A mechanistic model for eukaryotic gradient sensing: spontaneous and induced phosphoinositide polarization

The crawling movement of cells in response to a chemoattractant gradient is a complex process requiring coordination of various subcellular activities. Although a complete description of the mechanisms underlying cell movement remains elusive, the very first step of gradient sensing, enabling the cell to perceive the imposed gradient, is becoming more transparent. The increased understanding of this step has been driven by the discovery that within 5-10 s of applying a weak chemoattractant gradient, membrane phosphoinositides such as PIP(3) localize at the front end of the cell. It is currently believed that the gradient sensing mechanism is precisely the mechanism leading to this localization. We have formulated a reaction-diffusion model based on the phosphoinositide cycle which predicts various responses of motile cells in addition to the phosphoinositide polarization induced by chemoattractant gradients. The responses include: (a) Polarized sensitivity wherein a polarized cell responds to a change in the direction of the gradient by turning its existing front. (b) Spontaneous polarization wherein cells polarize in a random direction even if the surrounding chemoattractant concentration is uniform. (c) Unique localization which refers to the formation of a unique polarity even in the face of multiple chemoattractant sources. The above responses preclude the hypothesis that the cell merely amplifies the external signal. Our model indicates that the cell must be viewed as a system that nonlinearly processes chemoattractant inputs. We show in particular that these seemingly complex dynamics can be explained very simply in terms of the instabilities and wavefront dynamics that are characteristic of the activator-inhibitor class of models.