Excitable Signal Transduction Induces Both Spontaneous and Directional Cell Asymmetries in the Phosphatidylinositol Lipid Signaling System for Eukaryotic Chemotaxis

Abstract

Intracellular asymmetry in the signaling network works as a compass to navigate eukaryotic chemotaxis in response to guidance cues. Although the compass variable can be derived from a self-organization dynamics, such as excitability, the responsible mechanism remains to be clarified. Here, we analyzed the spatiotemporal dynamics of the phosphatidylinositol 3,4,5-trisphosphate (PtdInsP3) pathway, which is crucial for chemotaxis. We show that spontaneous activation of PtdInsP3-enriched domains is generated by an intrinsic excitable system. Formation of the same signal domain could be triggered by various perturbations, such as short impulse perturbations that triggered the activation of intrinsic dynamics to form signal domains. We also observed the refractory behavior exhibited in typical excitable systems. We show that the chemotactic response of PtdInsP3 involves biasing the spontaneous excitation to orient the activation site toward the chemoattractant. Thus, this biased excitability embodies the compass variable that is responsible for both random cell migration and biased random walk. Our finding may explain how cells achieve high sensitivity to and robust coordination of the downstream activation that allows chemotactic behavior in the noisy environment outside and inside the cells.