Ras/Raf dimerization model for activation of Raf kinase

Our previously proposed Ras dimerization model is consistent with recent details observed by NMR in that Raf activation is centered on the Ras/Raf dimer, distinct from one in which Ras activates Raf as a monomer with the Raf cysteine rich domain inserted in the membrane. We review mechanistic understanding of Raf activation within nanoclusters of Ras on the membrane, with a shift to dimers upon binding Raf. This sets the stage for a signaling platform composed of Ras/Raf and Galectin dimers that facilitates the release of Raf autoinhibition and folding of the Raf intrinsically disordered region between the Ras-binding domains and the kinase bound to 14-3-3 and MEK. This platform could provide synchronized units for signal amplification and is consistent with a Ras stationary phase observed in cells.