Baljuls Angela, Dobrzyński Maciej, Rauch Jens, Rauch Nora, Kolch Walter
Systems Biology Ireland, University College Dublin, Dublin 4, Ireland; Boehringer-Ingelheim Pharma, Birkendorfer Strasse 65, 88400 Biberach an der Riss, Germany.
Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
Cell Signal. 2016 Oct;28(10):1451-62. doi: 10.1016/j.cellsig.2016.06.019. Epub 2016 Jun 29.
RAF family kinases are central components of the Ras-RAF-MEK-ERK cascade. Dimerization is a key mechanism of RAF activation in response to physiological, pathological and pharmacological signals. It is mediated by a dimer interface region in the RAF kinase domain that is also conserved in KSR, a scaffolding protein that binds RAF, MEK and ERK. The regulation of RAF dimerization is incompletely understood. Especially little is known about the molecular mechanism involved in the selection of the dimerization partner. Previously, we reported that Ras-dependent binding of the tumour suppressor DiRas3 to C-RAF inhibits the C-RAF:B-RAF heterodimerization. Here we show that DiRas3 binds to KSR1 independently of its interaction with activated Ras and RAF. Our data also suggest that depending on the local stoichiometry between DiRas3 and oncogenic Ras, DiRas3 can either enhance homodimerization of KSR1 or recruit KSR1 to the Ras:C-RAF complex and thereby reduce the availability of C-RAF for binding to B-RAF. This mechanism, which is shared between A-RAF and C-RAF, may be involved in the regulation of Ras12V-induced cell transformation by DiRas3.
RAF家族激酶是Ras-RAF-MEK-ERK级联反应的核心组成部分。二聚化是RAF响应生理、病理和药理信号而激活的关键机制。它由RAF激酶结构域中的二聚体界面区域介导，该区域在KSR中也保守，KSR是一种结合RAF、MEK和ERK的支架蛋白。RAF二聚化的调控尚未完全了解。特别是关于二聚化伙伴选择所涉及的分子机制知之甚少。此前，我们报道肿瘤抑制因子DiRas3与C-RAF的Ras依赖性结合会抑制C-RAF:B-RAF异二聚化。在此我们表明，DiRas3独立于其与活化Ras和RAF的相互作用而与KSR1结合。我们的数据还表明，根据DiRas3与致癌Ras之间的局部化学计量，DiRas3既可以增强KSR1的同二聚化，也可以将KSR1募集到Ras:C-RAF复合物中，从而降低C-RAF与B-RAF结合的可用性。这种在A-RAF和C-RAF之间共享的机制可能参与了DiRas3对Ras12V诱导的细胞转化的调控。
