Disease relevance of EVPL

• Chromosomal localisation of the human envoplakin gene (EVPL) to the region of the tylosis oesophageal cancer gene (TOCG) on 17q25 [1].
• The chromosomal localisation of the envoplakin gene, the homology of the encoded protein to keratin-binding proteins, and its expression in epidermal and oesophageal keratinocytes all raise the possibility that loss of envoplakin function could be responsible for this form of palmoplantar keratoderma [1].
• Envoplakin and periplakin are the paraneoplastic pemphigus antigens [2].
• Envoplakin, a possible candidate gene for focal NEPPK/esophageal cancer (TOC): the integration of genetic and physical maps of the TOC region on 17q25 [3].
• CONCLUSION: The association with a lymphoproliferative disorder, the IIF labeling of rat bladder, and the immunoblotting recognition of envoplakin and/or periplakin are both sensitive and specific features in the diagnosis of PNP [4].

High impact information on EVPL

• A deregulated p210 tyrosine kinase is found in chronic myelogenous leukemia, while a p190 form predominates in Ph+ ALL [5].
• CML cells carrying the t(9;22) chromosomal translocation are known to produce an 8-kilobase (kb) c-abl transcript in addition to the normal 6- and 7-kb transcripts and to express the normal p145 abl protein and a p210 c-abl protein possessing a tyrosine kinase activity not detected in the p145 species [6].
• Results of our analyses using somatic cell hybrids between a mouse fibroblast line and two human CML-derived cell lines which carry the Ph1 chromosome and are phenotypically identical to the fibroblast parent indicate that only the hybrid cells containing Ph1 chromosome express both the 8-kb c-abl RNA and the p210 protein [6].
• Full length envoplakin also localized to desmosomes, but mainly accumulated in nuclear and cytoplasmic aggregates with associated intermediate filaments [7].
• The envoplakin rod domain was required for aggregation and the periplakin rod domain was necessary and sufficient to redistribute envoplakin to desmosomes and the cytoskeleton, confirming earlier predictions that the proteins can heterodimerize [7].

Chemical compound and disease context of EVPL

• Paraneoplastic pemphigus sera react with multiple plakin family proteins, among which only envoplakin and periplakin are constantly detected by immunoblotting using normal human epidermal extracts [8].
• Probed on human leukemia cell lines, phosphotyrosine antibodies recognized a 210,000-molecular-weight protein (p210) in K562 cells, a cell line derived from a Philadelphia (Ph)'-positive chronic myelogenous leukemia (CML), but recognized no protein in control Ph'-negative non-CML leukemia cells [9].
• Exposure to low-dose cytosine arabinoside (Ara-C; 10 nmol/L) increased hemoglobin levels in HL-60/Bcr-Abl and in the chronic myeloid leukemia (CML) blast crisis K562 cells, which express the p210 Bcr-Abl protein [10].
• Arginine butyrate downregulates p210 bcr-abl expression and induces apoptosis in chronic myelogenous leukemia cells [11].
• After treatment with imatinib, the p210 transcript could not be detected, whereas p190 was still present 6 months after initiation of imatinib therapy and progression to blast phase [12].

Biological context of EVPL

• Mutation analysis of EVPL in the three affected families failed to show tylosis-specific mutations, and haplotype analysis of three intragenic sequence polymorphisms of the EVPL gene placed it proximal to D17S1839 [3].
• The EVPL gene has been mapped to the tylosis oesophageal cancer (TOC) locus on chromosome 17q25, where it has been demonstrated to be frequently deleted in both familial and sporadic forms of oesophageal squamous cell carcinoma (OSC) [13].
• In this study, we examined EVPL gene mutations in 10 OSC cell lines and 20 sporadic OSCs using reverse transcription-polymerase chain reaction single-strand conformational analysis (RT-PCR SSCP) followed by direct sequencing [13].
• The rate of EVPL gene mutation was quite low in contrast to the frequency of LOH on the TOC locus in sporadic OSCs, and the high incidence of oesophageal cancer development in tylosis families [13].
• The exon-intron structure of the mouse envoplakin gene is common to all members of the plakin family: the N-terminal protein domain is encoded by 21 small exons, and the central rod domain and the C-terminal globular domain are coded by a single large exon [14].

