Ligand-independent receptor clustering modulates transmembrane signaling: a new paradigm

Cell-surface receptors mediate communication between cells and their environment. Lateral membrane organization and dynamic receptor cluster formation are fundamental in signal transduction and cell signaling. However, it is not yet fully understood how receptor clustering modulates a wide variety of physiologically relevant processes. Recent growing evidence indicates that biological responses triggered by membrane receptors can be modulated even in the absence of the natural receptor ligand. We review the most recent findings on how ligand-independent receptor clustering can regulate transmembrane signaling. We discuss the latest technologies to control receptor assembly, such as DNA nanotechnology, optogenetics, and optochemistry, focusing on the biological relevance and unraveling of ligand-independent signaling. Receptor clustering in living cells is being increasingly recognized not only as an essential facet of cell signaling but also as a physical modulator of physiological responses.Liquid–liquid phase separation as the main mechanism for cluster formation indicates that, in addition to ligand binding, proximity to molecules, critical concentration thresholds, physical forces, and other aspects may direct cell signaling.Novel approaches to modulate ligand–receptor interactions 'on-demand' show that receptor clustering can trigger diverse cellular outcomes in the absence of ligands.Studies of ligand-independent clustering may stimulate the future development of unique therapeutics that target and manipulate receptors and their signaling pathways with high specificity and spatiotemporal control.