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PubMed2005

A maturational model for the study of airway smooth muscle adaptation to mechanical oscillation.

It has been shown that mechanical stretches imposed on airway smooth muscle (ASM) by deep inspiration reduce the subsequent contractile response of the ASM. This passive maneuver of lengthening and retraction of the muscle is beneficial in normal subjects to counteract bronchospasm. However, it is detrimental to hyperresponsive airways because it triggers further bronchoconstriction. Although the exact mechanisms for this contrary response by normal and hyperresponsive airways are unclear, it has been suggested that the phenomenon is related to changes in ASM adaptability to mechanical oscillation. Healthy immature airways of both human and animal exhibit hyperresponsiveness, but whether the adaptative properties of hyperresponsive airway differ from normal is still unknown. In this article, we review the phenomenon of ASM adaptation to mechanical oscillation and its relevance and implication to airway hyperresponsiveness. We demonstrate that the age-specific expression of ASM adaptation is prominent using an established maturational animal model developed in our laboratory. Our data on immature ASM showed potentiated contractile force shortly after a length oscillation compared with the maximum force generated before oscillation. Several potential mechanisms such as myogenic response, changes in actin polymerization, or changes in the quantity of the cytoskeletal regulatory proteins plectin and vimentin, which may underlie this age-specific force potentiation, are discussed. We suggest a working model of the structure of smooth muscle associated with force transmission, which may help to elucidate the mechanisms responsible for the age-specific expression of smooth muscle adaptation. It is important to study the maturational profile of ASM adaptation as it could contribute to juvenile hyperresponsiveness.

Actins↗
PubMed2003

A novel cell-cell junction system: the cortex adhaerens mosaic of lens fiber cells.

The anucleate prismoid fiber cells of the eye lens are densely packed to form a tissue in which the plasma membranes and their associated cytoplasmic coat form a single giant cell-cell adhesive complex, the cortex adhaerens. Using biochemical and immunoprecipitation methods in various species (cow, pig, rat), in combination with immunolocalization microscopy, we have identified two different major kinds of cortical complex. In one, the transmembrane glycoproteins N-cadherin and cadherin-11 [which also occur in heterotypic ('mixed') complexes] are associated with alpha- and beta-catenin, plakoglobin (proportions variable among species), p120ctn and vinculin. The other complex contains ezrin, periplakin, periaxin and desmoyokin (and so is called the EPPD complex), usually together with moesin, spectrin(s) and plectin. In sections through lens fiber tissue, the short sides of the lens fiber hexagons appear to be enriched in the cadherin-based complexes, whereas the EPPD complexes also occur on the long sides. Moreover, high resolution double-label fluorescence microscopy has revealed, on the short sides, a finer, almost regular mosaicism of blocks comprising the cadherin-based, catenin-containing complexes, alternating with patches formed by the EPPD complexes. The latter, a new type of junctional plaque ensemble of proteins hitherto known only from certain other cell types, must be added to the list of major lens cortex proteins. We here discuss its possible functional importance for the maintenance of lens structure and functions, notably clear and sharp vision.

Animals↗
PubMed2005

Identification of trichoplein, a novel keratin filament-binding protein.

Keratins 8 and 18 (K8/18) are major components of the intermediate filaments (IFs) of simple epithelia. We report here the identification of a novel protein termed trichoplein. This protein shows a low degree of sequence similarity to trichohyalin, plectin and myosin heavy chain, and is a K8/18-binding protein. Among interactions between trichoplein and various IF proteins that we tested using two-hybrid methods, trichoplein interacted significantly with K16 and K18, and to some extent with K5, K6a, K8 and K14. In in vitro co-sedimentation assays, trichoplein directly binds to K8/18, but not with vimentin, desmin, actin filaments or microtubules. An antibody raised against trichoplein specifically recognized a polypeptide with a relative molecular mass of 61 kDa in cell lysates. Trichoplein was immunoprecipitated using this antibody in a complex with K8/18 and immunostaining revealed that trichoplein colocalized with K8/18 filaments in HeLa cells. In polarized Caco-2 cells, trichoplein colocalized not only with K8/18 filaments in the apical region but also with desmoplakin, a constituent of desmosomes. In the absorptive cells of the small intestine, trichoplein colocalized with K8/18 filaments at the apical cortical region, and was also concentrated at desmosomes. Taken together, these results suggest that trichoplein is a keratin-binding protein that may be involved in the organization of the apical network of keratin filaments and desmosomes in simple epithelial cells.

