Pulling the Back to Steer Cell Migration: Mechanisms of Structural Polarity in Confining Signaling and Protrusion

Directed cell migration is a coordinated process mediated by membrane protrusion at the front and contractile retraction at the back. This review compares a local excitation and global inhibition (LEGI) model and an emerging structural polarity of receptor activation (SPRA) model. The LEGI model posits that locally excitable signals generate membrane protrusions that become a single front through uncharacterized global inhibition that suppress competing protrusions. In contrast, the SPRA model proposes a central role of structural polarization, particularly membrane proximal F-actin, endoplasmic reticulum (ER)-plasma membrane (PM) contact sites, as well as actomyosin and nuclear positioning. In this model, the structural asymmetry ultimately sets up a stable front-to-back signal gradient, by enhancing receptor activity at the front and diminishing it at the back. Local differences in receptor sensitivity explains how uniform receptor stimuli initiate protrusions and trigger persistent cell migration. We discuss the mechanistic evidence for the two directed migration models and key open questions.