Structure and Function of Hemidesmosomes: More Than Simple Adhesion Complexes
1999; Elsevier BV; Volume: 112; Issue: 4 Linguagem: Inglês
10.1046/j.1523-1747.1999.00546.x
ISSN1523-1747
AutoresLuca Borradori, Arnoud Sonnenberg,
Tópico(s)Hair Growth and Disorders
ResumoThe attachment of cells to the extracellular matrix is of crucial importance in the maintenance of tissue structure and integrity. In stratified epithelia such as in skin as well as in other complex epithelia multiprotein complexes called hemidesmosomes are involved in promoting the adhesion of epithelial cells to the underlying basement membrane. In the past few years our understanding of the role of hemidesmosomes has improved considerably. Their importance has become apparent in clinical conditions, in which absence or defects of hemidesmosomal proteins result in devastating blistering diseases of the skin. Molecular genetic studies have increased our knowledge of the function of the various components of hemidesmosomes and enabled the characterization of protein–protein interactions involved in their assembly. It has become clear that the α6β4 integrin, a major component of hemidesmosomes, is able to transduce signals from the extracellular matrix to the interior of the cell, that critically modulate the organization of the cytoskeleton, proliferation, apoptosis, and differentiation. Nevertheless, our knowledge of the mechanisms regulating the functional state of hemidesmosomes and, hence, the dynamics of cell adhesion, a process of crucial importance in development, wound healing or tumor invasion, remains limited. The aims of this review are to highlight the recent progresses of our knowledge on the organization and assembly of hemidesmosomes, their involvement in signaling pathways as well as their participation in clinical pathologic conditions. The attachment of cells to the extracellular matrix is of crucial importance in the maintenance of tissue structure and integrity. In stratified epithelia such as in skin as well as in other complex epithelia multiprotein complexes called hemidesmosomes are involved in promoting the adhesion of epithelial cells to the underlying basement membrane. In the past few years our understanding of the role of hemidesmosomes has improved considerably. Their importance has become apparent in clinical conditions, in which absence or defects of hemidesmosomal proteins result in devastating blistering diseases of the skin. Molecular genetic studies have increased our knowledge of the function of the various components of hemidesmosomes and enabled the characterization of protein–protein interactions involved in their assembly. It has become clear that the α6β4 integrin, a major component of hemidesmosomes, is able to transduce signals from the extracellular matrix to the interior of the cell, that critically modulate the organization of the cytoskeleton, proliferation, apoptosis, and differentiation. Nevertheless, our knowledge of the mechanisms regulating the functional state of hemidesmosomes and, hence, the dynamics of cell adhesion, a process of crucial importance in development, wound healing or tumor invasion, remains limited. The aims of this review are to highlight the recent progresses of our knowledge on the organization and assembly of hemidesmosomes, their involvement in signaling pathways as well as their participation in clinical pathologic conditions. bullous pemphigoid antigen 180 bullous pemphigoid antigen 230 hemidesmosome Hemidesmosomes (HD) are specialized junctional complexes, that contribute to the attachment of epithelial cells to the underlying basement membrane in stratified and other complex epithelia, such as the skin, the cornea, parts of the gastrointestinal and respiratory