The Ins and Outs of RAS Effector Complexes

Abstract

RAS oncogenes are among the most commonly mutated proteins in human cancers. They regulate a wide range of effector pathways that control cell proliferation, survival, differentiation, migration and metabolic status. Including aberrations in these pathways, RAS-dependent signaling is altered in more than half of human cancers. Targeting mutant RAS proteins and their downstream oncogenic signaling pathways has been elusive. However, recent results comprising detailed molecular studies, large scale omics studies and computational modeling have painted a new and more comprehensive portrait of RAS signaling that helps us to understand the intricacies of RAS, how its physiological and pathophysiological functions are regulated, and how we can target them. Here, we review these efforts particularly trying to relate the detailed mechanistic studies with global functional studies. We highlight the importance of computational modeling and data integration to derive an actionable understanding of RAS signaling that will allow us to design new mechanism-based therapies for RAS mutated cancers.

Interplay Between KRAS and LZTR1 Protein Turnover, Controlled by CUL3/LZTR1 E3 Ubiquitin Ligase, is Disrupted by KRAS Mutations

“…Labelling conditions were optimised and levels of protein biotinylation assessed in whole cell lysates as well as streptavidin eluate material to control for consistency (Fig 1D). Previous proteomics-based studies exploring the KRAS "proximitome", based on BioID, revealed many shared proteins between WT & mutant KRAS (mainly G12V, S17N, C185S), predominantly involved in protein expression and trafficking (Kiel et al, 2021;Li et al, 2012;Matallanas et al, 2003). Additionally, there appears to be a large overlap between GTP/GDP KRAS interactors (proteins in closed proximity), indicating a more gradual KRAS activation transition rather than being an on/off switch.…”

“…First, KRAS interacting partners were divided into several categories including receptors, activators, repressors, interactors and canonical RAS effectors proteins (Kiel et al, 2021). Additionally, to "benchmark" our results, the BioGRID (https://thebiogrid.org/) database was used to retrieve the previously known KRAS 'proximitome' ( Adhikari and Counter, 2018;Bigenzahn et al, 2018).…”

The Crossroads between RAS and RHO Signaling Pathways in Cellular Transformation, Motility and Contraction

“…In the GTP-bound form, Ras switches into a conformation where it can bind and activate effector proteins, building different signaling networks at the membrane of cells, bridging extracellular cues into cellular events that regulate almost any aspect of cellular physiology, such as cell growth, proliferation, differentiation, and survival, having a decisive role in the acquisition of an oncogenic phenotype by healthy cells [9]. Activating mutations in Ras proteins diminishes their ability to hydrolyze the bound GTP to GDP, thus rendering it constitutively active even in the absence of receptor engagement.…”

Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling

“…RAS proteins often have been described as molecular switches that cycle between GDP-bound off and GTP-bound on states. When switched on by the (normally receptor-induced) exchange of GDP versus GTP, they can bind to an array of >20 different types of effector proteins which mediate the downstream biochemical and biological effects of RAS [2,3]. Oncogenic mutations keep RAS proteins in the GTP bound state resulting in the constitutive activation of pathways that stimulate cell proliferation, survival, invasiveness and drug resistance.…”