DSG2 stands for desmoglein-2, which is a type of desmosomal cadherin protein. It is a well-established fact that mutations in a variety of desmogleins can lead to the development of cardiomyopathy, like Desmocollin-2, Desmoplakin, and Plakophilin-2, etc. Among them, the DSG2 gene mutation is a prevalent cause. Recent studies suggested that DSG2 is also involved in various pathological conditions. For example, DSG2 has emerged as a key receptor for human adenovirus type 55 (HAdV55); DSG2 regulates the release of exosomes (Extracellular Vesicles, EVs), which can affect the tumor microenvironment.
Notably, there are approaches targeting DSG2 mutations or modulating its activity, which offers new hope for advancing the diseases treatment like cardiomyopathy, adenovirus infections, and tumors, etc. All in all, DSG2 as a subfamily of desmosomal cadherins, has emerged as an exciting therapeutic target for multiple diseases!
1. What are Members of Desmosomal Cadherin Family?
3. How's the Mechanism of Action of DSG2 in Tumors?
Desmogleins (DSGs) are a group of transmembrane proteins, which belong to the cadherin family, more specifically, a subfamily called desmosomal cadherins. Desmosomal cadherins, specifically desmogleins, are essential for facilitating cell-cell adhesion within desmosomes. Desmosomes are composed of transmembrane proteins from two specialized cadherin subfamilies: desmogleins (DSG1, DSG2, DSG3, and DSG4) and desmocollins (DSC1, DSC2, and DSC3), where the desmogleins serve a crucial role in intercellular adhesion [1-3].
In humans, DSGs is mainly found in tissues such as epidermis, hair follicles, nails and heart [4]. Abnormal expression of DSGs is involved in a wide range of diseases, including skin disorders, heart disease, autoimmune conditions, and tumors. Intriguingly, studies have indicated that targeting DSGs can lead to effective treatment for diseases such as aspergillosis, cardiomyopathy, and tumors [5-7]. Its wide expression and emerging importance in multiple pathological conditions make it an exciting target for scientists and researchers.
Desmoglein 2 (DSG2), which is also known as ARVC10, ARVD10, CDHF5, and CMD1BB, belongs to the DSGs family. It plays a crucial role in the structural composition of desmosomes by contributing to their assembly and stabilization. In particular, DSG2 is an essential component for maintaining the integrity of desmosome structures. Desmosomes are associated with cell adhesion junctions, which play an important role in tumor development. DSG2 protein structure mainly includes: four cadherin repeats (EC1–4), transmembrane domain (TM), intracellular domain (ICD), a linker domain (LD), repeat unit domain (RUD), and terminal domain (TD) (Figure 1) [8].
Figure 1. DSG2 structure [8]
DSG2 protein is the most widely distributed isoform of the DSGs family. Its expression is found in many tissues of epithelial and non-epithelial origin, such as brain, heart, liver, skeletal muscle, skin, colon, bladder, stomach, myocardium, and lymphoid follicular dendrites [9-10]. Existing studies have found that abnormal DSG2 expression is associated with a variety of tumors, such as gastric, skin, breast, esophageal squamous cell, prostate, pancreatic, and multiple myeloma [11-14].
DSG2 is considered to be one of the most important part in desmosomes. In addition to maintaining intercellular adhesion and preserving tissue integrity, DSG2 regulates many cellular processes, including cell proliferation, differentiation, apoptosis, and tissue formation. It has been found that mutations in DSG2 lead to disruption of adhesion and can cause structural changes in cardiac intercalated discs, leading to arrhythmogenic right ventricular cardiomyopathy (ARVC) or dilated cardiomyopathy (DCM) [15-16]; DSG2 regulates the EGFR signaling pathway to stimulate cell growth and migration through C Src and Cav1 dependent mechanisms [17]; DSG2 gene deletion at embryo implantation can cause defective embryonic stem cell proliferation and induce apoptotic cell death in embryonic stem cell (ESCs) [18-19].
Recent research has established a link between DSG2 expression, cell-cell adhesion, and tumorigenesis. It is widely acknowledged that reduced cell adhesion is correlated with the infiltration and metastasis of malignant tumors. In fact, changes in desmogleins are often observed in various diseases. Further investigation has indicated that DSG2 facilitates cellular interactions by regulating the formation of desmosomes, which serve as crucial junctions connecting neighboring cells. Current findings suggested that the impact of DSG2 expression on different types of cancer varies greatly.
In colorectal cancer, suppression of DSG2 expression leads to a decrease in EGFR phosphorylation, which hinders cell proliferation [20]. In skin cancer, an increase in DSG2 expression activates several signaling pathways including PI3-kinase/AKT, MEK/MAPK, and NF-κB, all of which accelerate tumor cell growth [21-23]. In prostate cancer, the snail protein regulates E-cadherin expression without affecting DSG2 expression [24].
In ovarian clear cell carcinoma stem cells with knockdown of CD133/PROM1, DSG2 expression was markedly reduced [25]. Further studies implied that DSG2 confered stem cells with malignancy through wnt/β-catenin signaling pathway [25-26]. In cervical cancer, downregulation of E-cadherin led to changes in the structure of DSG2, disrupting the adhesion between cells and promoting cancer development [27]. In lung adenocarcinoma, DSG2 over-expression was found to stimulate cancer progression through EGFR/Src/PAK1 pathway, and also increased resistance to Osimertinib (Figure 2) [28].
