Robert M. Harmon

Desmoglein 1–dependent suppression of EGFR signaling promotes epidermal differentiation and morphogenesis

Dsg1 (desmoglein 1) is a member of the cadherin family of Ca2+-dependent cell adhesion molecules that is first expressed in the epidermis as keratinocytes transit out of the basal layer and becomes concentrated in the uppermost cell layers of this stratified epithelium. In this study, we show that Dsg1 is not only required for maintaining epidermal tissue integrity in the superficial layers but also supports keratinocyte differentiation and suprabasal morphogenesis. Dsg1 lacking N-terminal ectodomain residues required for adhesion remained capable of promoting keratinocyte differentiation. Moreover, this capability did not depend on cytodomain interactions with the armadillo protein plakoglobin or coexpression of its companion suprabasal cadherin, Dsc1 (desmocollin 1). Instead, Dsg1 was required for suppression of epidermal growth factor receptor–Erk1/2 (extracellular signal-regulated kinase 1/2) signaling, thereby facilitating keratinocyte progression through a terminal differentiation program. In addition to serving as a rigid anchor between adjacent cells, this study implicates desmosomal cadherins as key components of a signaling axis governing epithelial morphogenesis.

Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting

The relative contribution of immunological dysregulation and impaired epithelial barrier function to allergic diseases is still a matter of debate. Here we describe a new syndrome featuring severe dermatitis, multiple allergies and metabolic wasting (SAM syndrome) caused by homozygous mutations in DSG1. DSG1 encodes desmoglein 1, a major constituent of desmosomes, which connect the cell surface to the keratin cytoskeleton and have a crucial role in maintaining epidermal integrity and barrier function. Mutations causing SAM syndrome resulted in lack of membrane expression of DSG1, leading to loss of cell-cell adhesion. In addition, DSG1 deficiency was associated with increased expression of a number of genes encoding allergy-related cytokines. Our deciphering of the pathogenesis of SAM syndrome substantiates the notion that allergy may result from a primary structural epidermal defect.

Desmosomes at a glance

Desmosomes are one of four intercellular junctions present on the lateral side of neighboring polarized epithelial cells. Tight junctions and adherens junctions (AJs) are restricted to the apical domain, where they form the epithelial barrier and organize cortical actin, respectively. Desmosomes are

Desmoglein-1/Erbin interaction suppresses ERK activation to support epidermal differentiation

Genetic disorders of the Ras/MAPK pathway, termed RASopathies, produce numerous abnormalities, including cutaneous keratodermas. The desmosomal cadherin, desmoglein-1 (DSG1), promotes keratinocyte differentiation by attenuating MAPK/ERK signaling and is linked to striate palmoplantar keratoderma (SPPK). This raises the possibility that cutaneous defects associated with SPPK and RASopathies share certain molecular faults. To identify intermediates responsible for executing the inhibition of ERK by DSG1, we conducted a yeast 2-hybrid screen. The screen revealed that Erbin (also known as ERBB2IP), a known ERK regulator, binds DSG1. Erbin silencing disrupted keratinocyte differentiation in culture, mimicking aspects of DSG1 deficiency. Furthermore, ERK inhibition and the induction of differentiation markers by DSG1 required both Erbin and DSG1 domains that participate in binding Erbin. Erbin blocks ERK signaling by interacting with and disrupting Ras-Raf scaffolds mediated by SHOC2, a protein genetically linked to the RASopathy, Noonan-like syndrome with loose anagen hair (NS/LAH). DSG1 overexpression enhanced this inhibitory function, increasing Erbin-SHOC2 interactions and decreasing Ras-SHOC2 interactions. Conversely, analysis of epidermis from DSG1-deficient patients with SPPK demonstrated increased Ras-SHOC2 colocalization and decreased Erbin-SHOC2 colocalization, offering a possible explanation for the observed epidermal defects. These findings suggest a mechanism by which DSG1 and Erbin cooperate to repress MAPK signaling and promote keratinocyte differentiation.

Structural and Functional Diversity of Desmosomes

Abstract Desmosomes anchor intermediate filaments at sites of cell contact established by the interaction of cadherins extending from opposing cells. The incorporation of cadherins, catenin adaptors, and cytoskeletal elements resembles the closely related adherens junction. However, the recruitment of intermediate filaments distinguishes desmosomes and imparts a unique function. By linking the load-bearing intermediate filaments of neighboring cells, desmosomes create mechanically contiguous cell sheets and, in so doing, confer structural integrity to the tissues they populate. This trait and a well-established role in human disease have long captured the attention of cell biologists, as evidenced by a publication record dating back to the mid-1860s. Likewise, emerging data implicating the desmosome in signaling events pertinent to organismal development, carcinogenesis, and genetic disorders will secure a prominent role for desmosomes in future biological and biomedical investigations.