tract, and the amnion. These multiprotein complexes determine cell–stromal coherence and provide cells with cues critical for their polarization, their spatial organization, and for tissue architecture (Borradori and Sonnenberg, 1996Borradori L. Sonnenberg A. et al.Hemidesmosomes: roles in adhesion, signaling and human diseases.Curr Opin Cell Biol. 1996; 8: 647-656Crossref PubMed Scopus (192) Google Scholar;Green and Jones, 1996Green K.J. Jones J.C.R. et al.Desmosomes and hemidesmosomes: structure and function of molecular components.Faseb J. 1996; 10: 871-881Crossref PubMed Scopus (288) Google Scholar;Gumbiner, 1996Gumbiner B.M. et al.Cell adhesion: the molecular basis of tissue architecture and morphogenesis.Cell. 1996; 84: 345-357Abstract Full Text Full Text PDF PubMed Scopus (2797) Google Scholar). Although these structures appear relatively stable, which would counteract cell migration and displacement, their functional activity can be modulated. The regulation of the adhesive interactions of HD with the underlying basement membrane is essential in various normal biologic processes, such as wound healing and tissue morphogenesis. The importance of these complexes is attested by the fact that an altered expression of hemidesmosomal constituents results in several types of blistering disorders of the skin (Table 1) (Christiano and Uitto, 1996Christiano A.M. Uitto J. et al.Molecular complexity of the cutaneous basement membrane zone. Revelations from the paradigms of epidermolysis bullosa.Exp Dermatol. 1996; 5: 1-11Crossref PubMed Scopus (176) Google Scholar) and is likely involved in the development and progression of certain cancers (Rabinovitz and Mercurio, 1996Rabinovitz I. Mercurio A.M. et al.The integrin α6β4 and the biology of carcinoma.Biochem Cell Biol. 1996; 74: 811-821Crossref PubMed Scopus (100) Google Scholar). Considerable progress has been made in defining the molecular structure and architecture of HD. There is accumulating evidence which indicates that different factors, such as extracellular matrix (ECM) proteins and growth factors, regulate their function (Giancotti, 1996Giancotti F.G. et al.Signal transduction by the α6β4 integrin: charting the path between laminin binding and nuclear events.J Cell Sci. 1996; 109: 1165-1172Crossref PubMed Google Scholar). The α6β4 integrin appears to act as a regulatory component by transducing signals that profoundly affect the entire cellular machinery (Mainiero et al., 1995Mainiero F. Pepe A. Wary K.K. Spinardi L. Mohammadi M. Schlessinger J. Giancotti F.G. et al.Signal transduction by the α6β4 integrin: distinct β4 subunit sites mediate recruitment of Shc/Grb2 and association with the cytoskeleton of hemidesmosomes.Embo J. 1995; 14: 4470-4481Crossref PubMed Scopus (225) Google Scholar,Mainiero et al., 1996Mainiero F. Pepe A. Yeon M. Ren Y. Giancotti F.G. et al.The intracellular functions of α6β4 integrin are regulated by EGF.J Cell Biol. 1996; 134: 241-253Crossref PubMed Scopus (159) Google Scholar,Mainiero et al., 1997Mainiero F. Murgia C. Wary K.K. et al.The coupling of α6β4 integrin to Ras-MAP kinase pathways mediated by Shc controls keratinocyte proliferation.Embo J. 1997; 16: 2365-2375Crossref PubMed Scopus (293) Google Scholar). Hence, HD may not only represent structural adhesion complexes, but they may also serve via the α6β4 integrin as "signaling devices" affecting the cell phenotype. The aim of this review is to summarize recent developments in our understanding of the molecular organization of HD. Clinical observations as well as cell biologic studies, including gene targeting experiments, transfection, and yeast two-hybrid system analyses, have dramatically increased our knowledge of the function of the various hemidesmosomal