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Expression of aberrantly spliced BRAF V600E isoforms (BRAF V600E ΔEx) mediates resistance in 13%-30% of melanoma patients progressing on RAF inhibitors. BRAF V600E ΔEx confers resistance, in part, through enhanced dimerization. Here, we uncoupled BRAF V600E ΔEx dimerization from maintenance of MEK-ERK1/2 signaling. Furthermore, we show BRAF V600E ΔEx association with its substrate, MEK, is enhanced and required for RAF inhibitor resistance. RAF inhibitor treatment increased phosphorylation at serine 729 (S729) in BRAF V600E ΔEx. Mutation of S729 to a non-phosphorylatable residue reduced BRAF V600E ΔEx-MEK interaction, reduced dimerization or oligomerization, and increased RAF inhibitor sensitivity. Conversely, mutation of the BRAF dimerization domain elicited partial effects on MEK association and RAF inhibitor sensitivity. Our data implicate BRAF S729 in resistance to RAF inhibitor and underscore the importance of substrate association with BRAF V600E ΔEx. These findings may provide opportunities to target resistance driven by aberrantly spliced forms of BRAF V600E.
Pubmed ID: 30404005 RIS Download
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This polyclonal targets MEK1
View all literature mentionsThis monoclonal targets Hsp90aa1
View all literature mentionsThis polyclonal targets A-Raf (C-20)
View all literature mentionsThis monoclonal targets ERK 2 (D-2)
View all literature mentionsThis polyclonal targets Phospho-MEK1/2 (Ser217/221)
View all literature mentionsThis polyclonal targets Erk1/2
View all literature mentionsThis monoclonal targets Myc-Tag
View all literature mentionsThis polyclonal targets DYKDDDK
View all literature mentionsThis polyclonal targets Phospho-Acetyl-CoA Carboxylase (Ser79)
View all literature mentionsThis polyclonal targets Fra-1 (R-20)
View all literature mentionsThis monoclonal targets MEK1
View all literature mentionsThis unknown targets ANTI-FLAG(R) M2 Affinity Gel
View all literature mentionsThis unknown targets Protein A/G PLUS-Agarose
View all literature mentionsThis polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis polyclonal targets MEK1/2
View all literature mentionsThis monoclonal targets Raf-B (F-7)
View all literature mentionsThis polyclonal targets 14-3-3 (pan)
View all literature mentionsThis monoclonal targets beta-Actin
View all literature mentionsThis monoclonal targets ImmunogenSynthetic peptide representing the BRAF V600E mutated amino acid sequence from amino acid 596 to 606 (GLATEKSRWSG)
View all literature mentionsThis monoclonal targets B Raf (phospho S729) antibody [EPR2207]
View all literature mentionsMus musculus with name J:NU from IMSR.
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line A375-P is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsMus musculus with name J:NU from IMSR.
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line A375-P is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis polyclonal targets Erk1/2
View all literature mentionsThis unknown targets ANTI-FLAG(R) M2 Affinity Gel
View all literature mentionsThis polyclonal targets Phospho-MEK1/2 (Ser217/221)
View all literature mentionsThis polyclonal targets Phospho-Acetyl-CoA Carboxylase (Ser79)
View all literature mentionsThis unknown targets Protein A/G PLUS-Agarose
View all literature mentionsThis monoclonal targets B Raf (phospho S729) antibody [EPR2207]
View all literature mentionsMus musculus with name J:NU from IMSR.
View all literature mentionsThis monoclonal targets B Raf (phospho S729) antibody [EPR2207]
View all literature mentionsThis monoclonal targets Raf-B (F-7)
View all literature mentionsThis polyclonal targets MEK1/2
View all literature mentionsThis monoclonal targets MEK1
View all literature mentionsThis monoclonal targets Myc-Tag
View all literature mentionsThis polyclonal targets MEK1
View all literature mentionsThis monoclonal targets Hsp90aa1
View all literature mentionsThis polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis polyclonal targets 14-3-3 (pan)
View all literature mentionsThis polyclonal targets DYKDDDK
View all literature mentionsThis monoclonal targets ERK 2 (D-2)
View all literature mentionsThis monoclonal targets ImmunogenSynthetic peptide representing the BRAF V600E mutated amino acid sequence from amino acid 596 to 606 (GLATEKSRWSG)
View all literature mentionsThis polyclonal targets Fra-1 (R-20)
View all literature mentionsThis polyclonal targets A-Raf (C-20)
View all literature mentionsThis unknown targets Protein A/G PLUS-Agarose
View all literature mentionsThis monoclonal targets beta-Actin
View all literature mentionsThis polyclonal targets Erk1/2
View all literature mentionsCell line A375-P is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis polyclonal targets Phospho-Acetyl-CoA Carboxylase (Ser79)
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis polyclonal targets Phospho-MEK1/2 (Ser217/221)
View all literature mentionsThis polyclonal targets 14-3-3 (pan)
View all literature mentionsThis monoclonal targets MEK1
View all literature mentionsThis polyclonal targets MEK1
View all literature mentionsThis polyclonal targets MEK1/2
View all literature mentionsThis monoclonal targets Myc-Tag
View all literature mentionsThis monoclonal targets Hsp90aa1
View all literature mentionsThis polyclonal targets Fra-1 (R-20)
View all literature mentionsThis polyclonal targets DYKDDDK
View all literature mentionsThis monoclonal targets ERK 2 (D-2)
View all literature mentionsThis polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis monoclonal targets ImmunogenSynthetic peptide representing the BRAF V600E mutated amino acid sequence from amino acid 596 to 606 (GLATEKSRWSG)
View all literature mentionsThis monoclonal targets Raf-B (F-7)
View all literature mentionsThis polyclonal targets A-Raf (C-20)
View all literature mentionsThis monoclonal targets beta-Actin
View all literature mentionsMus musculus with name J:NU from IMSR.
View all literature mentionsThis unknown targets ANTI-FLAG(R) M2 Affinity Gel
View all literature mentionsThe SciCrunch Infrastructure was developed as a cooperative data platform to be used by diverse communities in making data more FAIR.
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