Different roles of cadherins in the assembly and structural integrity of the desmosome complex.

ABSTRACT Adhesion between cells is established by the formation of specialized intercellular junctional complexes, such as desmosomes. Desmosomes contain isoforms of two members of the cadherin superfamily of cell adhesion proteins, desmocollins (Dsc) and desmogleins (Dsg), but their combinatorial roles in desmosome assembly are not understood. To uncouple desmosome assembly from other cell–cell adhesion complexes, we used micro-patterned substrates of Dsc2aFc and/or Dsg2Fc and collagen IV; we show that Dsc2aFc, but not Dsg2Fc, was necessary and sufficient to recruit desmosome-specific desmoplakin into desmosome puncta and produce strong adhesive binding. Single-molecule force spectroscopy showed that monomeric Dsc2a, but not Dsg2, formed Ca2+-dependent homophilic bonds, and that Dsg2 formed Ca2+-independent heterophilic bonds with Dsc2a. A W2A mutation in Dsc2a inhibited Ca2+-dependent homophilic binding, similar to classical cadherins, and Dsc2aW2A, but not Dsg2W2A, was excluded from desmosomes in MDCK cells. These results indicate that Dsc2a, but not Dsg2, is required for desmosome assembly through homophilic Ca2+- and W2-dependent binding, and that Dsg2 might be involved later in regulating a switch to Ca2+-independent adhesion in mature desmosomes.

The GEF Bcr activates RhoA/MAL signaling to promote keratinocyte differentiation via desmoglein-1

The GEF Bcr promotes RhoA-dependent actin remodeling and MAL/SRF signaling in keratinocytes, which in turn promotes differentiation via regulation of desmoglein-1 expression.

Intermediate Filaments and the Plasma Membrane

A variety of intermediate filament (IF) types show intricate association with plasma membrane proteins, including receptors and adhesion molecules. The molecular basis of linkage of IFs to desmosomes at sites of cell-cell interaction and hemidesmosomes at sites of cell-matrix adhesion has been elucidated and involves IF-associated proteins. However, IFs also interact with focal adhesions and cell-surface molecules, including dystroglycan. Through such membrane interactions, it is well accepted that IFs play important roles in the establishment and maintenance of tissue integrity. However, by organizing cell-surface complexes, IFs likely regulate, albeit indirectly, signaling pathways that are key to tissue homeostasis and repair.

Regulatory roles of the cadherin superfamily

Charged with the task of providing a molecular link between adjacent cells, the cadherin superfamily consists of over 100 members and populates the genomes of organisms ranging from vertebrates to cniderians. This breadth hints at what decades of research has confirmed: that cadherin-based adhesion and signaling events regulate diverse cellular processes including cell-sorting, differentiation, cell survival, proliferation, cell polarity, and cytoskeletal organization.

Desmosomal cadherin association with Tctex-1 and cortactin-Arp2/3 drives perijunctional actin polymerization to promote keratinocyte delamination

The epidermis is a multi-layered epithelium that serves as a barrier against water loss and environmental insults. Its morphogenesis occurs through a tightly regulated program of biochemical and architectural changes during which basal cells commit to differentiate and move towards the skin’s surface. Here, we reveal an unexpected role for the vertebrate cadherin desmoglein 1 (Dsg1) in remodeling the actin cytoskeleton to promote the transit of basal cells into the suprabasal layer through a process of delamination, one mechanism of epidermal stratification. Actin remodeling requires the interaction of Dsg1 with the dynein light chain, Tctex-1 and the actin scaffolding protein, cortactin. We demonstrate that Tctex-1 ensures the correct membrane compartmentalization of Dsg1-containing desmosomes, allowing cortactin/Arp2/3-dependent perijunctional actin polymerization and decreasing tension at E-cadherin junctions to promote keratinocyte delamination. Moreover, Dsg1 is sufficient to enable simple epithelial cells to exit a monolayer to form a second layer, highlighting its morphogenetic potential.The epidermis is a multi-layered epithelium formed by the differentiation of basal cells and movement into suprabasal layers. Here the authors define a role for the desmosomal cadherin desmoglein-1 in promoting the delamination of basal cells by remodeling the actin cytoskeleton through interactions with the dynein light chain Tctex-1 and cortactin.