constituents and allowed defining functionally important domains within these proteins.Table 1Molecular constituents of hemidesmosomes and functionally associated structures and their involvement in human diseases (see text for References)Structural elementProteinKnockout animal modelDisease aAutoimmune blistering diseases are associated with autoantibodies directed against constituents of the hemidesmosomal adhesion complex, while mutations in their genes result in inherited bullous disorders with often a similar phenotype. In autoimmune blistering diseases autoantibodies might be directed against additional target antigens. EBS, epidermolysis bullosa simplex; MD, muscular dystrophy; GABEB, generalized atrophic benign epidermolysis bullosa; JEB, junctional epidermolysis bullosa; PA, pyloric atresia; DEB, dystrophic epidermolysis bullosa; LABD, linear IgA bullous dermatosis; SLE, systemic lupus erythematosus.AutoimmuneInheritedIntermediate filamentsKeratins 5 and 14Yes–EBSHemidesmosomesBP230 (BPAG1)YesBullous pemphigoid–HemidesmosomesPlectinYesPemphigoid-like disease(?)EBS-MDHemidesmosomesα6 integrin subunitYes–JEB-PAβ4 integrin subunitYesCicatricial pemphigoid(?)JEB-PAHemidesmosomes—BP180 (BPAG2)NoBullous pemphigoidGABEBAnchoring filamentsCicatricial pemphigoidGestational pemphigoidAnchoring filamentsLaminin-5 (α3β3γ2)Yes (α3,β3 bA spontaneous mutation in the murine β3 gene resulting in a JEB phenotype has been described (Kuster et al. 1997).)Cicatricial pemphigoidJEBGABEBAnchoring filamentsLAD-1 cLAD-1, the linear IgA bullous dermatosis antigen 1, might represent a proteolytic product of BP180 encompassing its extracellular domain.NoLABDGABEB dLack of immunoreactivity in patients' skin.Anchoring fibrilsType VII collagenYes eUitto J et al. 1988 (personal communication).EBADEBBullous SLEa Autoimmune blistering diseases are associated with autoantibodies directed against constituents of the hemidesmosomal adhesion complex, while mutations in their genes result in inherited bullous disorders with often a similar phenotype. In autoimmune blistering diseases autoantibodies might be directed against additional target antigens. EBS, epidermolysis bullosa simplex; MD, muscular dystrophy; GABEB, generalized atrophic benign epidermolysis bullosa; JEB, junctional epidermolysis bullosa; PA, pyloric atresia; DEB, dystrophic epidermolysis bullosa; LABD, linear IgA bullous dermatosis; SLE, systemic lupus erythematosus.b A spontaneous mutation in the murine β3 gene resulting in a JEB phenotype has been described (Kuster et al., 1997Kuster J.E. Guarnieri M.H. Ault J.G. Flaherty L. Swiatek P.J. et al.IAP insertion in the murine LamB3 gene results in junctional epidermolysis bullosa.Mamm Genome. 1997; 8: 673-681Crossref PubMed Scopus (77) Google Scholar).c LAD-1, the linear IgA bullous dermatosis antigen 1, might represent a proteolytic product of BP180 encompassing its extracellular domain.d Lack of immunoreactivity in patients' skin.e Uitto J et al. 1988 (personal communication). Open table in a new tab Ultrastructurally, HD appear as small electron dense domains (less than 0.5 μm) of the plasma membrane on the ventral surface of basal keratinocytes of human skin. Their most conspicuous component is a tripartite cytoplasmic plaque, to which the bundles of intermediate filaments (IF) are attached (Figure 1). HD are associated with a sub-basal dense plate in the lamina lucida and are connected via fine thread-like anchoring filaments to the lamina densa. In its turn, the latter seems to be anchored to the underlying papillary dermis by the cross-banded anchoring fibrils. These various morphological structures, i.e., IF, hemidesmosomal plaque, anchoring filaments, and anchoring fibrils, constitute a functional unit named the