Disease relevance of PLEC1

• Homozygous deletion mutations in the plectin gene (PLEC1) in patients with epidermolysis bullosa simplex associated with late-onset muscular dystrophy [1].
• Instead, PCR amplification followed by heteroduplex scanning and/or direct nucleotide sequencing revealed homozygous mutations in the plectin gene (PLEC1), encoding another hemidesmosomal protein previously linked to EB with muscular dystrophy [2].
• Structural and functional characteristics of plectin from intermediate filament preparations of rat glioma C6 cells were compared to those of the intermediate filament-associated protein of Mr = 300,000 (IFAP-300K) of baby hamster kidney cells (Yang, H.-S., Lieska, N., Goldman, A.E., and Goldman, R.D. (1985) J. Cell Biol. 100, 620-631) [3].
• Plectin regulates the organization of glial fibrillary acidic protein in Alexander disease [4].
• Pemphigoid gestationis (PG) is a subepidermal autoimmune blistering disease characterized by self-reactive T and B cells specific for the transmembrane hemidesmosomal protein type XVII collagen/BP180 [5].

High impact information on PLEC1

• Plectin deficiency results in muscular dystrophy with epidermolysis bullosa [6].
• Absence of the large multifunctional cytoskeleton protein plectin can simultaneously account for structural failure in both muscle and skin [6].
• The mouse basal cell carcinomas and trichoblastoma-like tumors resemble human basal cell carcinomas in their loss of normal hemidesmosomal components, presence of p53 mutations, frequent loss of the normal remaining Ptch allele, and activation of hedgehog target gene transcription [7].
• Our understanding of the role of hemidesmosomes in cell-substratum adhesion has greatly improved both as a result of targeted gene mutation experiments and by means of observations of several blistering disorders of the skin in which the absence or defects of hemidesmosomal proteins have been demonstrated [8].
• Studying fibroblast and astroglial cell cultures derived from plectin (-/-) mice, we found that their actin cytoskeleton, including focal adhesion contacts, was developed more extensively than in wild-type cells [9].

Chemical compound and disease context of PLEC1

• Bullous pemphigoid (BP) and herpes gestationis (HG) are subepidermal blistering diseases associated with an autoimmune response directed against BP180, an epidermal hemidesmosomal glycoprotein [10].
• Other acquired skin diseases of the hemidesmosomes reveal autoantibodies to a plectin-like protein, the beta4 subunit of alpha6beta4 integrin, uncein and a not yet characterized 168 kDa protein [11].
• PURPOSE: To evaluate the in vitro and in vivo activity of unencapsulated doxorubicin (DOX) and cisplatin (CDDP) and their pegylated liposome encapsulated counterparts (PLED and PLEC) in a subcutaneous model of human squamous cell cancer of the head and neck [12].
• Both the enantiomers (-)dOTC (BCH-10618) and (+)dOTC (BCH-10619) had equivalent activity against wild-type strains of HIV-1 in C8166 T-cells (EC50 1.0-10.0 microM) and in PBMCs (EC50 0.1-3.0 microM) [13].

Biological context of PLEC1

• The corresponding human gene (PLEC1), consisting of 33 exons spanning >26 kb of genomic DNA was cloned, sequenced, and mapped to chromosomal band 8q24 [14].
• Second, a heterozygous missense mutation (R2110W) in PLEC1 has been documented in patients with EB simplex of the Ogna type, a rare autosomal dominant disorder [15].
• Transient transfection of full-length plectin cDNA converted these aggregates to thin filaments, which exhibited diffuse cytoplasmic distribution [4].
• We show here sequestering of receptor for activated C kinase 1 (RACK1) to the cytoskeleton through the cytoskeletal linker protein plectin during the initial stages of cell adhesion [16].
• Human plectin: organization of the gene, sequence analysis, and chromosome localization (8q24) [17].

Anatomical context of PLEC1

• Cutting edge: integration of human T lymphocyte cytoskeleton by the cytolinker plectin [18].
• Similar characteristics were revealed for corresponding 300-kDa components of various other cell lines, supporting the concept that plectin is a general cytoskeletal cross-linking element, probably of multiple function [3].
• A much higher proportion of total GFAP was found in the Triton X-insoluble fraction of plectin-deficient fibroblasts than in wild-type fibroblasts [4].
• We demonstrate that human peripheral blood T lymphocytes express plectin, an IF-binding, cytoskeletal cross-linking protein [18].
• Plectin is therefore likely to serve as an important organizer of the lymphocyte cytoskeleton and may regulate changes of lymphocyte cytoarchitecture during polarization and extravasation [18].

