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Structure of the BRAF-MEK complex reveals a kinase activity independent role for BRAF in MAPK signaling.
- Source :
-
Cancer cell [Cancer Cell] 2014 Sep 08; Vol. 26 (3), pp. 402-413. Date of Electronic Publication: 2014 Aug 21. - Publication Year :
- 2014
-
Abstract
- Numerous oncogenic mutations occur within the BRAF kinase domain (BRAF(KD)). Here we show that stable BRAF-MEK1 complexes are enriched in BRAF(WT) and KRAS mutant (MT) cells but not in BRAF(MT) cells. The crystal structure of the BRAF(KD) in a complex with MEK1 reveals a face-to-face dimer sensitive to MEK1 phosphorylation but insensitive to BRAF dimerization. Structure-guided studies reveal that oncogenic BRAF mutations function by bypassing the requirement for BRAF dimerization for activity or weakening the interaction with MEK1. Finally, we show that conformation-specific BRAF inhibitors can sequester a dormant BRAF-MEK1 complex resulting in pathway inhibition. Taken together, these findings reveal a regulatory role for BRAF in the MAPK pathway independent of its kinase activity but dependent on interaction with MEK.<br /> (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Subjects :
- Catalytic Domain
Crystallography, X-Ray
HCT116 Cells
HEK293 Cells
Humans
MAP Kinase Kinase 1 genetics
MAP Kinase Kinase 1 metabolism
Models, Molecular
Mutation, Missense
Point Mutation
Protein Structure, Quaternary
Protein Structure, Secondary
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins B-raf genetics
Proto-Oncogene Proteins B-raf metabolism
Proto-Oncogene Proteins p21(ras)
Signal Transduction
ras Proteins genetics
MAP Kinase Kinase 1 chemistry
Proto-Oncogene Proteins B-raf chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1878-3686
- Volume :
- 26
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cancer cell
- Publication Type :
- Academic Journal
- Accession number :
- 25155755
- Full Text :
- https://doi.org/10.1016/j.ccr.2014.07.007