| First Author | Röring M | Year | 2012 |
| Journal | EMBO J | Volume | 31 |
| Issue | 11 | Pages | 2629-47 |
| PubMed ID | 22510884 | Mgi Jnum | J:184683 |
| Mgi Id | MGI:5426077 | Doi | 10.1038/emboj.2012.100 |
| Citation | Roring M, et al. (2012) Distinct requirement for an intact dimer interface in wild-type, V600E and kinase-dead B-Raf signalling. EMBO J 31(11):2629-47 |
| abstractText | 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-1(wt) 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. |
