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Results for “Desmoglein 2”

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At least 19 recordsLinked to original sources

PubMed2000

The amino- and carboxyl-terminal tails of (beta)-catenin reduce its affinity for desmoglein 2.

beta-catenin and plakoglobin are members of the armadillo family of proteins and were first identified as components of intercellular adhering junctions. In the adherens junction beta-catenin and plakoglobin serve to link classical cadherins to the actin-based cytoskeleton. In the desmosome plakoglobin links the desmosomal cadherins, the desmogleins and the desmocollins, to the intermediate filament cytoskeleton. beta-catenin is not a component of the desmosome. Previously we have shown that the central armadillo repeat region of plakoglobin is the site for desmosomal cadherin binding. We hypothesized that the unique amino- and/or carboxyl-terminal ends of beta-catenin may regulate its exclusion from the desmosomal plaque. To test this hypothesis we used chimeras between beta-catenin and plakoglobin to identify domain(s) that modulate association with desmoglein 2. Chimeric constructs, each capable of associating with classical cadherins, were assayed for association with the desmosomal cadherin desmoglein 2. Addition of either the N- or C-terminal tail of beta-catenin to the armadillo repeats of plakoglobin did not interfere with desmoglein 2 association. However, when both beta-catenin amino terminus and carboxyl terminus were added to the plakoglobin armadillo repeats, association with desmoglein 2 was diminished. Removal of the first 26 amino acids from this construct restored association. We show evidence for direct protein-protein interactions between the amino- and carboxyl-terminal tails of beta-catenin and propose that a sequence in the first 26 amino acids of beta-catenin along with its carboxyl-terminal tail decrease its affinity for desmoglein and prevent its inclusion in the desmosome.

Amino Acid Sequence↗

PubMed2002

Loss of desmoglein 2 suggests essential functions for early embryonic development and proliferation of embryonal stem cells.

Desmoglein 2 (Dsg2) is a Ca(2+)-dependent adhesion molecule of desmosomes and is synthesized in all desmosome-bearing tissues from their earliest appearance onward. To examine the function of Dsg2, its gene was inactivated by homologous recombination in embryonal stem (ES) cells for the generation of knockout mice. DSG2 -/- mice and a considerable number of DSG2 +/- mice died at or shortly after implantation. On the other hand, DSG2 -/- blastocysts developed an apparently normal trophectoderm layer, the first tissue known to produce desmosomes, and hatched properly. Immunofluorescence analyses of these blastocysts showed, however, that the distribution of the desmosomal plaque protein desmoplakin was disturbed, whereas the adherens junction proteins E-cadherin and beta-catenin appeared to be unaffected. Unexpectedly, we found that Dsg2 seems to be essential for the inner cell mass and the ES cell population derived there from. We present evidence that Dsg2, which is located in desmoplakin-negative wild-type ES cells in non-desmosomal junctions, is needed for normal ES cell proliferation. Our observations thus reveal that important Dsg2 functions are desmosome-independent during early development and are needed for ES cell and early embryo survival.

Animals↗

PubMed2005

Desmoglein 2 is expressed abnormally rather than mutated in familial and sporadic gastric cancer.

Alterations of the cell adhesion molecule E-cadherin have been demonstrated in sporadic and hereditary gastric carcinomas. A cell adhesion molecule with functional similarity to E-cadherin is desmoglein 2 (Dsg2), a major component of the desmosomes. In this study, we investigated whether alterations of Dsg2 are involved in gastric carcinogenesis and whether germline mutations contribute to a genetic predisposition in familial gastric cancer patients with no germline mutations in the E-cadherin gene. Seventy-five formalin-fixed, paraffin-embedded tissues from 37 familial and 38 sporadic gastric carcinomas were analysed for Dsg2 expression by immunohistochemistry. DNA from 31 familial gastric cancer patients was analysed for germline mutations and five sporadic tumours were analysed for somatic mutations by DHPLC. Of the 75 tumours, 25 (33%) demonstrated abnormal (reduced and/or non-membrane-associated) Dsg2 expression. There was a trend towards more frequent abnormal expression in diffuse type (42%) than in intestinal type tumours (18%) (p = 0.066). One germline missense variant leading to a non-conservative amino acid change (c. 2810 C > A, Thr 937 Asn) was found in a familial gastric cancer patient with a diffuse type tumour. No somatic mutations were identified. 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. Somatic mutations in the gene do not seem to be a very frequent inactivation event and the finding of no clear pathogenic germline mutation rules out Dsg2 as a major gastric cancer predisposition gene.

