RAS Nanoclusters: Dynamic Signaling Platforms Amenable to Therapeutic Intervention

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.

Crystal Structure Reveals the Full Ras–Raf Interface and Advances Mechanistic Understanding of Raf Activation

“…We recognize that the specific interface through which Ras dimerizes has not yet been unequivocally determined [64]. However, both the HRas-CRaf-RBD (PDB ID 4G0N) and the KRas-CRaf-RBD_CRD (PDB ID 6XI7) dimer structures with the α4-α5 Ras dimer interface, as well as the many studies supporting Ras dimerization through this interface [8,9,50,51,71], point to our proposed model for the dimer.…”

“…Ras nanoclustering on the membrane modulates Ras activation of MAPK signaling, but the significance of Ras dimers as functional signaling units is still not fully resolved in the literature [64]. Weak binding is predicted for Ras dimers in the absence of other factors [25,[64][65][66][67], putting in question its viability as a robust signaling unit.…”

“…Ras nanoclustering on the membrane modulates Ras activation of MAPK signaling, but the significance of Ras dimers as functional signaling units is still not fully resolved in the literature [64]. Weak binding is predicted for Ras dimers in the absence of other factors [25,[64][65][66][67], putting in question its viability as a robust signaling unit. However, we have recently shown that Raf-RBD promotes robust dimerization of Ras on supported lipid bilayers even at very low surface densities, in contrast with Ras in the absence of Raf-RBD, for which no dimers can be detected [8,68].…”

Crosstalk between KRAS, SRC and YAP Signaling in Pancreatic Cancer: Interactions Leading to Aggressive Disease and Drug Resistance

“…RAF dimerization is of critical importance in the mechanisms leading to drug resistance [46]. Collectively, these studies emphasize that RAS dimerization is a critical step in RAS signaling, though methodological inconsistencies also remain [47].…”

RAS Nanoclusters Selectively Sort Distinct Lipid Headgroups and Acyl Chains

“…However, there are conflicting reports on whether oligomerization involves direct protein-protein interaction or is primarily mediated by lipids. Moreover, there are multiple predicted RAS dimerization interfaces [e.g., (Güldenhaupt et al, 2012;Muratcioglu et al, 2015;Sayyed-Ahmad et al, 2016)], which have been discussed in detail in several recent review articles included in refs (Abankwa and Gorfe, 2021;Van et al, 2021). There is debate regarding which of these interfaces is most relevant for function.…”