Key Points
• In this review, authors described how RAS proteins localize to and distribute on the plasma membrane in an attempt to elucidate RAS biology and contribute to the development of new strategies to treat RAS pathology.
• The reviewers assessed the nuanced abilities of RAS proteins to selectively sort lipids in a headgroup- and acyl chain structure-dependent manner.
• The authors stressed that although KRAS is hard to directly inhibit by small molecule ligands, the targeting the interactions of RAS with the plasma membrane may serve as an alternative target.
• “This specific lipid sorting capability not only allows RAS proteins to recruit effectors in an isoform-specific manner, but also allows RAS nanoclusters to sense and respond to various membrane perturbations in distinct manners,” the authors wrote. “This is because plasma membrane domains that vary in lipid and protein content as well as mechanical and electrostatic properties respond to membrane perturbations in distinct manners.”
• The authors hypothesized that RAS/lipid nanoclusters act as important transition hubs on the cell surface. At these hubs, extracellular mechanical and electrostatic stimuli are communicated to specific intracellular signal output. “These nanometer-sized transition hubs intricately connect extracellular stimuli with intracellular signaling networks and may contribute to mechanosensing and mechanotransduction,” the authors noted.