Kinetic proofreading decouples signal strength and range in paracrine gradient formation

Abstract

Spatial gradients of signaling molecules pattern multicellular tissues with high precision. The canonical synthesis-diffusion-degradation (SDD) framework imposes a tradeoff on these gradients: ligand-receptor interactions that generate downstream signaling activity are also responsible for consuming the ligand. Correspondingly, at a fixed ligand synthesis rate, raising ligand-receptor affinity increases local signal strength at the expense of spatial range, and lowering it extends range at the expense of strength. Recent live-imaging measurements appear to violate this seemingly fundamental tradeoff, with low-affinity ligands of the epidermal growth factor receptor (EGFR) diffusing farther and driving spatially broader signaling activity compared to high-affinity ligands. Here we explain these observations with a model of multi-step ligand processing at the receptor, and show that the activity-range tradeoff is a consequence of receptor architecture rather than a physical necessity. When receptors process ligand through a multi-step phosphorylation cascade with kinetic-proofreading-like resetting, the states that generate activity decouple from those that consume ligand, and signaling activity and range increase together over a finite window of ligand residence time. This lets cells tune how far a signal travels independently of how strongly it acts through tuning signaling parameters. Realistic EGFR parameters place the low-affinity ligands in this window. Because multi-site phosphorylation and preferential degradation of the active receptor recur across multiple receptor families, kinetic proofreading may be a general strategy for controlling signaling range. Significance StatementCells coordinate by releasing molecules that bind receptors on neighboring cells. For a fixed supply, how strongly a signal acts and how far it spreads are locked together: tight binding gives a strong response but the molecule is captured near its source, while weak binding spreads farther but signals feebly. Yet recent imaging of epidermal growth factor receptor ligands shows the opposite: weak binders activate a broader field of cells. We show this limit reflects how receptors read the signal, not physics. A receptor that processes a bound molecule through several steps, and can release it partway, separates the states that signal from those that destroy it. Cells, and engineers, can then set a signals reach independently of its strength.