hemidesmosomal adhesion complex, that provides stable adherence of keratinocytes to the underlying epidermal basement membrane. As the identification of the first constituent of HD almost three decades ago (Stanley et al., 1981Stanley J.R. Hawley-Nelson P. Yuspa S.H. Shevach E.M. Katz S.I. et al.Characterization of bullous pemphigoid antigen: a unique basement membrane protein of stratified squamous epithelia.Cell. 1981; 24: 897-903Abstract Full Text PDF PubMed Scopus (423) Google Scholar), the biochemical characterization and the primary molecular sequencing of the various constituents of HD and associated structures has progressed enormously. The molecular organization of HD is based on three classes of proteins: the cytoplasmic plaque proteins acting as linkers for elements of the cytoskeleton at the cytoplasmic surface of the plasma membrane, the transmembrane proteins serving as cell receptors connecting the cell interior to the ECM, and finally, the basement membrane-associated proteins of the ECM (Figure 2 and Figure 3).Figure 3Schematic model of a hemidesmosome (HD) illustrating the molecular interactions potentially involved in its assembly. The nucleation of HD involves the clustering of the α6β4 integrin at the basal cell side of the cells, which depends on its interaction with ECM ligands, such as laminin-5. α6β4 can also polarize at the basal cell surface in a ligand-independent way (Nievers et al., 1998Nievers M.G. Schaapveld R.Q.J. Oomen L.C.J.M. Fontao L. Geerts D. Sonnenberg A. et al.Ligand-independent role of the β4 integrin subunit in the formation of hemidesmosomes.J Cell Sci. 1998; 111: 1659-1672PubMed Google Scholar). The capacity of α6β4 and plectin to associate with each other and to self-polymerize facilitates the formation of a core, that might serve as attachment site for BP180 and BP230. The stabilization of HD is then achieved by multiple protein–protein interactions. The β4 cytoplasmic domain has the ability to interact, in addition to plectin, with BP180 and possibly with BP230. In turn, BP180 associates with plectin and BP230, both implicated in the attachment of the keratin networks to the plasma membrane. Various signals have an effect on the adhesive state of HD and modulate the cross-talk between HD and structures mediating dynamic adhesion, such as focal contacts.View Large Image Figure ViewerDownload (PPT) The cytoplasmic plaque constituents include the bullous pemphigoid antigen 230 (BP230, also named bullous pemphigoid antigen 1) (Stanley et al., 1988Stanley J.R. Tanaka T. Mueller S. Klaus-Kovtun V. Roop D. et al.Isolation of cDNA for bullous pemphigoid antigen by use of patients' autoantibodies.J Clin Invest. 1988; 82: 1864-1870Crossref PubMed Scopus (265) Google Scholar;Sawamura et al., 1991Sawamura D. Li K. Chu M.L. Uitto J. et al.Human bullous pemphigoid antigen (BPAG1). Amino acid sequences deduced from cloned cDNAs predict biologically important peptide segments and protein domains.J Biol Chem. 1991; 266: 17784-17790Abstract Full Text PDF PubMed Google Scholar), plectin (Wiche et al., 1991Wiche G. Becker B. Luber K. et al.Cloning and sequencing of rat plectin indicates a 466-kD polypeptide chain with a three domain structure based on a central alpha-helical coiled-coil.J Cell Biol. 1991; 114: 83-99Crossref PubMed Scopus (149) Google Scholar;McLean et al., 1996McLean W.H.I. Pulkkinen L. Smith F.J.D. et al.Loss of plectin causes epidermolysis bullosa with muscular dystrophy: cDNA cloning and genomic organization.Genes Dev. 1996; 10: 1724-1735Crossref PubMed Scopus (272) Google Scholar), and other less well characterized proteins, the two high molecular weight proteins called HD1 (Hieda et al., 1992Hieda Y. Nishizawa Y. Uematsu J. Owaribe K. et al.Identification