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Gene Review

DSP  -  desmoplakin

Homo sapiens

Synonyms: 250/210 kDa paraneoplastic pemphigus antigen, DCWHKTA, DP, DPI, DPII, ...
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Disease relevance of DSP


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


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


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


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


  1. Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy. Yang, Z., Bowles, N.E., Scherer, S.E., Taylor, M.D., Kearney, D.L., Ge, S., Nadvoretskiy, V.V., DeFreitas, G., Carabello, B., Brandon, L.I., Godsel, L.M., Green, K.J., Saffitz, J.E., Li, H., Danieli, G.A., Calkins, H., Marcus, F., Towbin, J.A. Circ. Res. (2006) [Pubmed]
  2. Immunohistochemical staining of desmosomal components in oral squamous cell carcinomas and its association with tumour behaviour. Hiraki, A., Shinohara, M., Ikebe, T., Nakamura, S., Kurahara, S., Garrod, D.R. Br. J. Cancer (1996) [Pubmed]
  3. Striate palmoplantar keratoderma arising from desmoplakin and desmoglein 1 mutations is associated with contrasting perturbations of desmosomes and the keratin filament network. Wan, H., Dopping-Hepenstal, P.J., Gratian, M.J., Stone, M.G., Zhu, G., Purkis, P.E., South, A.P., Keane, F., Armstrong, D.K., Buxton, R.S., McGrath, J.A., Eady, R.A. Br. J. Dermatol. (2004) [Pubmed]
  4. Mucosal dominant pemphigus vulgaris with anti-desmoplakin autoantibodies. Mimouni, D., Foedinger, D., Kouba, D.J., Orlow, S.J., Rappersberger, K., Sciubba, J.J., Nikolskaia, O.V., Cohen, B.A., Anhalt, G.J., Nousari, C.H. J. Am. Acad. Dermatol. (2004) [Pubmed]
  5. Clinical profile of four families with arrhythmogenic right ventricular cardiomyopathy caused by dominant desmoplakin mutations. Bauce, B., Basso, C., Rampazzo, A., Beffagna, G., Daliento, L., Frigo, G., Malacrida, S., Settimo, L., Danieli, G., Thiene, G., Nava, A. Eur. Heart J. (2005) [Pubmed]
  6. Effect of daily spermatozoan production but not age on transit time of spermatozoa through the human epididymis. Johnson, L., Varner, D.D. Biol. Reprod. (1988) [Pubmed]
  7. Personality correlates of study difficulty and academic performance in university students. I. The Middlesex Hospital Questionnaire and Dynamic Personality Inventory. Stringer, P., Crown, S., Lucas, C.J., Supramanium, S. The British journal of medical psychology. (1977) [Pubmed]
  8. Adolescent parenting: outcomes and maternal perceptions. Thompson, P.J., Powell, M.J., Patterson, R.J., Ellerbee, S.M. Journal of obstetric, gynecologic, and neonatal nursing : JOGNN / NAACOG. (1995) [Pubmed]
  9. Contributions of cytoplasmic domains of desmosomal cadherins to desmosome assembly and intermediate filament anchorage. Troyanovsky, S.M., Eshkind, L.G., Troyanovsky, R.B., Leube, R.E., Franke, W.W. Cell (1993) [Pubmed]
  10. Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. Anhalt, G.J., Kim, S.C., Stanley, J.R., Korman, N.J., Jabs, D.A., Kory, M., Izumi, H., Ratrie, H., Mutasim, D., Ariss-Abdo, L. N. Engl. J. Med. (1990) [Pubmed]
  11. DP and E2F proteins: coordinating transcription with cell cycle progression. Lam, E.W., La Thangue, N.B. Curr. Opin. Cell Biol. (1994) [Pubmed]
  12. Novel mutation in desmoplakin causes arrhythmogenic left ventricular cardiomyopathy. Norman, M., Simpson, M., Mogensen, J., Shaw, A., Hughes, S., Syrris, P., Sen-Chowdhry, S., Rowland, E., Crosby, A., McKenna, W.J. Circulation (2005) [Pubmed]
  13. Keratin subsets in spindle cell sarcomas. Keratins are widespread but synovial sarcoma contains a distinctive keratin polypeptide pattern and desmoplakins. Miettinen, M. Am. J. Pathol. (1991) [Pubmed]
  14. Involvement of the retinoblastoma (pRb)-E2F/DP pathway during antiproliferative effects of resveratrol in human epidermoid carcinoma (A431) cells. Adhami, V.M., Afaq, F., Ahmad, N. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  15. Role of the retinoblastoma (pRb)-E2F/DP pathway in cancer chemopreventive effects of green tea polyphenol epigallocatechin-3-gallate. Ahmad, N., Adhami, V.M., Gupta, S., Cheng, P., Mukhtar, H. Arch. Biochem. Biophys. (2002) [Pubmed]
  16. Two-hybrid analysis reveals fundamental differences in direct interactions between desmoplakin and cell type-specific intermediate filaments. Meng, J.J., Bornslaeger, E.A., Green, K.J., Steinert, P.M., Ip, W. J. Biol. Chem. (1997) [Pubmed]
  17. A novel E2F binding protein with Myc-type HLH motif stimulates E2F-dependent transcription by forming a heterodimer. Suzuki, M., Okuyama, S., Okamoto, S., Shirasuna, K., Nakajima, T., Hachiya, T., Nojima, H., Sekiya, S., Oda, K. Oncogene (1998) [Pubmed]