Amino Acid Sequence↗
PubMed1997

Altered distribution of plectin/HD1 in dystrophinopathies.

Plectin/HD1 is a high molecular weight protein (approximately 500 kDa) that has been proposed to act as an important and versatile cytoskeletal cross-linker molecule. Mutations of the human plectin gene have recently been associated with the autosomal recessive disorder epidermolysis bullosa simplex with muscular dystrophy. We studied the expression of plectin/HD1 in various neuromuscular disorders by indirect immunofluorescence. In cross sections of normal human muscle, plectin/HD1 showed a checkerboard-like distribution with moderate to intense cytoplasmic and sarcolemmal staining in type 1 fibers and a faint staining of the sarcolemma in type 2 fibers. In longitudinal sections of plectin/HD1-positive fibers a cross-striation staining pattern was noted. This fiber type-related expression was significantly altered in the group of dystrophinopathies, whereas it was maintained in all other myopathies and denervating disorders. In seven dystrophinopathies studied, a markedly increased plectin/HD1 immunoreactivity at the sarcolemmal level of type 2 fibers was observed. Confocal laser microscopy of normal skeletal muscle revealed a colocalization of desmin and plectin/HD1 at the level of the sarcolemma. This suggests that plectin/HD1- in analogy to its demonstrated involvement in cytokeratin-hemidesmosome linkage in epidermis-may mediate the anchorage of desmin to the sarcolemma (i.e. to costameres).

Blotting, Southern↗
PubMed1996

Cytoskeleton architecture of C6 rat glioma cell subclones whole mount electron microscopy and immunogold labeling.

Whole mount electron microscopy of extracted cells combined with immunogold labeling techniques can be used to characterize the cytoskeletal architecture of cultured cells. As shown with subclones of the C6 rat glioma cell line, heavy metal shadowing was suitable for getting basic information concerning the arrangement of the various filament types within the networks. Pure carbon shadowing combined with immunogold double labeling proved to be optimal to identify linkages between filaments, to localize filament associated proteins and to follow the arrangement of filaments in dense arrays such as lamellipodiae and cell margins. Thin connecting filaments which interact with actin as well as with vimentin filaments and can be labeled with antibodies to the intermediate filament associated protein plectin may play a major role in the structural organization of the cytoskeleton of these cells.

Actins↗
PubMed1990

Identification and characterization of a novel mammalian intermediate filament-associated protein.

A novel monoclonal antibody, designated M1.4, recognizes the high molecular weight microtubule-associated protein MAP1A (ca. Mr 380 kD) in both bovine and rat brain. In HeLa cells, however, M1.4 binds to a 240 kD polypeptide on immunoblots and co-localizes with both vimentin and cytokeratin filaments using double-label immunofluorescence microscopy. Immunoelectron microscopy indicates that the 240 kD polypeptide localizes along bundled intermediate filaments in a periodic manner. Two-dimensional electrophoretic analysis indicates that the 240 kD polypeptide has a basic pI of 7.7. When HeLa cell intermediate filaments are isolated using standard non-ionic detergent/high-salt conditions the 240 kD polypeptide does not sediment with the intermediate filaments, unlike the established intermediate filament-associated protein plectin. Immunoblot analysis with M1.4 shows the 240 kD polypeptide is expressed in a number of mammalian cell lines. Additionally, double-label immunofluorescence shows the 240 kD polypeptide to associate with vimentin filaments in African Green Monkey kidney (CV-1) and JC neuroblastoma cells. Due to its unique biochemical and biological characteristics, the 240 kD polypeptide is clearly a novel intermediate filament-associated protein for which we have proposed the designation gyronemin (Gr. gyros: around; nemin: filament).

Animals↗
PubMed1996

Chromosomal localisation of the human envoplakin gene (EVPL) to the region of the tylosis oesophageal cancer gene (TOCG) on 17q25.

