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You are here: Home Current affairs Input Distinct requirement for an intact dimer interface in wild-type, V600E and kinase-dead B-Raf signalling.
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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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Roering M, Herr R, Fiala GJ, Heilmann K, Braun S, Eisenhardt AE, Halbach S, Capper D, von Deimling A, Schamel WW, Saunders DN, Brummer T; The EMBO Journal (2012) 31, 2629 - 2647

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-Raf wt) and its oncogenic counterparts remains unknown. Here, we show that the DIF plays a pivotal role for the activity of B-Raf wt and several of its gain-of-function (g-o-f) mutants. In contrast, the B-Raf V600E, B-Raf insT and B-Raf G469A oncoproteins are remarkably resistant to mutations in the DIF. However, compared with B-Raf wt, B-Raf V600E displays extended protomer contacts, increased homodimerisation and incorporation into larger protein complexes. In contrast, B-Raf wt 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.

PubMed

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