Adult↗

PubMed2003

No involvement of IgG autoantibodies against extracellular domains of desmoglein 2 in paraneoplastic pemphigus or inflammatory bowel diseases.

BACKGROUND: Patients with paraneoplastic pemphigus (PNP) and inflammatory bowel diseases, such as Crohn's disease (CD) and ulcerative colitis (UC), develop autoantibodies against simple epithelial cells. About 20-30% of patients with PNP develop fatal bronchiolitis obliterans, in which autoantibody-mediated injury is suspected because of in vivo IgG deposition on cell surfaces of bronchial epithelia. OBJECTIVE: The purpose of this study is to determine whether patients with PNP, CD and UC have IgG autoantibodies against desmoglein 2 (Dsg2), which is expressed in all desmosome-bearing cells including respiratory and intestinal epithelia. METHODS: A secreted form of recombinant Dsg2 (rDsg2-His) which contains its entire extracellular domains was produced by baculovirus expression. The reactivity of patients' sera against rDsg2-His was examined by ELISA as well as immunoprecipitation. RESULTS: An anti-Dsg2 mouse monoclonal antibody, 6D8, showed positive reactivity against rDsg2-His in both methods. However, none of 38 PNP sera reacted with rDsg2-His by ELISA and none of 15 PNP sera tested immunoprecipitated rDsg2-His. Furthermore, none of 12 CD or 27 UC sera reacted with rDsg2-His by ELISA. CONCLUSION: These findings indicate that IgG autoantibodies against Dsg2 are not involved in PNP, CD or UC and suggest the existence of other unknown cell surface target antigen(s) in bronchiolitis obliterans in PNP.

Autoantibodies↗

PubMed2006

Proteomic identification of desmoglein 2 and activated leukocyte cell adhesion molecule as substrates of ADAM17 and ADAM10 by difference gel electrophoresis.

In contrast with the early view of metalloproteases as simple extracellular matrix-degrading entities, recent findings show that they are highly specific modulators of different signaling pathways involved, positively or negatively, in tumor development. Thus, before considering a given metalloprotease a therapeutic target, it seems advisable to characterize its function by identifying its repertoire of substrates. Here, we present a proteomic approach to identify ADAM17 substrates by difference gel electrophoresis. We found that the shedding of the extracellular domain of the transferrin receptor and those of two cell-cell adhesion molecules, activated leukocyte cell adhesion molecule (ALCAM) and desmoglein 2 (Dsg-2), is increased in cells overexpressing ADAM17. Genetic evidence shows that while ADAM17 is responsible for the shedding of ALCAM, both ADAM17 and ADAM10 can act on Dsg-2. Activation of the epidermal growth factor receptor leads to the upregulation of the shedding of Dsg-2 and to the concomitant upregulation of ADAM17, but not ADAM10, supporting the ability of overexpressed ADAM17 to shed Dsg-2. These results unveil a role of ADAM10 and ADAM17 in the shedding of cell-cell adhesion molecules. Since loss of cell adhesion is an early event in tumor development, these results suggest that ADAM17 is a useful target in anticancer therapy.

ADAM Proteins↗

PubMed1999

Internalization of constitutive desmogleins with the subsequent induction of desmoglein 2 in pemphigus lesions.