Envoplakin is a membrane-associated precursor of the epidermal cornified envelope. Envoplakin is homologous to desmoplakin I and desmoplakin II (DPI/II), bullous pemphigoid antigen 1 (BPAG1), and plectin and is proposed to link desmosomes and keratin filaments to the cornified envelope. We describe the isolation of cosmids and yeast artificial chromosomes containing the complete human envoplakin gene (EVPL) and show, by analysis of somatic cell hybrids and chromosomal in situ hybridisation, that the envoplakin gene, unlike the genes encoding BPAG1 and DPI/II, maps to 17q25 and is physically linked to D17S1603. This sequence-tagged site segregates with the autosomal dominant human disease focal nonepidermolytic palmoplantar keratosis (NEPKK; "tylosis"), which is associated with an increased risk of oesophageal cancer. 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.

Chromosome Mapping↗
PubMed2000

[Pemphigus. Loss of desmosomal cell-cell contact].

Pemphigus diseases comprise a group of autoimmune disorders which are characterized by intraepidermal blisters and autoantibodies to components of desmosomes. Desmosomes mediate adhesion between neighbouring keratinocytes. A common feature of pemphigus diseases are intercellular deposits of IgG or, less frequently, of IgA within the epidermis. The group of pemphigus diseases includes pemphigus vulgaris, pemphigus foliaceus, pemphigus vegetans, pemphigus herpetiformis, pemphigus erythematosus, paraneoplastic pemphigus, drug-induced pemphigus, and IgA pemphigus. Using molecular tools, some of the autoantigens in these diseases have been characterized. In pemphigus vulgaris, autoantibodies are directed to desmoglein 3 and in pemphigus foliaceus to desmoglein 1. Target antigens in IgA pemphigus are desmocollin 1 and desmoglein 3. In paraneoplastic pemphigus, autoantibodies react with a complex of various proteins, including desmoplakin 1 and 2, BP230, envoplakin, periplakin, plectin, desmoglein 3, and a yet uncharacterized 170 kD protein. This review summarizes new insights into the immunopathogenesis and diagnosis of pemphigus diseases.

Animals↗
PubMed2001

Immunohistochemical investigation of actin-anchoring proteins vinculin, talin and paxillin in rat brain following lesion: a moderate reaction, confined to the astroglia of brain tracts.

The present study investigated the immunoreactivity of vinculin, talin and paxillin following stab wounds in the cortex and the underlying white matter of adult rats. These proteins participate in the anchoring of actin filaments to the cell membrane at the focal adhesion plaques, and they are of essential importance in cell motility. Without lesion, vinculin, talin and paxillin immunopositive astrocytes were not recognizable in the cortex and only scarcely in the white matter, if at all. Following lesion, several astrocytes immunopositive to vinculin, talin and paxillin appeared in the white matter, whereas none of them was found in the overlying cortex. Glial fibrillary acidic protein (GFAP) immunopositivity was intense in both areas. The distribution of the actin-anchoring proteins following lesions was similar to that found of the intermediate-filament associated protein plectin, in our previous study.

Animals↗
PubMed2003

Genetic abnormalities and clinical classification of epidermolysis bullosa.

Genetic abnormalities for different subtypes of epidermolysis bullosa (EB) have been described. In dominant simplex type EB, mutations of the K5 or K14 gene lead to disruption of basal cells and the formation of bullae. The recessive simplex types include EB with muscular dystrophy due to abnormal plectin, EB without muscular dystrophy in patients homozygous for K14 gene abnormalities, and skin fragility syndrome, with formation of acantholytic vesicles within the epidermis due to PKP1 gene mutations. In junctional EB, mutations of the laminin 5, type XVII collagen, and alpha 6 beta 4 integrin genes have been reported. Dystrophic type EB is associated with various abnormalities of the type VII collagen gene. A new classification of EB based on these genetic abnormalities has been proposed. However, some concern has been voiced regarding the clinical utility of a classification based solely on genetic abnormalities. Although the reasons are unclear, identical genetic abnormalities have been known to be associated with different clinical features. A classification including a component based on clinical features would therefore be preferable. This article describes recently discovered genetic abnormalities and offers a new classification scheme for EB.

