Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF.
MetadataShow full item record
Over 30 mutations of the B-RAF gene associated with human cancers have been identified, the majority of which are located within the kinase domain. Here we show that of 22 B-RAF mutants analyzed, 18 have elevated kinase activity and signal to ERK in vivo. Surprisingly, three mutants have reduced kinase activity towards MEK in vitro but, by activating C-RAF in vivo, signal to ERK in cells. The structures of wild type and oncogenic V599EB-RAF kinase domains in complex with the RAF inhibitor BAY43-9006 show that the activation segment is held in an inactive conformation by association with the P loop. The clustering of most mutations to these two regions suggests that disruption of this interaction converts B-RAF into its active conformation. The high activity mutants signal to ERK by directly phosphorylating MEK, whereas the impaired activity mutants stimulate MEK by activating endogenous C-RAF, possibly via an allosteric or transphosphorylation mechanism.
Open access locationhttps://doi.org/10.1016/S0092-8674(04)00215-6
Version of record
Cancer Genome Project
NIH 3T3 Cells
Cell Transformation, Neoplastic
Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins c-raf
Mitogen-Activated Protein Kinase Kinases
MAP Kinase Kinase 1
Mitogen-Activated Protein Kinases
MAP Kinase Signaling System
Gene Expression Regulation, Enzymologic
Gene & Oncogene Targeting
License start date
Cell, 2004, 116 (6), pp. 855 - 867
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/
Showing items related by title, author, creator and subject.
D'Abaco, GM; Hooper, S; Paterson, H; Marshall, CJ (2002-12)The Ras GTPase is a critical transducer of mitogenic signals ultimately leading to inactivation of the retinoblastoma (Rb) protein, but the molecular basis underlying Ras-dependent control of cell cycle kinetics remains ...
Activation of either ERK1/2 or ERK5 MAP kinase pathways can lead to disruption of the actin cytoskeleton. Barros, JC; Marshall, CJ (2005-04)Oncogenic transformation often leads to the disruption of the actin cytoskeleton. Activation of the classical Ras-Raf-MEK1/2-ERK1/2 signalling cascade has been implicated in the effects of oncogenes such as Ras and Src on ...
Annibaldi, A; Wicky John, S; Vanden Berghe, T; Swatek, KN; Ruan, J; Liccardi, G; Bianchi, K; Elliott, PR; Choi, SM; Van Coillie, S; Bertin, J; Wu, H; Komander, D; Vandenabeele, P; Silke, J; Meier, P (2018-02-15)Tumor necrosis factor (TNF) can drive inflammation, cell survival, and death. While ubiquitylation-, phosphorylation-, and nuclear factor κB (NF-κB)-dependent checkpoints suppress the cytotoxic potential of TNF, it remains ...