Disease relevance of 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 [1].
• We show that reduction of Dp staining correlates with loss of differentiation of the primary tumour, degree of invasion and presence of lymph node metastases [2].
• Striate palmoplantar keratoderma arising from desmoplakin and desmoglein 1 mutations is associated with contrasting perturbations of desmosomes and the keratin filament network [3].
• Mucosal dominant pemphigus vulgaris with anti-desmoplakin autoantibodies [4].
• AIMS: To characterize the clinical profile of patients belonging to families affected with autosomal dominant arrhythmogenic right ventricular cardiomyopathy (ARVC) due to mutations of the gene encoding for the cell-to-cell adhesion protein desmoplakin (DSP) [5].

Psychiatry related information on DSP

• However, parenchymal weights and numbers of epididymal spermatozoa were similar (p greater than 0.05) between DSP/T groups [6].
• DPI scores were more closely related to study difficulty in the patients than controls; and served particularly to characterize their sylbism and work satisfaction [7].
• MAIN OUTCOME MEASURES: Subsequent pregnancies; school completion; children's development, indicated by the Developmental Profile II (DPII); parental attitudes, indicated by the Adult-Adolescent Parenting Inventory (AAPI); and maternal perceptions [8].

High impact information on DSP

• The results show that the tail of the long splice form a of Dsc, but not its shorter splice form b, contains sufficient information to recruit desmoplakin and plakoglobin to connexon membrane paracrystals (gap junctions) and to form a novel kind of plaque at which cytokeratin IFs attach [9].
• The 250-kd polypeptide comigrated with desmoplakin I (a protein found in the desmosomes of all epithelia), and the 230-kd antigen comigrated with the antigen of bullous pemphigoid [10].
• The autoantibodies from these patients reacted with an antigen complex composed of desmoplakin I and the 230-kd antigen of bullous pemphigoid and two as yet unidentified epithelial antigens [10].
• DP and E2F proteins: coordinating transcription with cell cycle progression [11].
• Both DP and E2F proteins are endowed with proto-oncogenic activity and, conversely, have been implicated in regulating apoptosis [11].

Chemical compound and disease context of DSP

• BACKGROUND: Anti-desmoplakin (DP) antibodies are present in paraneoplastic pemphigus (PNP) as a component of a complex humoral autoimmune reaction characterized by antibodies against proteins of the plakin family, desmogleins, and an unidentified 170 kd protein [4].
• CONCLUSIONS: We have described a new dominant mutation in desmoplakin that causes left-sided ARVC, with arrhythmias of LV origin, lateral T-wave inversion, and late gadolinium enhancement in the LV on magnetic resonance images [12].
• Also the glandular epithelial cells in synovial sarcoma showed desmoplakin immunoreactivity preferentially in a luminal distribution, but desmoplakin was absent in other spindle cell sarcomas [13].
• Involvement of the retinoblastoma (pRb)-E2F/DP pathway during antiproliferative effects of resveratrol in human epidermoid carcinoma (A431) cells [14].
• Role of the retinoblastoma (pRb)-E2F/DP pathway in cancer chemopreventive effects of green tea polyphenol epigallocatechin-3-gallate [15].

Biological context of DSP

• 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 [1].
• 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 [1].
• 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 [1].
• In the case of K8/K18, however, the interaction as assessed by yeast two-hybrid assays increased 9-fold when a serine located in a protein kinase A consensus phosphorylation site 23 residues from the end of DP was altered to a glycine [16].
• Transcription factors of the E2F/DP family have been shown to be closely related to the regulation of cell proliferation [17].

Anatomical context of DSP

• 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 [1].
• Conversely, when linked to a foreign protein, as few as 86 NH2-terminal DP residues are sufficient to target to desmosomes efficiently [18].
• Desmoplakin (DPI), a desmosomal component lacking a transmembrane domain, has been implicated in this interaction, although most studies have been conducted with cells that contain few or no desmosomes, and efforts to demonstrate direct interactions between desmoplakin and intermediate filaments have not been successful [19].
• In confluent cells vimentin forms peripheral filaments which attach to the cell membrane in areas at desmoplakin localization [20].
• In addition, DP-NTP colocalized at cell-cell borders with alpha-catenin in the L-cell lines, and endogenous desmoplakin and alpha-catenin colocalized in cultured dermal microvascular endothelial cells [21].