Epidermolysis Bullosa↗
PubMed2003

A genomewide survey of developmentally relevant genes in Ciona intestinalis. X. Genes for cell junctions and extracellular matrix.

Cell junctions and the extracellular matrix (ECM) are crucial components in intercellular communication. These systems are thought to have become highly diversified during the course of vertebrate evolution. In the present study, we have examined whether the ancestral chordate already had such vertebrate systems for intercellular communication, for which we have searched the genome of the ascidian Ciona intestinalis. From this molecular perspective, the Ciona genome contains genes that encode protein components of tight junctions, hemidesmosomes and connexin-based gap junctions, as well as of adherens junctions and focal adhesions, but it does not have those for desmosomes. The latter omission is curious, and the ascidian type-I cadherins may represent an ancestral form of the vertebrate type-I cadherins and desmosomal cadherins, while Ci-Plakin may represent an ancestral protein of the vertebrate desmoplakins and plectins. If this is the case, then ascidians may have retained ancestral desmosome-like structures, as suggested by previous electron-microscopic observations. In addition, ECM genes that have been regarded as vertebrate-specific were also found in the Ciona genome. These results suggest that the last common ancestor shared by ascidians and vertebrates, the ancestor of the entire chordate clade, had essentially the same systems of cell junctions as those in extant vertebrates. However, the number of such genes for each family in the Ciona genome is far smaller than that in vertebrate genomes. In vertebrates these ancestral cell junctions appear to have evolved into more diverse, and possibly more complex, forms, compared with those in their urochordate siblings.

Animals↗
PubMed2002

Differential display of mRNAs associated with blood feeding in the midgut of the bloodsucking bug, Triatoma infestans.

An arbitrary-primed RNA PCR differential display strategy was used to identify midgut genes of the reduviid bug Triatoma infestans that were differentially expressed after a blood meal. From interesting bands, 33 distinct cDNAs were cloned and sequenced. Although many had long open reading frames, most of the transcripts were unrelated to any other sequences in any databases. Only 14 Triatoma sequences had strong homologies to those from other organisms, including genes encoding for 2-oxoglutarate dehydrogenase, CAD protein, NADH-ubiquinone-oxoreductase, epidermal growth factor, plectin, aminopeptidase, heat-shock-related 70-kDa protein, golgin, mitochondrial carrier protein and high-density lipoprotein. RT-PCR was used to demonstrate constitutive expression in four of five of these sequences. Northern hybridisation was difficult due to the very low expression levels of most of the genes. However, a gene-fragment highly homologous to a heat-shock-related 70-kDa protein was strongly expressed in starved bugs, down-regulated after feeding and again expressed later, suggesting a role for a heat-shock protein in starvation survival.

Amino Acid Sequence↗
PubMed2005

Both type-I hemidesmosomes and adherens-type junctions contribute to the cell-substratum adhesion system in myoepithelial cells.

Myoepithelial cells present in exocrine glands cause secretion from the glands by contraction. They have mixed characteristics with regard to cytoskeletal elements, containing both epithelial-type intermediate filaments and smooth muscle-type myofilaments. For further characterization, myoepithelial cells from bovine apocrine sweat glands and tracheal glands were here examined with special attention to the cell-substratum adhesion system. Immunofluorescence microscopy using a panel of antibodies against adherens-type junctional and hemidesmosomal proteins demonstrated two types of cell-substratum junctions in myoepithelial cells from both glands. Type-I hemidesmosomes (HDs) consisting of plectin, BP230, integrin alpha6beta4, and BP180 were thus observed as punctate arrays longitudinally arranged along myoepithelial cell surfaces, while adherens-type junctions were similarly evident as linear rib-like structures. Double-label immunofluoresence revealed the two junctions to be distributed in a mutually exclusive or independent manner. Electron microscopy further demonstrated that apocrine myoepithelial cells surround secretory epithelial cells completely, without any gaps, HDs being abundant along the basement membrane, but with no distinct structures in the inter-hemidesmosomal regions. Immunoelectron microscopy, however, revealed an interhemidesmosomal localization of vinculin, pointing to the existence of adherens-type junctions. Secretory epithelial cells in tracheal glands were found not to be completely covered with myoepithelial cells, so that more than half of them are directly attached to the basement membrane, where they form type II-HDs lacking BP230 and BP180, but no detectable adherens junctions, like epidermal basal cells and sebaceous gland cells. These observations demonstrate that, in addition to their cytoskeleton, myoepithelial cells have both epithelial- and smooth muscle-type cell-substratum adhesion structures, i.e. HDs and dense plaque-like adherens junctions.