Acantholytic blisters in pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are caused by a dissociation of desmosomes mediated by autoantibodies against desmoglein (Dsg) 3 and Dsg 1, respectively. The blistering occurs at the suprabasilar level in PV and at the subcorneal level in PF, which corresponds to the distribution of target antigens in the epidermis: there is a more prominent expression of Dsg 1 in the upper layer, whereas Dsg 3 is more prominent in the lower layer. To elucidate the histogenesis of acantholysis, we studied the alterations of the desmosomal components and the expression pattern of Dsg isoforms in the lesional and perilesional epidermis of pemphigus patients. The results demonstrated an internalization of the desmosomes in the lower epidermis of PV, PF and pemphigus vegetans. A similar phenomenon was induced in monolayers of keratinocytes cultured with PV sera. However, little change was observed in E-cadherin expression until acantholysis became manifest. This internalization occurred prior to overt acantholysis, and was frequently associated with the induction of Dsg 2 expression in the basilar or lower layers of the epidermis. These findings indicate an alteration of Dsg isoform expression in subclinical pemphigus lesions, which might be related to the characteristic acantholytic patterns: the suprabasilar layer in PV and the upper epidermis in PF.

Cells, Cultured↗

PubMed1996

Abnormal desmoglein expression by squamous cell carcinoma cells.

Abnormal expression of cell adhesion molecules and related proteins has been observed in various carcinoma cells. We compared expression patterns of desmosomal cadherins, E-cadherin, and cytoplasmic plaque proteins of four different human squamous cell carcinoma cell lines and in vivo squamous cell carcinoma cells with those of normal human keratinocytes. Unlike normal human keratinocytes, the squamous cell carcinoma cells, both in culture and in vivo, exhibited diminished or unusual expression of desmoglein 3 and desmoglein 1, which bear pemphigus vulgaris and pemphigus foliaceus antigens, respectively. Abnormal expression of E-cadherin and cytoplasmic plaque proteins such as desmoplakin and plakoglobin was also observed. Western blotting study demonstrated that three squamous cell carcinoma cell lines expressed two desmogleins with a predominant 150 kDa molecule, and a minor 130 kDa one. Although these molecular sizes were similar to those of cultured normal human keratinocytes, the 130 kDa desmoglein, which usually carries pemphigus antigenic epitopes, was weakly or negatively reactive with pemphigus vulgaris serum. One squamous cell carcinoma cell line showed a doublet of 140 and 145 kDa bands in addition to the 130 kDa band. All the carcinoma cell lines constantly expressed desmoglein 2 and desmoglein 3 mRNA, whereas cultured normal human keratinocytes always expressed desmoglein 1 and desmoglein 3 mRNA, with or without desmoglein 2 mRNA. These findings indicate that the squamous cell carcinoma cells revealed abnormal expression of desmoglein isoforms, which may be related to tumor cell kinetics such as cell invasion and metastasis.

Antigens↗

PubMed2000

Coordinated reassembly of the basement membrane and junctional proteins during corneal epithelial wound healing.

PURPOSE: To characterize changes in the localizations of the basement membrane protein laminin-1 and of adhesion proteins of intercellular junctions during wound healing after epithelial ablation in the rat cornea. METHODS: Epithelial ablation was performed with an excimer laser. Rats were killed immediately, 12 hours, 24 hours, 3 days, or 4 weeks after ablation, and corneal cryosections were subjected to two-color immunofluorescence staining with antibodies to laminin-1 and antibodies to connexin43 for gap junctions, desmoglein 1 or 2 (desmoglein 1 + 2) for desmosomes, or E-cadherin for adherens junctions. Sections were also stained with antibodies to occludin for examination of tight junctions. RESULTS: Laminin-1 was detected in the basement membrane, connexin43 in the basal cell layer, desmoglein 1 + 2 in the wing cell layer, E-cadherin in all cell layers, and occludin in the wing and superficial cell layers of the intact corneal epithelium. Laminin-1 immunostaining was not detected at the leading edge of migrating epithelial cells until 24 hours after ablation. Expression of connexin43 and desmoglein 1 + 2 coincided with the reappearance of laminin-1, whereas that of E-cadherin and occludin was apparent regardless of the absence or presence of laminin-1. Epithelial remodeling was complete after 4 weeks. The basement membrane was re-established, and the expression patterns for all the adhesion proteins were identical with those characteristic of the intact cornea. CONCLUSIONS: Actively migrating epithelial cells no longer manifested gap junctions and desmosomes in the wounded area with no basement membrane. Re-establishment of the basement membrane coincided with reassembly of these intercellular junctions, suggesting that the presence of the basement membrane may be required for their reformation in the rat cornea.