of a new hemidesmosomal protein, HD1: a major, high molecular mass component of isolated hemidesmosomes.J Cell Biol. 1992; 116: 1497-1506Crossref PubMed Scopus (185) Google Scholar) and IFAP 300 (Skalli et al., 1994Skalli O. Jones J.C.R. Gagescu R. Goldman R.D. et al.IFAP 300 is common to desmosomes and hemidesmosomes and is a possible linker of intermediate filaments to these junctions.J Cell Biol. 1994; 125: 159-170Crossref PubMed Scopus (81) Google Scholar), and the protein P200 (Kurpakus and Jones, 1991Kurpakus M.A. Jones J.C.R. et al.A novel hemidesmosomal plaque component: tissue distribution and incorporation into assembling hemidesmosomes in an in vitro model.Exp Cell Res. 1991; 194: 139-146Crossref PubMed Scopus (39) Google Scholar). BP230 and plectin are proteins with related sequences belonging to the plakin family of proteins implicated in the organization of the cytoskeletal architecture (Tanaka et al., 1991Tanaka T. Parry D.A.D. Klaus-Kovtun V. Steinert P.M. Stanley J.R. et al.Comparison of molecularly cloned bullous pemphigoid antigen to desmoplakin I confirms that they define a new family of cell adhesion junction plaque proteins.J Biol Chem. 1991; 266: 12555-12559Abstract Full Text PDF PubMed Google Scholar;Ruhrberg and Watt, 1997Ruhrberg C. Watt F.M. et al.The plakin family, versitile organizer of cytoskeletal architecture.Curr Opin Gen Dev. 1997; 7: 392-397Crossref PubMed Scopus (177) Google Scholar) (Figure 2). Based on their primary sequence, they are predicted to contain a central coil-coiled domain flanked by two globular domains. BP230 was first recognized as a target antigen in bullous pemphigoid, which is an autoimmune blistering disorder of the skin (Stanley et al., 1981Stanley J.R. Hawley-Nelson P. Yuspa S.H. Shevach E.M. Katz S.I. et al.Characterization of bullous pemphigoid antigen: a unique basement membrane protein of stratified squamous epithelia.Cell. 1981; 24: 897-903Abstract Full Text PDF PubMed Scopus (423) Google Scholar). Its COOH-terminal domain has the ability to associate with IF, implying a role of this protein in the attachment of the keratin IF to the hemidesmosomal plaque (Yang et al., 1996Yang Y. Dowling J. Yu Q.-C. Kouklis P. Cleveland D.W. Fuchs E. et al.An essential cytoskeletal linker protein connecting actin microfilaments to intermediate filaments.Cell. 1996; 86: 655-665Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar). In addition, transfection studies and yeast two-hybrid analyses have provided evidence that indicates that the NH2-terminus of BP230 interacts with the cytoplasmic domain of BP180 (Borradori et al., 1998Borradori L. Chavanas S. Schaapveld R.Q.J. Gagnoux-Palacios L. Calafat J. Meneguzzi G. Sonnenberg A. et al.Role of the bullous pemphigoid 180 (BP180) in the assembly of hemidesmosomes and cell adhesion. Re-expression of BP180 in generalized atrophic benign epidermolysis bullosa keratinocytes.Exp Cell Res. 1998; 239: 463-476Crossref PubMed Scopus (54) Google Scholar) (J. Koster and B. Favre, unpublished results) and probably also of the β4 integrin subunit (Schaapveld et al., 1998Schaapveld R.Q.J. Borradori L. Geerts D. et al.Hemidesmosomes formation is initiated by the β4 integrin subunit, requires complex formation with HD1/plectin and involves a direct interaction between β4 and the bullous pemphigoid antigen 180.J Cell Biol. 1998; 142: 271-284Crossref PubMed Scopus (147) Google Scholar), the two transmembrane constituents of HD (Figure 3). Plectin is a large phosphoprotein of ≈500 kDa expressed in a variety of stratified and simple epithelia, where it acts as a multifunctional cytoskeletal linker (Wiche, 1998Wiche G. et al.Role of plectin in cytoskeleton organization and dynamics.J Cell Sci. 1998; 111: 2477-2486Crossref PubMed Google Scholar). Variants of plectin due to alternative splicing have been identified, the specific function of which remain to be determined (Elliot et al., 1997Elliot C.E. Becker B. Oehler S. Castanon M.J. Hauptmann R. Wiche G. et al.Plectin transcript diversity: identification and tissue distribution of variants with distinct coding exons and rodless isoforms.Genomics. 