Positive Feedback Regulation Results in Spatial Clustering and Fast Spreading of Active Signaling Molecules on a Cell Membrane

TL;DR

This study demonstrates that positive feedback in cell signaling, combined with slow diffusion, causes clustering and rapid spreading of active molecules on cell membranes, with cluster fronts exhibiting KPZ-like roughness.

Contribution

We introduce a minimal model showing how positive feedback and slow diffusion lead to clustering and fast spreading of signaling molecules, revealing new insights into spatial signal propagation.

Findings

Positive feedback causes clustering of activated molecules.

Cluster fronts propagate with constant velocity.

Cluster roughness follows KPZ scaling.

Abstract

Positive feedback regulation is ubiquitous in cell signaling networks, often leading to binary outcomes in response to graded stimuli. However, the role of such feedbacks in clustering, and in spatial spreading of activated molecules, has come to be appreciated only recently. We focus on the latter, using a simple model developed in the context of Ras activation with competing negative and positive feedback mechanisms. We find that positive feedback, in the presence of slow diffusion, results in clustering of activated molecules on the plasma membrane, and rapid spatial spreading as the front of the cluster propagates with a constant velocity (dependent on the feedback strength). The advancing fronts of the clusters of the activated species are rough, with scaling consistent with the Kardar-Parisi-Zhang (KPZ) equation in one dimension. Our minimal model is general enough to describe signal transduction in a wide variety of biological networks where activity in the membrane-proximal region is subject to feedback regulation.