Animals↗

PubMed2004

Progesterone treatment and the progress of early pregnancy reduce desmoglein 1&2 staining along the lateral plasma membrane in rat uterine epithelial cells.

Uterine epithelium undergoes dramatic changes during early pregnancy in preparation for implantation. We have studied distribution patterns of the desmosomal marker, desmoglein 1&2, in rat uterine epithelial cells during early pregnancy as well as in hormonally stimulated ovariectomised animals. On day 1 of pregnancy as well as in oestradiol treated rats, desmoglein 1&2 staining was localized along the entire length of the lateral plasma membrane. By day 3 and on subsequent days of pregnancy as well as in ovariectomised animals treated with progesterone alone or in combination with oestradiol, desmoglein 1&2 staining was concentrated at the apical portion of the lateral plasma membrane. We suggest that the reorganisation of these desmosomal cadherins is an important component of uterine epithelial receptivity and this relocation is under the control of the ovarian hormone progesterone.

Animals↗

PubMed2003

Molecular characterization of desmosomes in meningiomas and arachnoidal tissue.

Intercellular junctions morphologically identical to epithelial desmosomes are known structures in meningiomas and arachnoidal tissue. Desmoplakin as one of the desmosomal plaque components has proven to be a reliable marker for diagnosis of meningeal tumors. Here we demonstrate by immunofluorescence microscopy, immunoblot and reverse transcription-PCR reactions that cells of arachnoidal tissue, of diverse meningioma subtypes and of a meningioma-derived cell line contain the full complement of the typical desmosomal proteins desmoplakin (DP), plakophilin 2 (PP2), desmocollin 2 (Dsc2) and desmoglein 2 (Dsg2). Consequently, all these molecules are suitable for diagnostic applications of meningioma tumors. In addition to these constitutive desmosomal components, representative for single-layered (simple) epithelia, the dural border cells of the arachnoid and about 60% of the meningiomas tested were positive for desmocollin 3 (Dsc3), a protein in epithelia taken as an indicator for differentiation.

Animals↗

PubMed2006

Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by progressive degeneration of the right ventricular myocardium, ventricular arrhythmias, fibrous-fatty replacement, and increased risk of sudden death. Mutations in 6 genes, including 4 encoding desmosomal proteins (Junctional plakoglobin (JUP), Desmoplakin (DSP), Plakophilin 2, and Desmoglein 2), have been identified in patients with ARVD/C. Mutation analysis of 66 probands identified 4 variants in DSP; V30M, Q90R, W233X, and R2834H. To establish a cause and effect relationship between those DSP missense mutations and ARVD/C, we performed in vitro and in vivo analyses of the mutated proteins. Unlike wild-type (WT) DSP, the N-terminal mutants (V30M and Q90R) failed to localize to the cell membrane in desomosome-forming cell line and failed to bind to and coimmunoprecipitate JUP. Multiple attempts to generate N-terminal DSP (V30M and Q90R) cardiac-specific transgenes have failed: analysis of embryos revealed evidence of profound ventricular dilation, which likely resulted in embryonic lethality. We were able to develop transgenic (Tg) mice with cardiac-restricted overexpression of the C-terminal mutant (R2834H) or WT DSP. Whereas mice overexpressing WT DSP had no detectable histologic, morphological, or functional cardiac changes, the R2834H-Tg mice had increased cardiomyocyte apoptosis, cardiac fibrosis, and lipid accumulation, along with ventricular enlargement and cardiac dysfunction in both ventricles. These mice also displayed interruption of DSP-desmin interaction at intercalated discs (IDs) and marked ultra-structural changes of IDs. These data suggest DSP expression in cardiomyocytes is crucial for maintaining cardiac tissue integrity, and DSP abnormalities result in ARVD/C by cardiomyocyte death, changes in lipid metabolism, and defects in cardiac development.