Figure 2. DSG2 is involved in the mechanism of resistance to Osimertinib [28]
DSG2, a transmembrane adhesion molecule, have been directly associated with diseases such as cardiomyopathies and intestinal inflammation. It has been demonstrated in a variety of tumor cells, the decreased cell adhesion caused by abnormal DSG2 deletion is closely associated with enhanced migration of cancer cells and poor prognosis of cancer.
In a mouse model, hybrids with DSG2 mutations exhibit clinical symptoms that closely resemble those of individuals diagnosed with ARVC. These symptoms include ventricular enlargement, wall thinning, decreased cardiac function, inflammation, and ventricular fibrosis. However, early diagnosis of ARVC has proven challenging as echocardiography, the primary diagnostic tool, lacks specificity. The discovery of mutations in the DSG2 gene presents an opportunity to utilize it as a clinical indicator for detecting patients with ARVC [29].
A study revealed that the knockdown of KLF5 led to a disruption in the cellular desmosomes structure, which further impairs the barrier function of the mouse intestine by inhibiting DSG2 expression. In patients suffering from Crohn's disease and ulcerative colitis, there was a significant downregulation of DSG2 and Claudin1(CLDN1), potentially influenced by TNF. However, the introduction of a tandem peptide (TP) that specifically binds to the structural domain of DSG2, stabilized its structure and impeded the TNF-induced increase in intestinal epithelial permeability [30].
Currently, intestinal inflammatory diseases, especially Crohn's disease and ulcerative colitis, are mainly treated by glucocorticoids with relatively large adverse effects. Therefore, further understanding the role and mechanism of DSG2 in intestinal inflammatory diseases is expected to provide new strategy for the treatment of intestinal inflammatory diseases.
Among the adenovirus subtypes, subtypes 3, 7, 11, and 14, as well as the new subtype 14p1, lead to the development of infection by specifically binding to the DSG2 receptor in epithelial cells. Studies on human DSG2 transgenic mice models have shown that the recombinant Ad3 PtDd, named junction opener protein (JO-1), can bind to DSG2 and trigger intracellular signaling [31-32]. Furthermore, recent research has revealed that DSG2 is the primary receptor for human adenovirus HAdV-B55, which causes community-acquired pneumonia (CAP) in adults, underscoring the importance of understanding how adenoviruses interact with host cells [33].
Numerous studies suggest that DSG2 exerts significant effects on tumors. Specifically, the overexpression of DSG2 protein is observed in several epithelial tumors such as squamous carcinoma, basal cell carcinoma, melanoma, colon cancer, and small cell lung cancer. Conversely, Downregulation of DSG2 is presented in gastric cancer, pancreatic cancer, and gallbladder cancer. These findings indicate the distinct roles of DSG2 in diverse tumors.
In pancreatic cancer, DSG2 expression decreases significantly, leading to loss of cell cohesion and enhanced tumor cell proliferation and invasion migration. Coincidentally, Kallikrein7 (KLK7) is markedly overexpressed in pancreatic cancer, wherein the degraded form of DSG2 is observed as multiple fragments due to KLK7's ability to promote its decomposition. However, the use of a KLK7 inhibitor can prevent this process [34].
In gastric cancer, DSG2 expression was significantly reduced, which is associated with poor prognosis in patients [35]. In squamous carcinoma, EGFR and ADAM can promote cell migration and reduce cancer cell adhesion by facilitating the degradation of DSG2 within cells [36].
In malignant melanoma, DSG2 expression is strongly associated with poor prognosis and regulates vasculogenic mimicry (VM). Owing to this, DSG2 is considered as an important regulator of VM activity in melanoma. The targeted therapy against DSG2 has the potential to inhibit tumor blood supply and metastatic spread [37].
A novel discovery in head and neck squamous cell carcinomas has shown that exosomes (Extracellular Vesicles, EVs) are enriched with the C-terminal fragment of DSG2 protein, which induces the release of mitogenic-related factors such as epidermal growth factor receptor C-Src from EVs. Additionally, a higher abundance of circulating blood with released EVs containing DSG2 suggests a promising new way to diagnose cancer [38-39].
According to recent data from Pharmsnap, there are two drugs targeting DSG2, from BRIM Biotechnology, Inc. (BRM-131), based in Taiwan and Renovacor, Inc. (DSG2 AAV gene therapy), based in the US. DSG2 as a crucial component of the desmosomes, it plays a crucial role in the formation and maintenance of desmosomes, which are cell structures that provide mechanical strength and integrity to tissues. Promisingly, many findings indicated that dysregulation of DSG2 expression can result in autoimmune disorders, infectious diseases, and tumors. Currently, DSG2, a widely expressed transmembrane protein of desmosomal cadherin family, is an emerging target for the treatment of cardiomyopathies, intestinal inflammation, adenovirus, and tumors.
To fully support researchers and pharmaceutical companies in their research on DSG2 in cardiomyopathies, intestinal inflammation, adenovirus, and tumors, CUSABIO presents DSG2 active proteins (Code: CSB-MP622752HU) to support your research on the mechanism of DSG2 or its potential clinical value (click for the full list of DSG2 products: DSG2 Proteins; DSG2 antibodies).
DSG2 proteins:
Recombinant Human Desmoglein-2(DSG2),partial (Active)
The purity was greater than 96.3% as determined by SDS-PAGE.(Tris-Glycine gel) Discontinuous SDS-PAGE (reduced) with 5% enrichment gel and 15% separation gel.
Immobilized Human DSG2 at 2μg/mL can bind Anti-DSG2 recombinant antibody (CSB-RA622752MA1HU), the EC50 is 20.26-38.00 ng/mL.
References
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