RAS Dimers: The Novice Couple at the RAS-ERK Pathway Ball

Abstract

Signals conveyed through the RAS-ERK pathway constitute a pivotal regulatory element in cancer-related cellular processes. Recently, RAS dimerization has been proposed as a key step in the relay of RAS signals, critically contributing to RAF activation. RAS clustering at plasma membrane microdomains and endomembranes facilitates RAS dimerization in response to stimulation, promoting RAF dimerization and subsequent activation. Remarkably, inhibiting RAS dimerization forestalls tumorigenesis in cellular and animal models. Thus, the pharmacological disruption of RAS dimers has emerged as an additional target for cancer researchers in the quest for a means to curtail aberrant RAS activity.

Keywords: RAS; RAS signaling; cancer; dimerization.

Figure 1

Schematic representation of the RAS structure. β-sheets (yellow) and α-helices (orange) are schematically shown in a linear representation of the RAS structure. Key RAS amino acids and regions involved in RAS oncogenicity (G12 and Q61) and dimerization (E49, H131, D154, and R161) are highlighted.

Figure 2

Representation of the RAS dimerization interface. β-sheets (yellow) and α-helices (orange) are schematically shown in a linear representation of the RAS structure. The dimerization interface of RAS dimers, comprising the α4 and α5 helices’ interaction, is represented, and the critical amino acids H131, E49, D154, and R161 (blue, yellow, green, and orange circles, respectively), involved in the interaction between two RAS protomers, are shown. The allosteric and effector lobes within the G-domain are highlighted, as well as the GEFs, GAPs, and effector binding sites (green squares).

Figure 3

RAS-ERK pathway activation overview. The RAS-GDP monomer is bound to the membrane. Once the guanine nucleotide is changed to GTP and thereby activated, RAS-GTP dimerizes and is stabilized. The RAS dimers interact with RAF, facilitating its dimerization and consequent activation.