Disease relevance of DSG2

• The other two known desmogleins are DGI, which is a target antigen in another autoantibody-mediated blistering disease of the epidermis, pemphigus foliaceous, and HDGC, which is expressed in the basal layer of the epidermis and in the simple epithelium of, for example, the colon [1].
• Human fibrosarcoma cells, HT-1080, feature extensive adherens junctions, lack mature desmosomes, and express a single known desmosomal protein, Desmoglein 2 (Dsg2) [2].
• Only desmoglein 2 expression correlates with risk of metastasis [3].
• Genetic factors, including germline mutations in E-cadherin (CDH1, MIM#192090) in hereditary diffuse gastric cancer (HDGC, MIM#137215), are implicated in this disease [4].
• The observed abnormal expression of Dsg2 protein suggests that this molecule is involved in the carcinogenesis of a subset of gastric carcinomas, in particular of the diffuse type [5].

High impact information on DSG2

• Both cadherins clustered in the areas of the adherens junctions, whereas only a minor portion of Dsg2 was seen in these areas in the parental cells [2].
• Deletion mapping showed that intact extracellular cadherin-like repeats of Dsc1a (Arg1-Thr170) are required for the translocation of Dsg2 [2].
• Transfection of these cells with bovine Desmocollin 1a (Dsc1a) caused dramatic changes in the subcellular distribution of endogenous Dsg2 [2].
• One of these probands has compound-heterozygous mutations in DSG2, and the remaining three have isolated heterozygous missense mutations, each disrupting known functional components of desmoglein-2 [6].
• The increase in Dsg2 protein was in part due to the inhibition of matrix metalloproteinase-dependent proteolysis of this desmosomal cadherin [7].

Chemical compound and disease context of DSG2

• Seventy-five formalin-fixed, paraffin-embedded tissues from 37 familial and 38 sporadic gastric carcinomas were analysed for Dsg2 expression by immunohistochemistry [5].

Biological context of DSG2

• From these results, and recently reported linkage of DSG1 and DSG2 on human chromosome 18 at 18q12.1 in a deletion panel of somatic cell hybrids, all the desmosomal cadherins genes so far examined are clustered on chromosome 18 in human and mouse, which may have implications for gene expression [8].
• The potential value of Dsg2-specific antibodies in histology and in tumor diagnosis as well as in studies of the mechanisms desmosomal cell coupling is discussed [9].
• Family studies have reported CDH1 germline mutations in HDGC but the role of CDH1 germline mutations in the general population remains unclear [4].
• A cell adhesion molecule with functional similarity to E-cadherin is desmoglein 2 (Dsg2), a major component of the desmosomes [5].
• We previously reported that loss of heterozygosity at chromosome 18q12, on which the Dsg2 gene exists, is frequently found in diffuse-type gastric cancers [10].

Anatomical context of DSG2

• In addition, we propose to use Dsg2 as a general marker common to all epithelial cells and tumors and to use the specific pattern of occurrence of Dsg and Dsc isoforms as an additional criterion for cell typing in tumor diagnosis [11].
• Furthermore, in several tissues and cell lines Dsg2 is the only Dsg isoform detected so far [11].
• We conclude that Dsg2, the largest molecule in this protein family, is the fundamental desmoglein common to all desmosome-possessing tissues, including simple epithelia and myocardium, and many cell cultures [11].
• Desmoglein 2 was highly expressed by the least differentiated cells of the cutaneous epithelium, including the hair follicle bulge of the fetus and adult, bulb matrix cells, and basal layer of the outer root sheath [12].
• Therefore, desmoglein-2 (DSG2), the only desmoglein isoform expressed in cardiac myocytes, was screened in subjects with ARVC [13].

Associations of DSG2 with chemical compounds

• After short term EGF treatment, plakoglobin was rapidly phosphorylated, and tyrosine-phosphorylated Pg was distributed predominantly in a membrane-associated Triton X-100-soluble pool, along with a co-precipitating high molecular weight tyrosine-phosphorylated protein identified as desmoglein 2 [14].
• Remarkably, in stratified squamous epithelia the Dsg2-reaction is not homogeneous, as this glycoprotein is detected only in the basal cell layer and appears to be absent from suprabasal strata [9].
• Our studies highlight a novel mechanism by which Dsg2 regulates IEC apoptosis driven by cysteine proteases during physiological differentiation and inflammation [15].

Other interactions of DSG2

• It was negative for desmocollin 1 but strongly immunopositive for desmoglein 1 suprabasally and for desmoglein 2 in the basal cells [16].
• To test this hypothesis we used chimeras between beta-catenin and plakoglobin to identify domain(s) that modulate association with desmoglein 2 [17].
• Long-term treatment with either the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) or bryostatin 1 inhibited levels of Dsg1 and Dsg3, but not Dsg2 in NHEKs and HaCaT cells [18].
• To investigate how intestinal epithelial cells respond to contact with Candida albicans, an organism able to invade the bloodstream via the gastrointestinal tract, we focused on the junction proteins occludin, E-cadherin, and desmoglein-2 [19].
• Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy [13].

Analytical, diagnostic and therapeutic context of DSG2

• We have examined staining for desmoglein using the monoclonal antibody 33-3D, a mouse IgM monoclonal antibody, that recognizes the cytoplasmic domains of desmoglein (Dsg)1 and Dsg2 on frozen sections [20].

References