Abstract
RAS proteins are mutated in approximately 20% of all cancers and are generally associated with poor clinical outcomes. RAS proteins are localized to the plasma membrane and function as molecular switches, turned on by partners that receive extracellular mitogenic signals. In the on-state, they activate intracellular signal transduction cascades. Membrane-bound RAS molecules segregate into multimers, known as nanoclusters. These nanoclusters, held together through weak protein–protein and protein–lipid associations, are highly dynamic and respond to cellular input signals and fluctuations in the local lipid environment. Disruption of RAS nanoclusters results in downregulation of RAS-mediated mitogenic signaling. In this review, we discuss the propensity of RAS proteins to display clustering behavior and the interfaces that are associated with these assemblies. Strategies to therapeutically disrupt nanocluster formation or the stabilization of signaling incompetent RAS complexes are discussed.
Highlights
RAS proteins are mutated in approximately 20% of all cancers and are generally associated with poor clinical outcomes
The recent revival in of RAS asnanoscale a therapeuticdomains target, coupled with the knowledge the membrane to smaller, where they cluster. that RAF dimerizes at the membrane [50], has led to an increase in studies investigating the nature of RAS dimers and multimers over the last few years (Figure 1), showing the existence of RAS dimers
To inherent experimental errors, a of RAS as a therapeutic target, coupled with the knowledge that RAF dimerizes at the membrane [50], has led to an increase in studies investigating the nature of RAS dimers and multimers over the last few years (Figure 1), showing the existence of RAS dimers and their role in modulating RAS signaling
Summary
The concept of RAS organization in nanoclusters on the plasma membrane is wellestablished. The spatial mapping of the state coordinates showed that the slow and intermediate diffusion states cluster within nested nanoscopic domains of 200 nm and 70 nm for the intermediate and slow states, respectively [21], further confirming that RAS is exploring a hierarchical membrane structure The formation of these states follows a nonequilibrium steady state where immobile KRAS molecules are endocytosed, and the endomembrane recycling system replenishes the fast-moving KRAS molecules. In contrast with these cell-based studies showing KRAS4b complex diffusion behavior, studies using a wide range of KRAS4b densities in synthetic membranes composed of cholesterol, unsaturated, saturated, and charged lipids showed that KRAS4b remained monomeric and did not display heterogeneous diffusional behavior [22]. On synthetic bilayers (Figure 4D) and computational simulations, researchers have shown that KRAS4b clusters are localized to Ld membrane regions enriched in anionic lipids such as phosphatidylserine [37,38,39,40,41] or inositol phosphate [42,43,44]
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