1997; 42: 115-125Crossref Scopus (99) Google Scholar). The COOH-terminal domain of plectin has been shown to bind to keratins, neurofilaments, and vimentin in vitro. The binding of plectin to vimentin and cytokeratins requires a specific 50 amino acid stretch within the COOH-terminal 5 repeat domain (Nikolic et al., 1996Nikolic B. MacNulty E. Mir B. Wiche G. et al.Basic amino acid residue cluster within nuclear targeting sequence motif is essential for cytoplasmic plectin-vimentin network junction.J Cell Biol. 1996; 134: 1455-1467Crossref PubMed Scopus (145) Google Scholar). The NH2-terminal domain of plectin contains an actin-binding domain homologous to that of spectrin and dystrophin (McLean et al., 1996McLean W.H.I. Pulkkinen L. Smith F.J.D. et al.Loss of plectin causes epidermolysis bullosa with muscular dystrophy: cDNA cloning and genomic organization.Genes Dev. 1996; 10: 1724-1735Crossref PubMed Scopus (272) Google Scholar). Strikingly, this region also contains sequences that interact with the cytoplasmic tail of β4 (Niessen et al., 1997aNiessen C.M. Hulsman E.H.M. Oomen L.C.J.M. Kuikman I. Sonnenberg A. et al.A minimal region on the integrin β4 subunit that is critical to its localization in hemidesmosomes regulates the distribution of HD1/plectin in COS-7 cells.J Cell Sci. 1997; 110: 1705-1716Crossref PubMed Google Scholar,Niessen et al., 1997bNiessen C.M. Hulsman E.H.M. Rots E.S. Sanchez-Aparicio P. Sonnenberg A. et al.Integrin α6β4 forms a complex with the cytoskeletal protein HD1 and induces its redistribution in transfected COS-7 cells.Mol Biol Cell. 1997; 8: 555-566Crossref PubMed Scopus (58) Google Scholar;Rezniczek et al., 1998Rezniczek G.A. de Pereda J.M. Reipert S. Wiche G. et al.Linking integrin α6β4-based cell adhesion to the intermediate filament cytoskeleton: direct interaction between the β4 subunit and plectin at multiple molecular sites.J Cell Biol. 1998; 141: 209-225Crossref PubMed Scopus (200) Google Scholar). It is likely that the association of plectin with β4 prevails over that with the actin cytoskeleton, explaining the preferential distribution of plectin in HD. Preliminary studies indicate that this protein associates with the cytoplasmic tail of BP180 (Figure 3). 1Aho S, Uitto J: Basement membrane interaction disclosed by yeast two-hybrid system. J Invest Dermatol 108:546 1997 (abstr.) Plectin is thus a multifunctional protein involved in both the attachment of IF to the plasma membrane and the linking of various hemidesmosomal constituents to each other. It is likely that phosphorylation of plectin by distinct kinases, such as p34cdc2, kinase A and kinase C, regulates its interactions with the cytoskeleton (Foisner et al., 1996Foisner R. Malecz N. Dressel N. Stadler C. Wiche G. et al.M-phase specific phosphorylation and structural rearrangement of the cytoplasmic cross-linking protein plectin involve p34cdc2 kinase.Mol Biol Cell. 1996; 7: 273-288Crossref PubMed Scopus (45) Google Scholar;Malecz et al., 1996Malecz N. Foisner R. Stadler C. Wiche G. et al.Identification of plectin as a substrate of p34cdc2 kinase and mapping of a single phosphorylation site.J Biol Chem. 1996; 271: 8203-8208Crossref PubMed Scopus (35) Google Scholar). The identity of IFAP300 and HD1 remains unclear. Their molecular size and tissue distribution are similar to those of plectin and they cross-react immunologically (Gache et al., 1996Gache Y. Chavanas S. Lacour J.