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.

A fluorescence imaging technique suggests that sweat leakage in the epidermis contributes to the pathomechanism of palmoplantar pustulosis

“…In normal human skin, classical and desmosomal cadherins are differentially expressed in different layers of the epidermis. E-cadherin is present in almost all layers while desmoglein-1 is dominant in upper layers and desmoglein-3 in lower layers 19 , 20 . Our focus was on the fluorescence signal intensity of Alexa-488-labeled E-cadherin and desmoglein-1 in the upper layers of the pustulo-vesicle (Fig.…”

Planar cell polarity is essential for the architectural patterning of the mammalian biliary tree

“…Keratin-19 is a basic, type-I Keratin that is part of the Keratin-Desmosome scaffold 33 and which provides structural integrity to epithelial cells. It is possible then that the loss of Keratin-19 in Vangl2 S464N mutant bile ducts is due to disruption of intermediate filament formation secondary to desmosome disruption.…”

“…Furthermore, when we quantify the differences between Keratin-19 positive bile ducts at E17.5 and E18.5 in Vangl2 +/+ compared to Vangl2 S464N animals we found that while there are similar numbers of bile ducts between the two genotypes at E17.5 there is a substantial reduction in bile duct number by E18.5 (Figure 3D and 3E) and the number of Keratin-19 positive cells within those bile ducts is also significantly reduced (Figure 3F). Keratin-19 is a basic, type-I Keratin that is part of the Keratin-Desmosome scaffold 33 and which provides structural integrity to epithelial cells. It is possible then that the loss of Keratin-19 in Vangl2 S464N mutant bile ducts is due to disruption of intermediate filament formation secondary to desmosome disruption.…”

Nuclear Softness Promotes the Metastatic Potential of Large-Nucleated Colorectal Cancer Cells via the ErbB4-Akt1-Lamin A/C Signaling Pathway

“…The mechanical force from the ECM must be transmitted to the nucleus and, hence, participate in the phosphorylation of lamin A/C [49,58]. Mechanical signals are transduced to receptor tyrosine kinases in the ErbB family, contributing to the activities of the ErbB family [27]. Once activated, ErbB4 is capable of activating multiple kinases, including Akt1, MAPK, and PI3K [59][60][61].…”

“…Once activated, the soluble intracellular domain of ErbB4 translocates to the nucleus and modulates nuclear signaling 26 . The ERBB family also converts mechanical stimuli in the microenvironment into biochemical signals that promote tumor progression 27 . However, it is not clear whether ErbB4 can directly alter the mechanotransduction and nuclear structures.…”