Animals↗

PubMed1999

Forms of epithelial differentiation of draining sinus in acne inversa (hidradenitis suppurativa).

The draining sinus is a late complication of several forms of severe acne, leading to extensive, periodically inflamed lesions that are undermined by a system of fistulas, supposed to be of follicular origin. We investigated the expression of various cytokeratins (CKs) and desmosomal proteins in the draining sinus of acne inversa (hidradenitis suppurativa) using monoclonal antibodies in immunohistochemistry on paraffin-embedded sections. We were able to define three different phenotypes of stratified squamous epithelia covering the sinus tracts. Type I epithelium was cornifying and characterized by the presence of CK 10, desmogleins 1-3 and desmocollins 1-3 in an epidermis-like pattern. Type II epithelium was non-cornifying, negative for CK 10 and positive for CK 13. It was negative for desmocollin 1 but strongly immunopositive for desmoglein 1 suprabasally and for desmoglein 2 in the basal cells. Type III epithelium was non-cornifying and strongly inflamed. It was marked by the presence of CK 7, CK 19 and desmoglein 2 and the absence of CK 10, desmoglein 1 and desmocollin 1. In both type II and III epithelium, desmoglein 3, desmocollin 2 and desmocollin 3 showed an inverted staining pattern as compared with normal epidermis and type I epithelium. Desmoglein 2 and CK 5/14 always remained restricted to the basal cell layer. Antibodies against CK 6 and CK 13/15/16 were immunopositive in all three phenotypes and CK 17 was predominantly immunolocalized to suprabasal layers of type II and III epithelium. The three phenotypes are characterized as pathological stratified squamous epithelia reflecting the dynamic process of inflammation, proliferation and stratification taking place in acne inversa.

Antibodies, Monoclonal↗

PubMed2003

De novo formation of desmosomes in cultured cells upon transfection of genes encoding specific desmosomal components.

Desmosomes are cell junctions and cytoskeleton-anchoring structures of epithelia, the myocardium, and dendritic reticulum cells of lymphatic follicles whose major components are known. Using cultured HT-1080 SL-1 fibrosarcoma-derived cells and transfection of cDNAs encoding specific desmosomal components, we have determined a minimum ensemble of proteins sufficient to introduce de novo structures, which, by morphology and functional competence, are indistinguishable from authentic desmosomes. In a more refined analysis, the influence of the desmosomal proteins desmoplakin (Dp), plakoglobin (Pg), and plakophilin 2 (Pp2) on the lateral clustering of the desmosomal transmembrane-glycoprotein desmoglein 2 (Dsg) was examined. We found that for efficient clustering of desmoglein 2 and desmosome structure formation, all three major plaque proteins-desmoplakin, plakoglobin, and plakophilin 2- were necessary. Furthermore, in this cell model, plakophilin 2 was capable of directing desmoplakin to adhaerens junctions (AJ), whereas plakoglobin was crucial for the segregation of desmosomal and AJ components. These results are discussed with respect to the variability in cell junction composition observed in various nonepithelial tissues.

Animals↗

PubMed1998

Contributions of extracellular and intracellular domains of full length and chimeric cadherin molecules to junction assembly in epithelial cells.

