Abstract
RAS proteins are lipid-anchored small GTPases that switch between the GTP-bound active and GDP-bound inactive states. RAS isoforms, including HRAS, NRAS and splice variants KRAS4A and KRAS4B, are some of the most frequently mutated proteins in cancer. In particular, constitutively active mutants of KRAS comprise ∼80% of all RAS oncogenic mutations and are found in 98% of pancreatic, 45% of colorectal and 31% of lung tumors. Plasma membrane (PM) is the primary location of RAS signaling in biology and pathology. Thus, a better understanding of how RAS proteins localize to and distribute on the PM is critical to better comprehend RAS biology and to develop new strategies to treat RAS pathology. In this review, we discuss recent findings on how RAS proteins sort lipids as they undergo macromolecular assembly on the PM. We also discuss how RAS/lipid nanoclusters serve as signaling platforms for the efficient recruitment of effectors and signal transduction, and how perturbing the PM biophysical properties affect the spatial distribution of RAS isoforms and their functions.
Highlights
Lbiv(r)-r values above the 95% confidence interval (95% C.I.) indicate statistically significant co-clustering of the two populations of gold particles (Ripley, 1977; Diggle, 1979; Diggle et al, 2000). Such bivariate coclustering analyses showed that co-clustering among HRAS, NRAS and KRAS4B is below the 95% C.I., suggesting minimal spatial overlap among the isoforms (Prior et al, 2003; Plowman et al, 2005)
This observation was made under multiple experimental conditions: 1) in intact Plasma membrane (PM) sheets with curvature manipulated by the expression of different curvature-molding BAR domains; 2) in live cells grown over nanobars that induced quantifiable curvatures of the basolateral PM; 3) in isolated PM blebs with curvatures induced by exposure to hypo- and hypertonic buffers; and 4) in two-component synthetic liposomes of different sizes and curvatures (Liang and et al, 2019)
We have focused on the intricate capabilities of RAS proteins to selectively sort lipids in a headgroup- and acyl chain structure-dependent manner
Summary
RAS proteins are lipid-anchored small GTPases that switch between the GTP-bound active and GDP-bound inactive states. RAS isoforms, including HRAS, NRAS and splice variants KRAS4A and KRAS4B, are some of the most frequently mutated proteins in cancer. Plasma membrane (PM) is the primary location of RAS signaling in biology and pathology. A better understanding of how RAS proteins localize to and distribute on the PM is critical to better comprehend RAS biology and to develop new strategies to treat RAS pathology. We discuss recent findings on how RAS proteins sort lipids as they undergo macromolecular assembly on the PM. We discuss how RAS/ lipid nanoclusters serve as signaling platforms for the efficient recruitment of effectors and signal transduction, and how perturbing the PM biophysical properties affect the spatial distribution of RAS isoforms and their functions
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