The Hemidesmosomal Protein Bullous Pemphigoid Antigen 1 and the Integrin β4 Subunit Bind to ERBIN

Abstract

The bullous pemphigoid antigen 1 (eBPAG1) is a constituent of hemidesmosomes (HDs), cell-substrate adhesion complexes in stratified epithelia. Although its COOH terminus interacts with intermediate filaments, its NH 2 terminus is important for its recruitment into HDs. To identify proteins that interact with the NH 2 terminus of human eBPAG1, we performed a yeast twohybrid screen, which uncovered a protein belonging to the LAP/LERP (for LRR and PDZ domain) protein family with 16 NH 2 -terminal leucine-rich repeats and a COOH-terminal PDZ domain. The gene for this LAP/ LERP protein comprises at least 26 exons located on the long arm of chromosome 5. In most human tissues, several transcripts were detected differing in the coding region situated upstream of or within the PDZ domain. One of the encoded variants was found to correspond to the recently described protein ERBIN. In yeast and in vitro binding experiments, ERBIN was shown to interact not only with eBPAG1 but also with the COOH-terminal region of the cytoplasmic domain of the integrin ␤4 subunit, another component of HDs. Antibodies raised against the COOH terminus showed that ERBIN is expressed in keratinocytes. In transfected epithelial cells the protein, however, was not localized in HDs but was either diffusely distributed over the cytoplasm or concentrated at the basolateral plasma membrane. Because ERBIN had been shown previously to interact with the transmembrane tyrosine kinase receptor Erb-B2, which in turn associates with the integrin ␤4 subunit, we suggest that ERBIN provides a link between HD assembly and Erb-B2 receptor signaling.Bullous pemphigoid antigen 1 (epithelial BPAG1 or eBPAG1)1 is a component of hemidesmosomes (HDs), multiprotein adhesion complexes promoting cell-substrate adhesion in stratified and complex epithelia. Ultrastructurally, these complexes appear as electron-dense structures in close contact with the basal cell membrane associated with the cytoskeleton (1, 2). eBPAG1 was identified originally as an autoantigen in the autoimmune subepidermal blistering disorder of the skin called bullous pemphigoid (3, 4). This protein is a member of a protein family involved in cytoskeletal organization, the plakins that also comprise desmoplakin, plectin, envoplakin, and periplakin (reviewed in Ref. 5). The structural organization of the plakins is similar, with a central coiled-coil domain responsible for dimerization flanked by two large globular end domains. Although the NH 2 termini of plakins seems to mediate their recruitment to distinct plasma membrane sites (6 -9), their COOH termini are implicated in their attachment to the intermediate filament cytoskeleton (7, 10, 11). Specifically, cell transfection and yeast two-hybrid analyses have demonstrated that the last 768 residues of human eBPAG1 contain sequences important for their interaction with intermediate filaments (7,12). Consistent with this result, BPAG1-knockout mice show discrete signs of blistering, most likely as a result of an impaired attachment of keratin-intermed...

Interaction between Erbin and a Catenin-related Protein in Epithelial Cells

“…The presence of Erbin in desmosomes (this study) and in hemidesmosomes, as suggested by others (32), leads us to propose that Erbin plays a role in the establishment and the maintenance of cell-cell and cell-basement membrane adhesion. Disruption of these structures required for stable epithelial cell anchorage and polarity is frequently observed in cancers.…”

“…It is likely that LET-413 and Scribble, as well as their mammalian homologues may be connected, directly or not, to cytoskeleton-associated proteins. Likewise, Erbin was recently shown to interact with BPAG1, a plakin associated with intermediate filaments in epithelial cells (32).…”

“…BPAG1 belongs to the plakin family and is involved in cytoskeletal organization (33). The integrin ␤ 4 subunit, a cell adhesion molecule involved in hemidesmosome assembly, also associates with Erbin through a protein interaction domain lying amino-terminal to the Erbin PDZ domain (32). It is unknown whether Erbin is present in hemidesmosomes.…”

“…The Erbin PDZ domain interacts with ERBB2 and controls its basolateral localization in epithelial cells (29 -31). Recently, it was demonstrated that Erbin directly binds to BPAG1 (bullous pemphigoid antigen-1), a component of hemidesmosomes, electron dense structures in contact with the basal membrane associated with the cytoskeleton (32). BPAG1 belongs to the plakin family and is involved in cytoskeletal organization (33).…”

Erbin Suppresses the MAP Kinase Pathway

“…Erbin is a protein that was identified as a binding partner for ErbB2, delta-catenin, and ARVCF (17)(18)(19)(20)(21)(22). The 180-kDa protein contains two identifiable domains: LRR and PDZ (17,19).…”