The Desmosome-Keratin Scaffold Integrates ErbB Family and Mechanical Signaling to Polarize Epidermal Structure and Function

Abstract

While classic cadherin-actin connections in adherens junctions (AJs) have ancient origins, intermediate filament (IF) linkages with desmosomal cadherins arose in vertebrate organisms. In this mini-review, we discuss how overlaying the IF-desmosome network onto the existing cadherin-actin network provided new opportunities to coordinate tissue mechanics with the positioning and function of chemical signaling mediators in the ErbB family of receptor tyrosine kinases. We focus in particular on the complex multi-layered outer covering of the skin, the epidermis, which serves essential barrier and stress sensing/responding functions in terrestrial vertebrates. We will review emerging data showing that desmosome-IF connections, AJ-actin interactions, ErbB family members, and membrane tension are all polarized across the multiple layers of the regenerating epidermis. Importantly, their integration generates differentiation-specific roles in each layer of the epidermis that dictate the form and function of the tissue. In the basal layer, the onset of the differentiation-specific desmosomal cadherin desmoglein 1 (Dsg1) dials down EGFR signaling while working with classic cadherins to remodel cortical actin cytoskeleton and decrease membrane tension to promote cell delamination. In the upper layers, Dsg1 and E-cadherin cooperate to maintain high tension and tune EGFR and ErbB2 activity to create the essential tight junction barrier. Our final outlook discusses the emerging appreciation that the desmosome-IF scaffold not only creates the architecture required for skin's physical barrier but also creates an immune barrier that keeps inflammation in check.

Keywords: EGFR signaling; actin cytoskeleton; desmoglein; epidermal polarity; intermediate filament.

FIGURE 1

Epithelial junction components. In simple epithelia, the apical junctional complex comprises apical tight junctions followed by adherens junctions, both anchored to the cortical actin ring, and then desmosomes, which anchor the intermediate filament network to the plasma membrane. Schematic shows these three major intercellular junctions associated with cytoskeletal filaments. Transmembrane components span the intercellular space as part of the adhesive core. On the intracellular side, these transmembrane components interact with plaque proteins that in turn anchor their respective cytoskeletal filaments. ZO, zonula occludens; β-cat, β-catenin; α-cat, α-catenin; Pg, plakoglobin; Pkp, plakophilin.

FIGURE 2

Apicobasolateral polarization of junctions and the cytoskeleton in the epidermis. The spatial distribution of adherens junction, desmosomal, and ErbB tyrosine kinase family proteins across the different layers of the epidermis is shown. This patterned expression is associated with development of mechanical boundaries in both the upper and lower layers. In the basal layer, cells experience compressive forces, while suprabasal layers experience tension. Moreover, there is a stiffness gradient ranging from least stiff in basal cells to most stiff in cornified cells. Green cells indicate onset of Dsg1 expression, induction of differentiation, and movement into the suprabasal layer. Vinc, vinculin; cad, cadherin; Dsc, desmocollin; Dsg, desmoglein; K, keratin.