-P. Wiche G. Owaribe K. Meneguzzi G. Ortonne J.P. et al.Defective expression of plectin/HD1 in epidermolysis bullosa simplex with muscular dystrophy.J Clin Invest. 1996; 97: 2289-2298Crossref PubMed Scopus (201) Google Scholar;McLean et al., 1996McLean W.H.I. Pulkkinen L. Smith F.J.D. et al.Loss of plectin causes epidermolysis bullosa with muscular dystrophy: cDNA cloning and genomic organization.Genes Dev. 1996; 10: 1724-1735Crossref PubMed Scopus (272) Google Scholar;Smith et al., 1996Smith F.J.D. Eady R.A.J. Leigh I.M. et al.Plectin deficiency results in muscular dystrophy with epidermolysis bullosa.Nature Genet. 1996; 13: 450-457Crossref PubMed Scopus (316) Google Scholar;Ruhrberg and Watt, 1997Ruhrberg C. Watt F.M. et al.The plakin family, versitile organizer of cytoskeletal architecture.Curr Opin Gen Dev. 1997; 7: 392-397Crossref PubMed Scopus (177) Google Scholar). It is noteworthy that mutations in the plectin gene in patients with epidermolysis bullosa simplex associated with muscular dystrophy result in the absence of expression of both plectin and HD1 (Gache et al., 1996Gache Y. Chavanas S. Lacour J.-P. Wiche G. Owaribe K. Meneguzzi G. Ortonne J.P. et al.Defective expression of plectin/HD1 in epidermolysis bullosa simplex with muscular dystrophy.J Clin Invest. 1996; 97: 2289-2298Crossref PubMed Scopus (201) Google Scholar;McLean et al., 1996McLean W.H.I. Pulkkinen L. Smith F.J.D. et al.Loss of plectin causes epidermolysis bullosa with muscular dystrophy: cDNA cloning and genomic organization.Genes Dev. 1996; 10: 1724-1735Crossref PubMed Scopus (272) Google Scholar;Smith et al., 1996Smith F.J.D. Eady R.A.J. Leigh I.M. et al.Plectin deficiency results in muscular dystrophy with epidermolysis bullosa.Nature Genet. 1996; 13: 450-457Crossref PubMed Scopus (316) Google Scholar). It is possible that IFAP300 and plectin are related proteins or even isoforms of a single protein, but characterization of their primary sequence is required. Finally, because of its localization to the inner hemidesmosomal plaque, it is likely that the 200 kDa protein P200 is implicated in the linkage of IF to the plasma membrane (Kurpakus and Jones, 1991Kurpakus M.A. Jones J.C.R. et al.A novel hemidesmosomal plaque component: tissue distribution and incorporation into assembling hemidesmosomes in an in vitro model.Exp Cell Res. 1991; 194: 139-146Crossref PubMed Scopus (39) Google Scholar). The transmembrane constituents of HD include the α6β4 integrin and BP180 [also termed bullous pemphigoid antigen 2 (BPAG2) or type XVII collagen] (Figure 2 and Figure 3). In contrast to most integrins that are associated with the actin cytoskeleton, the α6β4 integrin is particular in that it is found in HD at sites where keratin IF attach (Stepp et al., 1990Stepp M.A. Spurr-Michaud S. Tisdale A. Elwell J. Gipson I.K. et al.α6β4 integrin heterodimer is a component of hemidesmosomes.Proc Natl Acad Sci USA. 1990; 87: 8970-8974Crossref PubMed Scopus (412) Google Scholar;Tamura et al., 1990Tamura R.N. Rozzo C. Starr L. Chambers J. Reichardt L.F. Cooper H.M. Quaranta V. et al.Epithelial integrin α6β4: complete primary structure of α6 and variant forms of β4.J Cell Biol. 1990; 111: 1593-1604Crossref PubMed Scopus (256) Google Scholar;Sonnenberg et al., 1991Sonnenberg A. Calafat J. Janssen H. et al.Integrin α6/β4 complex is located in hemidesmosomes, suggesting a major role in epidermal cell-basement membrane adhesion.J Cell Biol. 1991; 113: 907-917Crossref PubMed Scopus (475) Google Scholar). The cytoplasmic tail of β4 is crucial for the interaction of α6β4 with various elements of HD (Giancotti, 1996Giancotti F.G. et al.Signal transduction by the α6β4 integrin: charting the path between laminin binding