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

Ana Herrero,Piero Crespo

doi:10.3390/genes12101556

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.

Highlights

The RAS-ERK pathway encompasses a series of biochemical processes whereby signals are relayed from the plasma membrane to the interior of the cell in response to stimulation.Its main participants are classed as four types of proteins: the RAS family of small GTPases, and the kinases included in a three-tier module made up of RAF family serine/threonine kinases, MEK dual-specificity kinases, and extracellular signal-regulated ERK1/2 MAP kinases
This study indicated that to form a dimer, a RAS monomer is slightly shifted with respect to its partner, forming a salt bridge between residues D154 and R161, and a second stabilizing, fluctuating interaction between residues E49 and H131
It has been suggested that RAS dimerization and clustering reduce its mobility and diffusion through the plasma membrane [76], partly as a consequence of dimerized/activated RAS recruiting other proteins such as effectors, regulators, and scaffold proteins, thereby increasing the molecular size of the activated complex, something that may even impact the mode in which RAS anchors to the membrane

Summary

Introduction

The RAS-ERK pathway encompasses a series of biochemical processes whereby signals are relayed from the plasma membrane to the interior of the cell in response to stimulation. RAF dimerizes through its catalytic such a processthat underlies the acquisition of resistance to BRAFdomain, kinase inhibitors in tumors harboring wild-type BRAF [31,32].residues. At this moment, newimpede generations of compounds forming “side to side” dimers, and mutations in critical therein. MEK1 and MEK2 can heterodimerize, and in so doing contribute to the tumors harboring wild-type BRAF [31,32] At this moment, new generations of comduration and intensity of MEK and ERK activity [37]. Data gathered over the past decade suggest that this may be the case for RAS

RAS Dimerization: A Biography

RAS Dimers’ Functional and Regulatory Interactions

RAS Dimers in Cancer

Conclusions and is stabilized