The K-, N-, and HRas small GTPases are key regulators of cell physiology and are
frequently mutated in human cancers. Despite intensive research, previous efforts to target hyperactive
Ras based on known mechanisms of Ras signaling have been met with little success. Several studies
have provided compelling evidence for the existence and biological relevance of Ras dimers,
establishing a new mechanism for regulating Ras activity in cells additionally to GTP-loading and
membrane localization. Existing data also start to reveal how Ras proteins dimerize on the membrane.
We propose a dimer model to describe Ras-mediated effector activation, which contrasts existing
models of Ras signaling as a monomer or as a 5-8 membered multimer. We also discuss potential implications of this
model in both basic and translational Ras biology.