Anatomical context of EVPL

• Envoplakin (EVPL) is a protein component of desmosomes and the cornified envelope that is expressed in epidermal and esophageal keratinocytes and has been localized to the TOC region [3].
• Envoplakin and periplakin are components of the cornified envelope, but less is known about their role in tissues other than the stratified epithelium [15].
• Both periplakin and envoplakin/periplakin oligomers were able to bind synthetic lipid vesicles whose composition mimicked the cytoplasmic side of the plasma membrane of eukaryotic cells [16].
• Together, these data stress the importance of juxtaposition of membranes, transglutaminases, and involucrin and envoplakin in the initiation of CE assembly of stratified squamous epithelia [17].
• Its N-terminal domain interacts with the plasma membrane; it heterodimerises with envoplakin via its rod domain; and its C-terminus interacts with intermediate filaments [18].

Associations of EVPL with chemical compounds

• Periplakin, a novel component of cornified envelopes and desmosomes that belongs to the plakin family and forms complexes with envoplakin [19].
• Together, these data indicate that involucrin, envoplakin, periplakin, and possibly other structural proteins serve as substrates for the attachment of ceramides by ester linkages to the CE for barrier function in human epidermis [20].
• These findings raise the possibility that envoplakin and periplakin bind to the plasma membrane upon elevation of intracellular [Ca(2+)] in differentiating keratinocytes, where they serve as a scaffold for cornified cell envelope assembly [16].
• Essentially only one lysine and two glutamine residues of involucrin and two glutamines of envoplakin were used initially [17].
• Upon brefeldin A treatment, p210 did not redistribute in the ER as did other Golgi proteins [21].

Other interactions of EVPL

• Confirmation of the exclusion of EVPL as the TOC gene by location was obtained by integration of the genetic and physical mapping data using radiation hybrid, YAC, BAC, and PAC clones [3].
• In contrast to desmoplakin II, envoplakin was detected by all PNP sera analyzed [2].
• Fragile CEs were stained with antibodies against other CE components, including loricrin, envoplakin, filaggrin, and isopeptides [22].
• The proteins characterized thus far as autoantigens in PNP all belong to the plakin family of proteins and include desmoplakin, the 230 kDa bullous pemphigoid antigen, and envoplakin [23].
• Immunoblotting of human epidermal extracts showed that the patient's serum IgG reacted with the 210-kDa envoplakin, 190-kDa periplakin, as well as the recombinant protein of BP180 NC16a domain [24].

Analytical, diagnostic and therapeutic context of EVPL

• Using immunoblotting and immunoprecipitation, we further showed that the 190 kDa PNP antigen is identical to periplakin, another recently identified envelope precursor that can form complexes with envoplakin [2].
• We then synthesized 12 peptides covering the linker subdomain of envoplakin for ELISA [25].
• Sequence analysis revealed that the cDNA insert of the PNP clone encodes a part of the central rod domain and the COOH-terminal C domain of envoplakin, a newly defined precursor of the cornified envelope that is homologous to desmoplakin [26].
• Immunoblotting disclosed antibodies to envoplakin (210 kd protein) and periplakin (190 kd protein); in addition, immunoprecipitation detected antibodies to desmoplakin I (250 kd protein) [27].
• RESULTS: One clinical and 2 biologic features had both high sensitivity (82%-86%) and high specificity (83%-100%) whatever the control group considered: (1) association with a lymphoproliferative disorder, (2) indirect immunofluorescence (IIF) labeling of rat bladder, and (3) recognition of the envoplakin and/or periplakin bands in immunoblotting [4].

References