The integrity of cell-cell junctions in epithelial cells depends on functional interactions of both extracellular and intracellular domains of cadherins with other junction proteins. To examine the roles of the different domains of E-cadherin and desmoglein in epithelial junctions, we stably expressed full length desmoglein 1 and chimeras of E-cadherin and desmoglein 1 in A431 epithelial cells. Full length desmoglein 1 was able to incorporate into or disrupt endogenous desmosomes depending on expression level. Each of the chimeric cadherin molecules exhibited distinct localization patterns at the cell surface. A chimera of the desmoglein 1 extracellular domain and the E-cadherin intracellular domain was distributed diffusely at the cell surface while the reverse chimera, comprising the E-cadherin extracellular domain and the desmoglein 1 intracellular domain, localized in large, sometimes contiguous patches at cell-cell interfaces. Nevertheless, both constructs disrupted desmosome assembly. Expression of constructs containing the desmoglein 1 cytoplasmic domain resulted in approximately a 3-fold decrease in E-cadherin bound to plakoglobin and a 5- to 10-fold reduction in the steady-state levels of the endogenous desmosomal cadherins, desmoglein 2 and desmocollin 2, possibly contributing to the dominant negative effect of the desmoglein 1 tail. In addition, biochemical analysis of protein complexes in the stable lines revealed novel in vivo protein interactions. Complexes containing beta-catenin and desmoglein 1 were identified in cells expressing constructs containing the desmoglein 1 tail. Furthermore, interactions were identified between endogenous E-cadherin and the chimera containing the E-cadherin extracellular domain and the desmoglein 1 intracellular domain providing in vivo evidence for previously predicted lateral interactions of E-cadherin extracellular domains.

Cadherins↗

PubMed2000

Expression of a single pair of desmosomal glycoproteins renders the corneal epithelium unique amongst stratified epithelia.

PURPOSE: To determine desmosomal glycoprotein isoform expression in bovine corneal, limbal, and conjunctival epithelium and desmosomal profile and distribution during corneal re-epithelialization. METHODS: Immunofluorescence (IF) for desmosomal components on cryostat sections of fresh epithelia was supported by immunoblot analysis of tissue lysates. Wounded corneas maintained in organ culture were examined by IF at times up to full re-epithelialization (96 hours). RESULT: Immunofluorescence for desmoplakin confirmed desmosome presence throughout all three epithelia. Plakoglobin was also ubiquitous. Of the desmosomal glycoproteins, desmocollin 2 (Dsc2) and desmoglein 2 (Dsg2) were expressed throughout, but Dsc3 and Dsg3 were confined to the limbus and conjunctiva, and Dscl and Dsgl were absent. Dsc2 and Dsg2 IFs were stronger in superficial layers, but Dsc3 and Dsg3 were stronger basally, fading suprabasally. Glycoprotein expression in cornea and conjunctiva was confirmed by immunoblot analysis. No change in glycoprotein expression occurred during re-epithelialization. CONCLUSIONS: Uniquely among stratified epithelia, cornea expresses only a single pair of desmosomal glycoproteins, Dsc2 and Dsg2. Expression of Dsc3 and Dsg3 in limbus and conjunctiva coincides with their association with cell proliferation in other epithelia, but corneal epithelial cells did not express Dsc3 or Dsg3 during re-epithelialization. Absence of Dscl and Dsgl correlates with lack of keratinization in ocular epithelia. These expression patterns may have significance for the specific properties and differentiation patterns of the epithelia. Presence of desmosomes throughout re-epithelialization raises the question of how migrating cells mutually re-position.

Animals↗

PubMed2001

Tyrosine-phosphorylated plakoglobin is associated with desmogleins but not desmoplakin after epidermal growth factor receptor activation.

Tyrosine phosphorylation of junctional components has been proposed as a mechanism for modulating cell-cell adhesion. Although a correlation exists between the tyrosine phosphorylation of the adherens junction protein beta-catenin and loss of classical cadherin-mediated adhesion, the effects of tyrosine phosphorylation on the function of the adherens junction and desmosome-associated protein plakoglobin is unknown. In the present study, we investigated the effects of epidermal growth factor receptor (EGFR) tyrosine kinase activation on the subcellular distribution of plakoglobin and its association with its junctional binding partners. Long term epidermal growth factor (EGF) treatment of A431 cells revealed a modest decrease in the cytoskeleton-associated pool of plakoglobin (Pg) and a corresponding increase in the cytosolic pool of Pg. 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. Analysis of deletion and point mutants defined the primary EGFR-dependent targets as one or more of three C-terminal tyrosine residues. Whereas phosphorylated Pg remained associated with the desmoglein tail after both short and long term EGFR activation, no phosphorylated Pg was found associated with the N-terminal Pg-binding domain (DPNTP) of the intermediate filament-associated protein, desmoplakin. Together these results are consistent with the possibility that EGF-dependent tyrosine phosphorylation of Pg may modulate cell-cell adhesion by compromising the link between desmosomal cadherins and the intermediate filament cytoskeleton.

