Abstract
The lipid-anchored RAS (Rat sarcoma) small GTPases (guanosine triphosphate hydrolases) are highly prevalent in human cancer. Traditional strategies of targeting the enzymatic activities of RAS have been shown to be difficult. Alternatively, RAS function and pathology are mostly restricted to nanoclusters on the plasma membrane (PM). Lipids are important structural components of these signaling platforms on the PM. However, how RAS nanoclusters selectively enrich distinct lipids in the PM, how different lipids contribute to RAS signaling and oncogenesis and whether the selective lipid sorting of RAS nanoclusters can be targeted have not been well-understood. Latest advances in quantitative super-resolution imaging and molecular dynamic simulations have allowed detailed characterization RAS/lipid interactions. In this review, we discuss the latest findings on the select lipid composition (with headgroup and acyl chain specificities) within RAS nanoclusters, the specific mechanisms for the select lipid sorting of RAS nanoclusters on the PM and how perturbing lipid compositions within RAS nanoclusters impacts RAS function and pathology. We also describe different strategies of manipulating lipid composition within RAS nanoclusters on the PM.
Highlights
The restrictive nature of RAS biological activities to the plasma membrane (PM) implies that RAS function and pathology can be very sensitive to changing PM properties
Consistent in electronelectron microscopy (EM)-univariate nanoclustering analyses on intact PM sheets, Raster image correlation spectroscopy in live cells, whole cells grown on arrays of nano-fabricated nanobars, fluorescence lifetime imaging combined with fluorescence resonance energy transfer in isolated PM blebs and synthetic two-component vesicles, induction of positive curvature of the PM compromised the PM localization and nanoclustering of the full-length oncogenic mutant KRASG12V or the minimal membrane anchor tK [24]
Of mammalian cells treatedand by fendiline imaging experiments, the fendiline treatment consequentially led to mislocalization of the GFP-tagged oncogenic mutant KRASG12V from the PM, disruption of the nanoclustering of GFP-KRASG12V left on the PM [55,57,58]
Summary
The plasma membrane (PM) is the main functioning compartment for the highly oncogenic lipid-anchored RAS small GTPases [1,2,3,4,5,6]. Hydrophobic and electrostatic interactions between the isoform-specific C-terminal lipid-modified membrane-anchoring domains of RAS proteins and distinct lipids in the PM result in the formation of nanoclusters [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26]. RAS nanoclusters are biologically important for several reasons: (1) These nano-domains concentrate multiple RAS molecules and present larger targets for more efficient recruitment of effectors; (2) RAS nanoclusters concentrate additional protein and lipid contents that are essential to the efficient binding of effectors (will be the focus of this article);. We will discuss in detail the structural constituents of RAS nanoclusters and how the structural integrity of these nano-domains can be modulated to manipulate RAS signaling
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