  18. Defining the interactions between intermediate filaments and desmosomes. Smith, E.A., Fuchs, E. J. Cell Biol. (1998) [Pubmed]
  19. Making a connection: direct binding between keratin intermediate filaments and desmosomal proteins. Kouklis, P.D., Hutton, E., Fuchs, E. J. Cell Biol. (1994) [Pubmed]
  20. Desmoplakin expression and organization at human umbilical vein endothelial cell-to-cell junctions. Valiron, O., Chevrier, V., Usson, Y., Breviario, F., Job, D., Dejana, E. J. Cell. Sci. (1996) [Pubmed]
  21. VE-cadherin and desmoplakin are assembled into dermal microvascular endothelial intercellular junctions: a pivotal role for plakoglobin in the recruitment of desmoplakin to intercellular junctions. Kowalczyk, A.P., Navarro, P., Dejana, E., Bornslaeger, E.A., Green, K.J., Kopp, D.S., Borgwardt, J.E. J. Cell. Sci. (1998) [Pubmed]
  22. Plakophilin 1 interferes with plakoglobin binding to desmoplakin, yet together with plakoglobin promotes clustering of desmosomal plaque complexes at cell-cell borders. Bornslaeger, E.A., Godsel, L.M., Corcoran, C.M., Park, J.K., Hatzfeld, M., Kowalczyk, A.P., Green, K.J. J. Cell. Sci. (2001) [Pubmed]
  23. Interaction of plakophilins with desmoplakin and intermediate filament proteins: an in vitro analysis. Hofmann, I., Mertens, C., Brettel, M., Nimmrich, V., Schnölzer, M., Herrmann, H. J. Cell. Sci. (2000) [Pubmed]
  24. Subcellular distribution of envoplakin and periplakin: insights into their role as precursors of the epidermal cornified envelope. DiColandrea, T., Karashima, T., Määttä, A., Watt, F.M. J. Cell Biol. (2000) [Pubmed]
  25. Structures of two intermediate filament-binding fragments of desmoplakin reveal a unique repeat motif structure. Choi, H.J., Park-Snyder, S., Pascoe, L.T., Green, K.J., Weis, W.I. Nat. Struct. Biol. (2002) [Pubmed]
  26. Direct evidence that involucrin is a major early isopeptide cross-linked component of the keratinocyte cornified cell envelope. Steinert, P.M., Marekov, L.N. J. Biol. Chem. (1997) [Pubmed]
  27. Comparative analysis of armadillo family proteins in the regulation of a431 epithelial cell junction assembly, adhesion and migration. Setzer, S.V., Calkins, C.C., Garner, J., Summers, S., Green, K.J., Kowalczyk, A.P. J. Invest. Dermatol. (2004) [Pubmed]
  28. Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Rampazzo, A., Nava, A., Malacrida, S., Beffagna, G., Bauce, B., Rossi, V., Zimbello, R., Simionati, B., Basso, C., Thiene, G., Towbin, J.A., Danieli, G.A. Am. J. Hum. Genet. (2002) [Pubmed]
  29. Subunit composition determines E2F DNA-binding site specificity. Tao, Y., Kassatly, R.F., Cress, W.D., Horowitz, J.M. Mol. Cell. Biol. (1997) [Pubmed]
  30. Desmoglein endocytosis and desmosome disassembly are coordinated responses to pemphigus autoantibodies. Calkins, C.C., Setzer, S.V., Jennings, J.M., Summers, S., Tsunoda, K., Amagai, M., Kowalczyk, A.P. J. Biol. Chem. (2006) [Pubmed]
  31. Phosphorylation of the desmoplakin COOH terminus negatively regulates its interaction with keratin intermediate filament networks. Stappenbeck, T.S., Lamb, J.A., Corcoran, C.M., Green, K.J. J. Biol. Chem. (1994) [Pubmed]
  32. Synaptophysin expression in neuroendocrine neoplasms as determined by immunocytochemistry. Gould, V.E., Wiedenmann, B., Lee, I., Schwechheimer, K., Dockhorn-Dworniczak, B., Radosevich, J.A., Moll, R., Franke, W.W. Am. J. Pathol. (1987) [Pubmed]
  33. Epidermal growth factor suppresses induction by progestin of the adhesion protein desmoplakin in T47D breast cancer cells. Pang, H., Rowan, B.G., Al-Dhaheri, M., Faber, L.E. Breast Cancer Res. (2004) [Pubmed]
  34. The Armadillo family protein p0071 is a VE-cadherin- and desmoplakin-binding protein. Calkins, C.C., Hoepner, B.L., Law, C.M., Novak, M.R., Setzer, S.V., Hatzfeld, M., Kowalczyk, A.P. J. Biol. Chem. (2003) [Pubmed]
  35. Differential expression and biodistribution of cytokeratin 18 and desmoplakins in non-small cell lung carcinoma subtypes. Young, G.D., Winokur, T.S., Cerfolio, R.J., Van Tine, B.A., Chow, L.T., Okoh, V., Garver, R.I. Lung Cancer (2002) [Pubmed]
  36. Plakin proteins are coordinately cleaved during apoptosis but preferentially through the action of different caspases. Aho, S. Exp. Dermatol. (2004) [Pubmed]
  37. Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa. Jonkman, M.F., Pasmooij, A.M., Pasmans, S.G., van den Berg, M.P., Ter Horst, H.J., Timmer, A., Pas, H.H. Am. J. Hum. Genet. (2005) [Pubmed]
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