping patient outcomes ( Figure S1 ); this is consistent with previous studies that suggest these alleles can direct elevated pathway activity in a context-dependent fashion (e.g. ( Oishi et al., 2006 ; Pandit et al., 2007 ; Machado et al., 2017 ; Li et al., 2018 ; Cope et al., 2020 ; Lorca et al., 2020 ; Lu et al., 2020 )). Using standard transgenic technology ( Venken and Bellen, 2012 ), each transgene was inserted into the same genomic site to reduce expression differences due to insertion site.…”
Section: Resultssupporting
confidence: 89%
“…Of note, some variants act as inactivating mutations but still give rise to overlapping patient outcomes ( Figure S1 ); this is consistent with previous studies that suggest these alleles can direct elevated pathway activity in a context-dependent fashion (e.g. ( Oishi et al., 2006 ; Pandit et al., 2007 ; Machado et al., 2017 ; Li et al., 2018 ; Cope et al., 2020 ; Lorca et al., 2020 ; Lu et al., 2020 )). Using standard transgenic technology ( Venken and Bellen, 2012 ), each transgene was inserted into the same genomic site to reduce expression differences due to insertion site.…”
Section: Resultssupporting
confidence: 89%
“…One notable exception to these subgroup definitions is for the class 3 kinase-dead BRAF D594G variant, which does not confer similar actionability as the class 1 BRAF V600E despite its position nearby within Exon 15. 39 , 40 This distinction is important because these BRAF variants are considered RAS -dependent and enriched for co-occurrence with KRAS mutations. In the Clinical Cohort, all but two of the BRAF short variants identified in protein-coding regions outside of Exons 11 and 15 were found alongside a confounding driver (Fig 1 A).…”
Section: Resultsmentioning
confidence: 99%
“…[81]. In a subsequent study, Raf dimer breaker has been shown to be active against oncogenic B-Raf D594G :C-Raf dimers [82], thus providing further evidence that allosteric type IV inhibitors targeting the Raf dimer interface have potential to be developed as an anticancer drug.…”
Section: Raf Inhibitorsmentioning
confidence: 86%