Animals↗

PubMed2001

Assembly of desmosomal cadherins into desmosomes is isoform dependent.

Desmosomes are intercellular adhesive junctions that exhibit cell- and differentiation-specific differences in their molecular composition. In complex epithelia, desmosomes contain multiple representatives of the desmosomal cadherin family, which includes three desmogleins and three desmocollins. Rules governing the assembly of desmosomal cadherin isoforms into desmosomes of different cell types are unknown. Here we compared the assembly properties of desmoglein 2 (Dsg2) and desmocollin 2 (Dsc2), which are widely expressed, with Dsg1 and Dsc1, which are expressed in the differentiated layers of complex epithelia, by introducing myc-tagged forms into simple and squamous epithelial cells that do not express Dsg1 or Dsc1. Dsc2.myc and Dsg2.myc assembled efficiently into desmosomes in every cell type in spite of significant shifts in the stoichiometric relationship between desmogleins and desmocollins. In contrast, Dsc1a.myc, Dsc1b.myc, and Dsg1.myc did not stably incorporate into desmosomes in any line. Coexpression of Dsc1a.myc or Dsc1b.myc and Dsg1.myc did not lead to their colocalization and failed to enhance incorporation of either cadherin into desmosomes. Dsg1.myc, but not Dsc1a, Dsc1b, disrupted desmosome assembly in a cell-type-specific manner, and disruption correlated with the recruitment of Dsg1.myc, but not Dsc1a or Dsc1b, into a Triton-insoluble pool. The plakoglobin:E-cadherin ratio decreased in Dsg1-expressing cells with disrupted desmosomes, but a decrease was also observed in a Dsc1a line. Thus, a modest reduction of plakoglobin associated with E-cadherin is apparently not sufficient to disrupt desmosome assembly. Our results demonstrate that desmosome assembly tolerates large shifts in cadherin stoichiometry, but is sensitive to isoform-specific differences exhibited by desmogleins and desmocollins.

Animals↗

PubMed1997

Direct Ca2+-dependent heterophilic interaction between desmosomal cadherins, desmoglein and desmocollin, contributes to cell-cell adhesion.

Human fibrosarcoma cells, HT-1080, feature extensive adherens junctions, lack mature desmosomes, and express a single known desmosomal protein, Desmoglein 2 (Dsg2). Transfection of these cells with bovine Desmocollin 1a (Dsc1a) caused dramatic changes in the subcellular distribution of endogenous 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. Deletion mapping showed that intact extracellular cadherin-like repeats of Dsc1a (Arg1-Thr170) are required for the translocation of Dsg2. Deletion of the intracellular C-domain that mediates the interaction of Dsc1a with plakoglobin, or the CSI region that is involved in the binding to desmoplakin, had no effect. Coimmunoprecipitation experiments of cell lysates stably expressing Dsc1a with anti-Dsc or -Dsg antibodies demonstrate that the desmosomal cadherins, Dsg2 and Dsc1a, are involved in a direct Ca2+-dependent interaction. This conclusion was further supported by the results of solid phase binding experiments. These showed that the Dsc1a fragment containing cadherin-like repeats 1 and 2 binds directly to the extracellular portion of Dsg in a Ca2+-dependent manner. The contribution of the Dsg/ Dsc interaction to cell-cell adhesion was tested by coculturing HT-1080 cells expressing Dsc1a with HT-1080 cells lacking Dsc but expressing myc-tagged plakoglobin (MPg). In the latter cells, MPg and the endogenous Dsg form stable complexes. The observed specific coimmunoprecipitation of MPg by anti-Dsc antibodies in coculture indicates that an intercellular interaction between Dsc1 and Dsg is involved in cell-cell adhesion.

Animals↗