Discrete cytosolic macromolecular BRAF complexes exhibit distinct activities and composition
- Diedrich, Britta Department of Dermatology, Medical Center ‐ University of Freiburg, Germany - ZBSA Center for Biological Systems Analysis, University of Freiburg, Germany
- Rigbolt, Kristoffer TG Department of Dermatology, Medical Center ‐ University of Freiburg, Germany - ZBSA Center for Biological Systems Analysis, University of Freiburg, Germany - Gubra, Hørsholm, Denmark
- Röring, Michael Faculty of Medicine, Institute of Molecular Medicine and Cell Research (IMMZ), University of Freiburg, Germany
- Herr, Ricarda Faculty of Medicine, Institute of Molecular Medicine and Cell Research (IMMZ), University of Freiburg, Germany
- Kaeser-Pebernard, Stéphanie Department of Biology, University of Fribourg, Switzerland
- Gretzmeier, Christine Department of Dermatology, Medical Center ‐ University of Freiburg, Germany - ZBSA Center for Biological Systems Analysis, University of Freiburg, Germany - Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Germany
- Murphy, Robert F Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Germany - Computational Biology Department and Department of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA, USA
- Brummer, Tilman ZBSA Center for Biological Systems Analysis, University of Freiburg, Germany - Faculty of Medicine, Institute of Molecular Medicine and Cell Research (IMMZ), University of Freiburg, Germany - Centre for Biological Signalling Studies BIOSS, University of Freiburg, Germany - Comprehensive Cancer Centre, Freiburg, Germany - German Cancer Consortium (DKTK), partner site Freiburg, and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Dengjel, Jörn Department of Dermatology, Medical Center ‐ University of Freiburg, Germany - ZBSA Center for Biological Systems Analysis, University of Freiburg, Germany - Department of Biology, University of Fribourg, Switzerland - Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Germany - Centre for Biological Signalling Studies BIOSS, University of Freiburg, Germany
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01.03.2017
Published in:
- The EMBO Journal. - 2017, vol. 36, no. 5, p. 646–663
English
As a central element within the RAS/ERK pathway, the serine/threonine kinase BRAF plays a key role in development and homeostasis and represents the most frequently mutated kinase in tumors. Consequently, it has emerged as an important therapeutic target in various malignancies. Nevertheless, the BRAF activation cycle still raises many mechanistic questions as illustrated by the paradoxical action and side effects of RAF inhibitors. By applying SEC‐PCP‐SILAC, we analyzed protein–protein interactions of hyperactive BRAFV600E and wild‐type BRAF (BRAFWT). We identified two macromolecular, cytosolic BRAF complexes of distinct molecular composition and phosphorylation status. Hyperactive BRAFV600E resides in large complexes of higher molecular mass and activity, while BRAFWT is confined to smaller, slightly less active complexes. However, expression of oncogenic K‐RasG12V, either by itself or in combination with RAF dimer promoting inhibitors, induces the incorporation of BRAFWT into large, active complexes, whereas pharmacological inhibition of BRAFV600E has the opposite effect. Thus, the quaternary structure of BRAF complexes is shaped by its activation status, the conformation of its kinase domain, and clinically relevant inhibitors.
- Faculty
- Faculté des sciences et de médecine
- Department
- Département de Biologie
- Language
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- English
- Classification
- Biological sciences
- License
- License undefined
- Identifiers
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- RERO DOC 288523
- DOI 10.15252/embj.201694732
- Persistent URL
- https://folia.unifr.ch/unifr/documents/305355
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