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Distinct requirement for an intact dimer interface in wild-type, V600E and kinase-dead B-Raf signalling

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Fiala,  Gina J.
Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Schamel,  Wolfgang W.
Research Group and Chair of Molecular Immunology of the University of Freiburg, Max Planck Institute of Immunobiology and Epigenetics, Max Planck Society;

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Citation

Röring, M., Herr, R., Fiala, G. J., Heilmann, K., Braun, S., Eisenhardt, A. E., et al. (2012). Distinct requirement for an intact dimer interface in wild-type, V600E and kinase-dead B-Raf signalling. The EMBO Journal, 31, 2629-2647.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002B-8D58-9
Abstract
The dimerisation of Raf kinases involves a central cluster within the kinase domain, the dimer interface (DIF). Yet, the importance of the DIF for the signalling potential of wild-type B-Raf (B-Rafwt) and its oncogenic counterparts remains unknown. Here, we show that the DIF plays a pivotal role for the activity of B-Rafwt and several of its gain-of-function (g-o-f) mutants. In contrast, the B-RafV600E, B-RafinsT and B-RafG469A oncoproteins are remarkably resistant to mutations in the DIF. However, compared with B-Rafwt, B-RafV600E displays extended protomer contacts, increased homodimerisation and incorporation into larger protein complexes. In contrast, B-Rafwt and Raf-1wt mediated signalling triggered by oncogenic Ras as well as the paradoxical activation of Raf-1 by kinase-inactivated B-Raf require an intact DIF. Surprisingly, the B-Raf DIF is not required for dimerisation between Raf-1 and B-Raf, which was inactivated by the D594A mutation, sorafenib or PLX4720. This suggests that paradoxical MEK/ERK activation represents a two-step mechanism consisting of dimerisation and DIF-dependent transactivation. Our data further implicate the Raf DIF as a potential target against Ras-driven Raf-mediated (paradoxical) ERK activation.