Dynamic seesaw model for rapid signaling responses in eukaryotic chemotaxis

Abstract

Directed movement of eukaryotic cells toward spatiotemporally varied chemotactic stimuli enables rapid intracellular signaling responses. While macroscopic cellular manifestation is shaped by balancing external stimuli strength with finite internal delays, the organizing principles of the underlying molecular mechanisms remain to be clarified. Here, we developed a novel modeling framework based on a simple seesaw mechanism to elucidate how cells repeatedly reverse polarity. As a key feature of the modeling, the bottom module of bidirectional molecular transport is successively controlled by three upstream modules of signal reception, initial signal processing, and Rho GTPase regulation. Our simulations indicated that an isotropic cell is polarized in response to a graded input signal. By applying a reversal gradient to a chemoattractant signal, lamellipod-specific molecules (i.e. PIP3 and PI3K) disappear, first from the cell front, and then they redistribute at the opposite side, whereas functional molecules at the rear of the cell (i.e. PIP2 and PTEN) act oppositely. In particular, the model cell exhibits a seesaw-like spatiotemporal pattern for the establishment of front and rear and interconversion, consistent with those related experimental observations. Increasing the switching frequency of the chemotactic gradient causes the cell to stay in a trapped state, further supporting the proposed dynamics of eukaryotic chemotaxis with the underlying cytoskeletal remodeling.