Recombinant Human Desmoplakin (DSP), partial

Function

A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion (PubMed:25733715). Critical for cell-cell adhesion in early stage blastocysts and progression through proamniotic cavity formation (By similarity). Not required for preimplantation morphogenic process in blastocysts (By similarity). Required for keratin filament anchoring at the desmosome junction and subsequent organization of the keratin intermediate filament network within the cytoplasm (By similarity). Required for anchoring of desmosomes to the microtubule architecture, via its interaction with NIN (By similarity). Promotes microtubule-mediated GJA1/CX43 trafficking to cell membranes via its interaction with MAPRE1/EB1, thereby facilitating gap junction intracellular communication (PubMed:25225338). Plays a key role in adhesion and organization of the dermal epithelial barrier (PubMed:26604139). Critical for the maintenance of the neural tube structure following formation and organization of the neuroepithelium (By similarity). Facilitates outgrowth and repair of motor neuron fibers in regenerating axons following injury, probably by promoting recruitment of a complex containing DSP, CDH2, VIM and JUP to the outgrowth tips (By similarity). Critical for the normal formation of heart and myocardial tissue during early embryogenesis (By similarity). Also required for development of vascular capillary structures and intact endothelial cell barriers (By similarity). Regulates profibrotic gene expression in cardiomyocytes via activation of the MAPK14/p38 MAPK signaling cascade and increase in TGFB1 protein abundance (By similarity). Maintains cardiac rhythmicity by ensuring correct cell-cell adhesion within the sinoatrial node, via stabilization of protein components of both desmosome and Gap junctions (By similarity). Involved in maintaining the protein stability and recruitment of GJA1 to functional gap junctions, via inhibition of KRAS-mediated MAPK1/MAPK3 phosphorylation of GJA1 (By similarity). Negative regulator of cell cycle progression and differentiation in keratinocytes, potentially via inhibition of MAPK and phosphoinositide-3-kinase (PI3K) signaling pathways (PubMed:17475244). Mediates the interaction between the desmosome and COP9 signalosome complex (CSN) protein complex (PubMed:28891468). As a result of this interaction, promotes keratinocyte differentiation via deneddylation of EGFR resulting in a reduction in EGFR protein stabilization and translocation away from the cell membrane (PubMed:28891468). Required for the maintenance of protein abundance of desmosome junction components DSG1, DSG2, DSC2, DSC3, PKP1, PKP2 and PKP3 (PubMed:17475244, PubMed:26073755). Required for the survival and maintenance of germ cells in the gonads during embryonic development (By similarity). Binds to telomere DNA (via C-terminus) and acts to prevent telomere damage and maintain telomere length via its interaction with TRF2 (PubMed:31595153)

Subcellular Location

Cell projection, axon; Cell junction, desmosome; Cell membrane; Cytoplasm; Nucleus

Disease Association

Keratoderma, palmoplantar, striate 2 (SPPK2) : A dermatological disorder characterized by thickening of the skin on the palms (linear pattern) and the soles (island-like pattern) and flexor aspect of the fingers. Abnormalities of the nails, the teeth and the hair are rarely present. [The disease is caused by variants affecting the gene represented in this entry] | Cardiomyopathy, dilated, with woolly hair and keratoderma (DCWHK) : An autosomal recessive cardiocutaneous syndrome characterized by a generalized striate keratoderma particularly affecting the palmoplantar epidermis, woolly hair, and dilated left ventricular cardiomyopathy. [The disease is caused by variants affecting the gene represented in this entry] | Arrhythmogenic right ventricular dysplasia, familial, 8 (ARVD8) : A congenital heart disease characterized by infiltration of adipose and fibrous tissue into the right ventricle and loss of myocardial cells, resulting in ventricular and supraventricular arrhythmias. [The disease is caused by variants affecting the gene represented in this entry] | Epidermolysis bullosa, lethal acantholytic (EBLA) : A form of epidermolysis bullosa characterized by severe fragility of skin and mucous membranes. The phenotype is lethal in the neonatal period because of immense transcutaneous fluid loss. Typical features include universal alopecia, neonatal teeth, and nail loss. Histopathology of the skin shows suprabasal clefting and acantholysis throughout the spinous layer, mimicking pemphigus. [The disease is caused by variants affecting the gene represented in this entry] | Erythroderma, congenital, with palmoplantar keratoderma, hypotrichosis, and hyper IgE (EPKHE) : A syndrome characterized by severe dermatitis, multiple allergies and metabolic wasting. Clinical features include erythroderma, yellowish papules and plaques arranged at the periphery of the palms, along the fingers and over weight-bearing areas of the feet, skin erosions and scaling, and hypotrichosis. Additionally, patients manifest severe food allergies, elevated immunoglobulin E (IgE) levels and recurrent infections with marked metabolic wasting. [The disease is caused by variants affecting the gene represented in this entry] | Cardiomyopathy, dilated, with woolly hair, keratoderma, and tooth agenesis (DCWHKTA) : A cardiocutaneous syndrome characterized by biventricular dilated cardiomyopathy, hyperkeratosis, woolly hair, palmoplantar keratoderma, and hypo/oligodontia. [The disease is caused by variants affecting the gene represented in this entry]

Tissue Specificity

Resides predominantly in tissues and cells of stratified origin

Subunit

Homodimer. Identified in a complex containing at least DSP, JUP, VIM and CDH2; the complex is more abundant following crush injury in regenerating motor neurons and may promote axon outgrowth and motor fiber repair (By similarity). Interacts with COL17A1 (via cytoplasmic region) (PubMed:12482924). Interacts with DSC2 (PubMed:21062920). Interacts with PKP2 (PubMed:11790773, PubMed:22781308). Interacts (via head domain) with PKP1 (PubMed:10852826, PubMed:11790773, PubMed:21756917, PubMed:23444369). Interacts weakly with TMEM65. Interacts with NIN: the interaction facilitates recruitment of NIN to desmosome cell-cell junctions (By similarity). Interacts with TRF2 in the nucleus; the interaction is required for DSP telomere binding (PubMed:31595153). Interacts (via N-terminus) with MAPRE1/EB1; the interaction stabilizes microtubules at cell-cell contacts and facilitates GJA1 trafficking to gap junctions (PubMed:25225338). Interacts with JUP (PubMed:16917092). Interacts with intermediate filament proteins (PubMed:30354334). Interacts (via C-terminus) with COPS3; facilitates the interaction between the desmosome and the COP9 signalosome complex (CSN), the interaction acts to mediate EGFR signaling and keratinocyte differentiation (PubMed:28891468)

• Virata M.L.A. et al. Molecular structure of the human desmoplakin I and II amino terminus. — Proc. Natl. Acad. Sci. U.S.A. (1992)
• Cabral R.M. et al. Identification and characterization of DSPIa, a novel isoform of human desmoplakin. — Cell Tissue Res. (2010)
• Mungall A.J. et al. The DNA sequence and analysis of human chromosome 6. — Nature (2003)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Green K.J. et al. Structure of the human desmoplakins. Implications for function in the desmosomal plaque. — J. Biol. Chem. (1990)
• Green K.J. et al. PubMed: 2391353 — J. Biol. Chem. (1990)
• Whittock N.V. et al. Striate palmoplantar keratoderma resulting from desmoplakin haploinsufficiency. — J. Invest. Dermatol. (1999)
• Kowalczyk A.P. et al. The amino-terminal domain of desmoplakin binds to plakoglobin and clusters desmosomal cadherin-plakoglobin complexes. — J. Cell Biol. (1997)