Phase separation in eukaryotic directional sensing

Many eukaryotic cell types share the ability to migrate directionally in response to external chemoattractant gradients. The binding of chemoattractants to specific receptors leads to a wide range of biochemical responses that become highly localized as cells polarize and migrate by chemotaxis. This ability is central in the development of complex organisms, and is the result of a billion,years of evolution. Cells exposed to shallow gradients in chemoattractant concentration respond with strongly asymmetric accumulation of several factors, including the phosphoinositides PIP3 and PIP2, the PI 3-kinase PI3K, and phosphatase PTEN. This early symmetry-breaking stage is believed to trigger effector pathways leading to cell movement. Although many signaling factors implied in directional sensing have been recently discovered the physical mechanism of signal amplification is not yet well understood. We propose that directional sensing is the consequence of a phase ordering process mediated by phosphoinositide diffusion and driven by the distribution of the chemotactic signal. By studying a realistic reaction-diffusion lattice model that describes PI3K and PTEN enzymatic activity, recruitment to the plasma membrane, and diffusion of their phosphoinositide products, we have shown that the effective enzyme-enzyme interaction induced by catalysis and diffusion introduces an instability of the system towards phase separation for realistic values of physical parameters. In this framework, large reversible amplification of shallow chemotactic gradients, selective localization of chemical factors, macroscopic response timescales, and spontaneous polarization arise naturally.