Associations of DSP with chemical compounds

• Our results suggest that, in the Triton soluble pool, PKP1 interferes with binding of plakoglobin to full length DP when these proteins are co-expressed [22].
• In extracts from HaCaT cells, distinct soluble complexes containing PKP1a and desmoplakin I (DPI) have been identified by co-immunoprecipitation and sucrose density fractionation [23].
• Like the NH(2) terminus of desmoplakin, that of periplakin localized to desmosomes; however, in addition, the periplakin NH(2) terminus accumulated at cell surface microvilli in association with cortical actin [24].
• Desmoplakin is a member of the plakin family of IF-binding proteins [25].
• By immunogold electron microscopy, this exposed large amounts of involucrin epitopes as well as of desmoplakin, a desmosomal structural protein [26].

Physical interactions of DSP

• Plakophilin 1 interferes with plakoglobin binding to desmoplakin, yet together with plakoglobin promotes clustering of desmosomal plaque complexes at cell-cell borders [22].
• Protein interaction studies revealed that p0071 bound to the first 160 amino-terminal residues of desmoplakin and also interacted directly with plakoglobin, suggesting that p0071 may regulate desmosome assembly by controlling plakoglobin availability [27].
• Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy [28].
• It is not yet clear whether E2F/DP complexes regulate overlapping and/or specific cellular genes [29].
• Immunofluorescence analysis indicated that PV IgG and Dsg3 were rapidly internalized from the cell surface in a complex with plakoglobin but not desmoplakin [30].

Regulatory relationships of DSP

• Phosphorylation of the desmoplakin COOH terminus negatively regulates its interaction with keratin intermediate filament networks [31].
• Synaptophysin was also demonstrated in NE neoplasms of "epithelial" type in which it was predominantly coexpressed with cytokeratins and desmoplakin [32].
• RESULTS: We found the cell adhesion protein desmoplakin to be upregulated by progesterone - a process that was suppressed by EGF [33].

Other interactions of DSP

• Interestingly, like DP, PG and PP1 associate with epidermal keratins, although PG is considerably weaker in its ability to do so [18].
• In contrast to VE-cadherin, desmoplakin was found to associate with the non-armadillo head domain of p0071 [34].
• Nevertheless, both plakoglobin and PKP1 are required for the formation of clustered structures containing DP and the Dsg1 tail that ultrastructurally appear similar to desmosomal plaques found in the epidermis [22].
• In contrast, in both AC and ASC, the CK18 protein was diffusely distributed within the cytoplasm, and DP showed both membranous and cytoplasmic localization [35].
• Closer examination in vitro revealed that while caspases 2 and 4 most efficiently cleaved DP, and plectin served as a target for caspases 3 and 7, periplakin as well as keratins were cleaved by caspase 6 [36].

Analytical, diagnostic and therapeutic context of DSP

• Immunofluorescence confocal microscopy showed that desmoplakin codistributes with VE-cadherin and plakoglobin along the lateral cell membrane [20].
• Desmoplakin I/II could be detected by western blot only in long confluent cells even if desmoplakin mRNA levels are unchanged by cell confluency [20].
• RESULTS: Using electron microscopy, we found abnormalities of desmosomes and cell-cell adhesion in the suprabasal layers in the epidermis from patients with both Dsg1- and Dp-associated SPPK [3].
• METHODS AND RESULTS: Thirty-eight subjects belonging to four families showing different DSP mutations (three missense and one in the intron-exon splicing region) underwent clinical and genetic investigation, including annual 12-lead ECG, signal averaged ECG, 24 h Holter ECG, and two-dimensional echocardiography [5].
• Immunofluorescence staining of DP showed a distinct punctate intercellular pattern in the patient's skin [37].

References