Adherens Junctions↗
PubMed2004

Mucosal dominant pemphigus vulgaris with anti-desmoplakin autoantibodies.

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. Anti-DP antibodies have also been rarely identified in other blistering diseases. The significance of anti-DP antibodies in the pathogenesis of bullous diseases is unclear. OBSERVATION: We studied 3 patients with severe and chronic mucosal dominant pemphigus vulgaris (PV). In addition to anti-desmoglein 3 antibodies, these patients had anti-DP autoantibodies, demonstrable by immunofluorescence (IF), immunoprecipitation (IP), and indirect immunoelectromicroscopy (IIEM). This finding suggested these patients may have had PNP and not PV. However, antibodies against periplakin, envoplakin, bullous pemphigoid antigen 1 (BPAG 1), plectin, and 170 kd PNP antigen could not be detected using IP and immunoblotting. Extensive and repeated investigations for an underlying neoplasm throughout the follow-up period were consistently negative for all patients. CONCLUSION: This study demonstrates that anti-DP antibodies without the presence of any other anti-plakin antibodies are not specific for PNP, and are present in some cases of PV. Cellular disadhesion induced by anti-desmoglein antibodies can trigger an epitope-spreading phenomenon with a secondary formation of autoantibodies against desmoplakins, intracellular desmosomal antigens. The role of anti-DP antibodies in the pathogenesis of these PV patients is still unclear. The presence of anti-DP antibodies will produce a false positive serologic interpretation for the diagnosis of PNP especially if one uses only indirect IF on murine bladder, the most commonly employed screening test to identify PNP. More specific immunologic tests are required in this subset of patients with PV.

Autoantibodies↗
PubMed2006

The CH-domain of calponin does not determine the modes of calponin binding to F-actin.

Many actin-binding proteins have been observed to have a modular architecture. One of the most abundant modules is the calponin-homology (CH) domain, found as tandem repeats in proteins that cross-link actin filaments (such as fimbrin, spectrin and alpha-actinin) or link the actin cytoskeleton to intermediate filaments (such as plectin). In proteins such as the eponymous calponin, IQGAP1, and Scp1, a single CH-domain exists, but there has been some controversy over whether this domain binds to actin filaments. A previous three-dimensional reconstruction of the calponin-F-actin complex has led to the conclusion that the visualized portion of calponin bound to actin belongs to its amino-terminal homology (CH) domain. We show, using a calponin fragment lacking the CH-domain, that this domain is not bound to F-actin, and cannot be positioning calponin on F-actin as hypothesized. Further, using classification methods, we show a multiplicity in cooperative modes of binding of calponin to F-actin, similar to what has been observed for other actin-binding proteins such as tropomyosin and cofilin. Our results suggest that the form and function of the structurally conserved CH-domain found in many other actin-binding proteins have diverged. This has broad implications for inferring function from the presence of structurally conserved domains.

Actins↗
PubMed2006

Transcriptional regulation of artemin is related to neurite outgrowth and actin polymerization in mature DRG neurons.

