Structure of the BRAF-MEK Complex Reveals a Kinase Activity Independent Role for BRAF in MAPK Signaling
| Autor: | Wendy Sandoval, Barbara J. Brandhuber, Brandon J. Bravo, Wilson Phung, Sarah G. Hymowitz, Steve Sideris, Darin Smith, Alexandre Masselot, Jacob R. Haling, Tony Morales, Shiva Malek, Ivana Yen, Ariana Peck, Anthony M. Giannetti, Jawahar Sudhamsu |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
MAPK/ERK pathway
Models Molecular Proto-Oncogene Proteins B-raf Cancer Research endocrine system diseases MAP Kinase Kinase 1 Mutation Missense Biology medicine.disease_cause Crystallography X-Ray Protein Structure Secondary Proto-Oncogene Proteins p21(ras) Catalytic Domain Proto-Oncogene Proteins medicine Humans Point Mutation Kinase activity skin and connective tissue diseases Protein Structure Quaternary neoplasms Mutation Point mutation Cell Biology HCT116 Cells digestive system diseases enzymes and coenzymes (carbohydrates) HEK293 Cells Protein kinase domain Oncology Cancer research ras Proteins Phosphorylation KRAS Signal transduction Signal Transduction |
| Zdroj: | Cancer Cell. 26(3):402-413 |
| ISSN: | 1535-6108 |
| DOI: | 10.1016/j.ccr.2014.07.007 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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