Excitable dynamics of Ras triggers spontaneous symmetry breaking of PIP3 signaling in motile cells

Abstract

Spontaneous cell movement is underpinned by an asymmetric distribution of signaling molecules including small G proteins and phosphoinositides on the cell membrane. A fundamental question lies in the molecular network for the spontaneous symmetry breaking. Here we report that spatiotemporal dynamics of GTP bound Ras (Ras-GTP) breaks the symmetry due to excitability even in the absence of extracellular spatial cues and downstream signaling activities. A stochastic excitation of local and transient Ras activation induced PIP3 accumulation via direct interaction with PI3K, causing tightly coupled traveling waves propagating along the membrane. Comprehensive phase analysis of the waves of Ras-GTP and PIP3 metabolism-related molecules revealed the network structure of the excitable system including positive feedback regulation of Ras-GTP by the downstream PIP3. A mathematical model reconstituted a series of the observed symmetry breaking phenomena, illustrating the essential involvement of Ras excitability in the cellular decision-making process.