Membrane lipids, EGF receptors, and intracellular signals colocalize and are polarized in epithelial cells moving directionally in a physiological electric field

TLDR

Cell migration is crucial for tissue formation, inflammation, and wound healing, and is guided by chemotaxis and endogenous electric fields that induce directional reorientation of cells. The study proposes a model in which electric‑field–polarized membrane lipid domains and EGF receptors generate asymmetric MAP kinase signaling that drives directional epithelial cell migration. EF‑induced polarization of membrane lipid domains and EGF receptors asymmetrically activates the MAP kinase ERK1/2 pathway, coordinating leading‑edge actin polymerization. Physiological electric fields redistribute EGF receptors and detergent‑insoluble lipids asymmetrically, enhancing MAP kinase activation, promoting leading‑edge actin polymerization, and increasing directional migration; inhibition of the EGF‑MAPK pathway diminishes actin asymmetry and migration.

Abstract

Directed cell migration is essential for tissue formation, inflammation, and wound healing. Chemotaxis plays a major role in these situations and is underpinned by asymmetric intracellular signaling. Endogenous electric fields (EFs) are common where cell movement occurs, such as in wound healing, and cells respond to electric field gradients by reorienting and migrating directionally (galvanotaxis/electrotaxis). We show that a physiological EF redistributed both EGF (epidermal growth factor) receptors and detergent-insoluble membrane lipids asymmetrically, leading to cathodal polarization and enhanced activation of the MAP kinase, ERK1/2. This induced leading-edge actin polymerization in directionally migrating mammalian epithelial cells. Inhibiting the EGF receptor-MAP kinase signaling pathway significantly decreased leading edge actin asymmetry and directional migration. We propose a model in which EF-polarized membrane lipid domains and EGF receptors cause asymmetric signaling through MAP kinase, which drives directional cell migration. A comparison is made with the mechanisms underpinning chemotaxis.