Disease relevance of Hemidesmosomes

• Isolation of a human epidermal cDNA corresponding to the 180-kD autoantigen recognized by bullous pemphigoid and herpes gestationis sera. Immunolocalization of this protein to the hemidesmosome [1].
• Gene correction of integrin beta4-dependent pyloric atresia-junctional epidermolysis bullosa keratinocytes establishes a role for beta4 tyrosines 1422 and 1440 in hemidesmosome assembly [2].
• These findings suggest that the molecular abnormalities underlying different forms of junctional epidermolysis bullosa appear to affect certain critical intracellular functions of hemidesmosomes, such as the normal connections with keratin intermediate filaments [3].
• Bullous pemphigoid is a blistering skin disease associated with autoantibodies against the BP180 antigen, a transmembrane component of the hemidesmosome [4].
• Although immunoblotting results were consistent with the autoantibody specificities previously described in paraneoplastic pemphigus sera, immunoelectron microscopy demonstrated the presence of Ig deposits on desmosomal plaques, on hemidesmosomes and, surprisingly, on both the extracellular part of desmosomes and the keratinocyte plasma membrane [5].

High impact information on Hemidesmosomes

• Epithelial detachment due to absence of hemidesmosomes in integrin beta 4 null mice [6].
• To study the contribution of the integrin alpha 6 beta 4 in hemidesmosome formation and their anchoring properties, we inactivated the beta 4 gene in mice by targeted gene disruption [6].
• This absence is likely to result from the lack of alpha 6/beta 4, the only integrin in hemidesmosomes of stratified squamous and transitional epithelia [7].
• In stratified epithelia, alpha 6 beta 4 is concentrated in specialised adhesion structures, called hemidesmosomes, which are implicated in the stable attachment of the basal cells to the underlying basement membrane by connecting the intermediate filaments with the extracellular matrix [6].
• Epiligrin is the ligand of an adhesion super complex composed of alpha 3 beta 1-FAs and alpha 6 beta 4-SACs (hemidesmosomes) [8].

Chemical compound and disease context of Hemidesmosomes

• Immunofluorescence studies of junctional epidermolysis bullosa with pyloric atresia (JEB-PA) have suggested abnormalities in the expression of the alpha6 beta4 integrin, an integral component of hemidesmosomes [9].
• 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 [10].

Biological context of Hemidesmosomes

• Beta4 integrin is required for hemidesmosome formation, cell adhesion and cell survival [11].
• Transient transfection studies of PA-JEB cells with beta4 revealed that the integrin alpha6beta4 becomes incorporated into the alpha3beta1-CD151 clusters where it induces the formation of hemidesmosomes [12].
• Together, these results highlight the importance of serine phosphorylation in regulating type II hemidesmosome disassembly, implicate a cluster of serine residues within the connecting segment of beta 4, and argue for a key role for PKC-alpha in regulating these structures [13].
• They have essentially normal blood and bone marrow cell counts and grossly normal tissue morphology, including hemidesmosomes in skin, and expression of alpha3 and alpha6 integrins [14].
• Cell adhesion and spreading were also impaired, and this correlated with decreased expression of the alpha6beta4 integrin, decreased formation of hemidesmosomes and decreased assembly of the actomyosin cytoskeleton [15].

Anatomical context of Hemidesmosomes

• Differential formation of desmosomes and hemidesmosomes in epidermal cell cultures treated with retinoic acid [16].
• This integrin was recently shown by several laboratories to be part of the hemidesmosome complex, an epithelial adhesive structure that is the plasma membrane anchoring site for keratin-containing intermediate filaments [17].
• Epiligrin, the major component of human keratinocyte extracellular matrix, serves as the preferred integrin ligand for alpha 3 beta 1 in plasma membranes and focal adhesions, and colocalizes with alpha 6 beta 4 in hemidesmosomes [18].
• EGF-R signaling through Fyn kinase disrupts the function of integrin alpha6beta4 at hemidesmosomes: role in epithelial cell migration and carcinoma invasion [19].
• Functional studies on the alpha6beta4 integrin have focused primarily on its role in the organization of hemidesmosomes, stable adhesive structures that associate with the intermediate filament cytoskeleton [20].

Associations of Hemidesmosomes with chemical compounds

• Upon ligand binding, the alpha6beta4 integrin becomes phosphorylated on tyrosine residues and combines sequentially with the adaptor molecules Shc and Grb2, linking to the ras pathway, and with cytoskeletal elements of hemidesmosomes [21].
• Expression of chimeric proteins, which consist of the membrane targeting sequence of K-Ras fused to the cytoplasmic domain of BP180 with increasing internal deletions or lacking the NH2 terminus, indicates that the localization of BP180 in hemidesmosomes is mediated by a segment that spans 265 amino acids [22].
• While alpha 3 beta 1 mediates adhesion, spreading, and migration (Kreidberg, J.A. 2000. Curr. Opin. Cell Biol. 12:548--553), alpha 6 beta 4 is involved in BM anchorage via hemidesmosomes (Borradori, L., and A. Sonnenberg. 1999. J. Invest. Dermatol. 112:411--418) [23].
• The members of the plakin family of proteins serve as epidermal cytolinkers and components of cell-cell and cell-matrix adhesion complexes, i.e., desmosomes and hemidesmosomes, respectively [24].
• The alpha6beta4 integrin-a laminin-5 receptor-mediates assembly of hemidesmosomes and recruitment of Shc and phosphoinositide 3-kinase through the unique cytoplasmic extension of beta4 [25].

Gene context of Hemidesmosomes

• We suggest that CD151 plays a role in the formation and stability of hemidesmosomes by providing a framework for the spatial organization of the different hemidesmosomal components [12].
• These observations suggest that the EGF-R causes disassembly of hemidesmosomes by activating Fyn, which in turn phosphorylates the beta4 cytoplasmic domain [19].
• Others, such as CD9 and CD81, remain diffusely distributed at the cell surface.In conclusion, we show that CD151 is a major component of (pre)-hemidesmosomal structures and that its recruitment into hemidesmosomes is regulated by the integrin alpha6beta4 [12].
• Elongation of the epidermis of the nematode Caenorhabditis elegans involves both actomyosin-mediated changes in lateral epidermal cell shape and body muscle attachment to dorsal and ventral epidermal cells via intermediate-filament/hemidesmosome structures. vab-19 mutants are defective in epidermal elongation and muscle attachment to the epidermis [26].
• We propose that the BP230 N terminus competes with endogenous BP230 protein for BP180 binding and inhibits incorporation of BP180 into the cell surface at the site of the hemidesmosome [27].

Analytical, diagnostic and therapeutic context of Hemidesmosomes

• A rabbit antiserum prepared against the lysogenic BP180 FP specifically recognized the BP180 antigen from human epidermal extracts by immunoblotting, labeled the BMZ by indirect immunofluorescence, and bound to human epidermal hemidesmosomes by immuno-electron microscopy [1].
• Immunoelectron microscopy showed that CD151 is concentrated in hemidesmosomes [12].
• Here we extend previous studies to report that by immunofluorescence microscopy the alpha 6 integrin subunit colocalizes with bullous pemphigoid antigen and type VII collagen in newly forming hemidesmosomes in the developing 17-day fetal rabbit eye [28].
• Video microscopy analysis reveals that assembly of hemidesmosomes is preceded by recruitment of beta4 integrin subunit to the actin core before its positioning at hemidesmosomes [29].
• Light and electron microscopy revealed that the dermo-epidermal separation occurred at the basement membrane between the sites of bullous pemphigoid antigen and laminin and that the hemidesmosomes were selectively disrupted [30].

References