and nuclear events.J Cell Sci. 1996; 109: 1165-1172Crossref PubMed Google Scholar;Murgia et al., 1998Murgia C. Blaikie P. Kim N. Dans M. Petrie H.T. Giancotti F.G. et al.Cell cycle and adhesion defects in mice carrying a targeted deletion of the integrin β4 cytoplasmic domain.Embo J. 1998; 17: 3940-3951Crossref PubMed Scopus (130) Google Scholar). It consists of over 1000 amino acids and contains two pairs of type III fibronectin (FNIII) repeats separated by a connecting segment (CS). Transfection studies have shown that the first pair of FNIII repeats and the adjacent stretch of 27 amino acids of the CS of the cytoplasmic tail of β4 are required for the localization of the α6β4 integrin in HD (Niessen et al., 1997aNiessen C.M. Hulsman E.H.M. Oomen L.C.J.M. Kuikman I. Sonnenberg A. et al.A minimal region on the integrin β4 subunit that is critical to its localization in hemidesmosomes regulates the distribution of HD1/plectin in COS-7 cells.J Cell Sci. 1997; 110: 1705-1716Crossref PubMed Google Scholar). While this membrane-proximal region of the β4 cytoplasmic tail can directly associate with plectin (Niessen et al., 1997bNiessen C.M. Hulsman E.H.M. Rots E.S. Sanchez-Aparicio P. Sonnenberg A. et al.Integrin α6β4 forms a complex with the cytoskeletal protein HD1 and induces its redistribution in transfected COS-7 cells.Mol Biol Cell. 1997; 8: 555-566Crossref PubMed Scopus (58) Google Scholar;Rezniczek et al., 1998Rezniczek G.A. de Pereda J.M. Reipert S. Wiche G. et al.Linking integrin α6β4-based cell adhesion to the intermediate filament cytoskeleton: direct interaction between the β4 subunit and plectin at multiple molecular sites.J Cell Biol. 1998; 141: 209-225Crossref PubMed Scopus (200) Google Scholar), its distal COOH-terminal half contains a major binding site for BP180 (Schaapveld et al., 1998Schaapveld R.Q.J. Borradori L. Geerts D. et al.Hemidesmosomes formation is initiated by the β4 integrin subunit, requires complex formation with HD1/plectin and involves a direct interaction between β4 and the bullous pemphigoid antigen 180.J Cell Biol. 1998; 142: 271-284Crossref PubMed Scopus (147) Google Scholar) (Figure 3). It is noteworthy that the COOH-terminal portion of the cytoplasmic tail of β4 is able to associate with a more proximal region of the molecule (Rezniczek et al., 1998Rezniczek G.A. de Pereda J.M. Reipert S. Wiche G. et al.Linking integrin α6β4-based cell adhesion to the intermediate filament cytoskeleton: direct interaction between the β4 subunit and plectin at multiple molecular sites.J Cell Biol. 1998; 141: 209-225Crossref PubMed Scopus (200) Google Scholar;Schaapveld et al., 1998Schaapveld R.Q.J. Borradori L. Geerts D. et al.Hemidesmosomes formation is initiated by the β4 integrin subunit, requires complex formation with HD1/plectin and involves a direct interaction between β4 and the bullous pemphigoid antigen 180.J Cell Biol. 1998; 142: 271-284Crossref PubMed Scopus (147) Google Scholar). Although the significance of this potential intramolecular folding remains to be established, it may represent a means by which the interaction of β4 with other elements of HD, such as plectin, is regulated. Finally, it is possible that the cytoplasmic domain of β4 also interacts with BP230. The importance of the cytoplasmic domain of β4 in the overall molecular organization of HD is illustrated by the observation that overexpression of a tail-less β4 molecule inhibits their formation, most likely by either interfering with the transduction of an intracellular signal by wild-type β4 or by blocking the propagation of a conformational change across the membrane (Spinardi et al., 1995Spinardi L. Einheber S. Cullen T. Milner T.A. Giancotti F.G
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