Associations of PLEC1 with chemical compounds

• Our findings provide evidence for additional molecular heterogeneity in EB, and emphasize the importance of screening EB-PA patients not only for alpha6beta4 integrin but also for plectin deficiency [2].
• In an in vitro overlay assay using recombinant plectin peptides spanning exons 2 to 15 the insertion of leucine resulted in markedly increased self-aggregation of plectin peptides [19].
• Mutation 2727del14 is the first genetic defect described in PLEC1 that disrupts the plakin domain of plectin [20].
• Sensitivity of plectin kinase activity to the inhibitor olomoucine, and two-dimensional tryptic peptide mapping of plectin phosphorylated by various kinase preparations suggested that the major plectin kinase activity in mitotic extracts is related to the cell cycle regulator kinase p34cdc2 [21].
• The primary target of HG autoantibodies is BP180, a 180-kDa hemidesmosomal glycoprotein [22].

Physical interactions of PLEC1

• Overexpression of the plectin IF-binding domain in the T cell line Jurkat induces the perinuclear aggregation of vimentin IFs [18].
• Modeling and experimental validation of the binary complex of the plectin actin-binding domain and the first pair of fibronectin type III (FNIII) domains of the beta4 integrin [23].
• Using postembedding immunogold electron microscopy, we previously demonstrated that autoantibodies against the 230-kDa BP antigen (BPAG1) bind to the intracellular hemidesmosomal component of normal skin, whereas those against the 180-kDa BP antigen (BPAG2) bind only along the plasma membrane of hemidesmosomes [24].
• An additional observation was that the cytoskeletal cross-linker protein plectin-1 coimmunoprecipitated with PDE3A independently of 14-3-3 binding [25].
• Intermyofibrillar and subsarcolemmal accumulations of assembled but highly unordered desmin filaments may be attributed to impaired desmin binding capability of the mutant plectin [26].

Co-localisations of PLEC1

• A protein, D1, lacking the collagen-like extracellular domains of BP180 polarizes normally in 804G epithelial cells and colocalizes with other hemidesmosomal components in the plane of the basal cell surface [27].
• In normal epithelial cells, the alpha 6 beta 4 integrin co-localizes with the hemidesmosomal anchoring complex on the basolateral surface of basal cells [28].
• In adult muscle, plectin is colocalized with desmin at structures forming the intermyofibrillar scaffold and beneath the plasma membrane [29].
• In particular, in early myotubes a specific plectin isoform colocalizes with the costameric proteins vinculin and beta1D integrin in longitudinally orientated structures which increased in number and longitudinal extension upon further maturation [30].

Other interactions of PLEC1

• The immunohistochemical results suggest that the keratin cytoskeleton is linked to the basal plasma membrane of migrating basal cells via BP230 and plectin/HD1 earlier in the more slowly re-epithelializing blisters than in open wounds [31].
• The hemidesmosomal plasma membrane contains integrin subunits alpha 6 and beta 4 and these are quantitatively retained as the basal cell surface during extraction, while nonjunctional plasma membrane is solubilised [32].
• In contrast, VifA45 and VifA45open form perinuclear aggregates in nearly all transfected HeLa cells; vimentin as well as the cytoskeletal-bridging protein plectin, but not the microtubular protein tubulin, become relocalized to these structures [33].
• Impaired expression of plectin in muscle correlated with an altered labeling pattern of the muscle intermediate filament protein desmin [34].
• The presence of plectin mRNA was demonstrated by a RNase protection assay [19].

Analytical, diagnostic and therapeutic context of PLEC1

• Co-localization, co-immunoprecipitation, and in vitro overlay analyses demonstrated direct interaction of plectin and GFAP [4].
• Furthermore, immunofluorescence analysis showed that HD1 is expressed in Z-lines in normal skeletal muscle; whereas this expression is deficient in patient muscle [34].
• By using fluorescence in situ hybridization, we have mapped the plectin gene to the long arm of chromosome 8 within the telomeric region [17].
• Electron microscopy of these patients' skin suggests that tissue separation occurs intracellularly at the level of the hemidesmosomal inner plaque, which contains plectin, a high molecular weight cytoskeletal associated protein, also expressed in the sarcolemma of the muscle [1].
• However, a marked reduction of plectin protein was found using immunofluorescence microscopy of the patient's skin and Western blot analysis of the patient's cultured keratinocytes [19].

References