Artemin is a member of the glial cell line-derived neurotrophic factor (GDNF) family of ligands that helps to ensure the survival of sensory neurons. We used an in vitro isolated dorsal root ganglia model to study the effects of artemin on the adult rat neuronal system and investigate differentially regulated genes. We found that 285 genes were differentially transcribed by artemin after 3 h of treatment, including genes related to cell adhesion and actin polymerization. A series of genes involved in the regulation of actin dynamics, including coronin, Myr 5, Wiskott-Aldrich syndrome protein interacting protein, cofilin, drebrin and dynamin were down-regulated by artemin, suggesting that it plays a previously undefined role in the regulation of actin polymerization and synaptic vesicle movement. Artemin also down-regulated the expression of genes related to cell adhesion and matrix assembly, including biglycan, plectin, nestin, neuronatin and the neuron-glia-CAM-related cell adhesion molecule, which is functionally relevant to neurite elongation in DRG neurons. Artemin resulted in increases in total neurite length and branching of the DRG neurons. Also artemin caused an increase of synaptic vesicle clustering. Our results showed that the inhibition of DNA methylation suppressed the artemin-dependent neurite growth, suggesting that the genetic regulation could be relevant to neurite elongation in mature DRG.

Actins↗
PubMed1999

Autoimmunity against desmosomal cadherins in pemphigus.

Pemphigus is a unique and interesting autoimmune disease, in which autoantibodies play a major pathogenic role and cause blister formation. Several questions raised from clinical observation in pemphigus have been answered with logic at the molecular level owing to recent remarkable progress in research in the field of pemphigus. The clinical phenotype of classic pemphigus, pemphigus vulgaris (PV) and pemphigus foliaceus (PF), is defined by anti-desmoglein autoantibody profile. Sera containing anti-Dsg3 IgG alone cause mucosal dominant PV with limited skin involvement. Sera containing both anti-Dsg3 and anti-Dsg1 cause mucocutaneous PV, which affects both the skin and mucous membrane. Sera containing only anti-Dsg1 cause PF, which shows cutaneous but no mucosal involvement. In herpetiform pemphigus (HP) most sera recognize Dsg1 and the rest of them recognize Dsg3, indicating that HP is a clinical variant of PF or PV. Patients with paraneoplastic pemphigus (PNP) have autoantibodies against multiple molecules. Now we know that they have autoantibodies against all members of the plakin family, which are cytoplasmic proteins and include desmoplakin, BPAG1, envoplakin, periplakin, and plectin. Cell surface target antigens of PNP, which blister-inducing pathogenic autoantibodies attack, were finally discovered to be Dsg3 and Dsg1. Therefore, PNP is characterized as an autoimmune disease against plakin molecules and desmogleins. Autoimmune targets of IgA pemphigus are likely more heterogeneous than originally thought. So far, desmocollin 1, Dsg3, and Dsg1 are known as their target antigens. Thus, pemphigus has become one of well-characterized tissue-specific autoimmune diseases. Pemphigus will be a good model disease in the next century to address the central issue of autoimmune disease and basic immunology; why and how do patients with autoimmune diseases start to recognize self as non-self?

Animals↗
PubMed1999

Acquired skin disease of hemidesmosomes.

The hemidesmosome is a membrane-associated supramolecular dermal epidermal complex linking the cytoskeleton of the basal keratinocyte to structures within the papillary dermis. Different components of this complex have been identified as autoantigens in autoimmune bullous skin diseases. Some of the autoantigens have been characterized at the molecular level. Little is known, however, about the factors that initiate the production of autoantibodies. By histopathology, acquired skin diseases of hemidesmosomes show subepidermal blisters and by direct immunofluorescence, linear deposits of IgG, C3 or IgA at the dermal epidermal junction. Bullous pemphigoid (BP) is the most common acquired disease of hemidesmosomes. Two proteins, BP180 and BP230, have been identified as primary targets of autoantibodies in BP. In addition, pemphigoid/herpes gestationis, lichen planus pemphigoides, cicatricial pemphigoid and linear IgA disease are characterized by an immune response to BP180. Laminin 5 is another well-characterized anchoring filament-lamina densa component of hemidesmosomes. Patients with autoantibodies to laminin 5 show the clinical phenotype of cicatricial pemphigoid. 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. Recently, diseases with autoantibodies to 105 and 200 kDa proteins of the lower lamina lucida have been reported. The association of these autoantigens with hemidesmosomes still needs to be demonstrated. Finally, anchoring fibrils associate with the dermal epidermal anchoring complex. The major structural component of anchoring fibrils is type VII collagen, the autoantigen of epidermolysis bullosa acquisita.

Animals↗