Faculty Bibliography

Dsg1 is a 165-kDa glycoprotein component of suprabasal epidermal desmosomes and the prototype of a subset of the cadherin superfamily of cell-cell adhesion proteins known as desmogleins. The adhesive function of classical cadherins is known to be dependent upon their association with cytoplasmic components called catenins. In the case of desmogleins, a single interaction has been described with a protein called plakoglobin that is found in desmosomal plaques, adherens junctions, and the cytosol. Several proteins with homology to plakoglobin have been described that regulate junction assembly and implement morphoregulatory signals. To address the functional significance of plakoglobin-desmoglein interaction, we have mapped the sequences of Dsg1 that are crucial for this association by using blot overlay techniques. By examining the binding of plakoglobin to a deletion series of the Dsg1 cytoplasmic domain expressed as fusion proteins, we have defined a 19-amino acid sequence that is important for association. This region of Dsg1 sequence shows significant similarity to the catenin-binding domain of classical cadherins, suggesting a common mechanism for the association of plakoglobin with desmosomes and adherens junctions

The cadherin superfamily of calcium-dependent cell-cell adhesion and recognition proteins can be categorized into a number of subsets on the basis of the distinct cytoplasmic sequences of their members. Currently these families include classical cadherins, desmogleins, desmocollins, protocadherins, and the products of the Drosophila genes FAT and Dachsous. Dsg1, the prototype of the desmoglein family, is a major component of epidermal desmosomes and the antigenic target of antibodies found in the sera of patients with the blistering disease, pemphigus foliaceus. In this study, we determined the organization of the bovine DSG1 gene. This gene consists of 15 exons distributed over > 37.5 kilobases of genomic DNA. A comparison of DSG1 with genes encoding classical cadherins revealed a striking conservation of exon boundaries in regions encoding the ectodomain and to a more limited extent among those encoding the cytoplasmic domain. Polymorphism was found in a sequence of DSG1 encoding protein proximal to the external face of the plasma membrane. This region is topologically equivalent to a domain of classical cadherins that harbors epitopes recognized by adhesion-disrupting antibodies. We discuss these results with regard to the evolution of the cadherin superfamily and their implications for the definition of pemphigus epitopes

The Wnt-1 gene plays an essential role in fetal brain development and encodes a secreted protein whose signaling mechanism is presently unknown. In this report we have investigated intracellular mechanisms by which the Wnt-1 gene induces morphological changes in PC12 pheochromocytoma cells. PC12 cells expressing Wnt-1 show increased steady-state levels of the adhesive junction protein plakoglobin, and an altered distribution of this protein within the cell. This effect appears similar to a modulation of the plakoglobin homolog, Armadillo, that occurs in Drosophila embryos in response to the Wnt-1 homolog, wingless (Riggleman, B., P. Schedl, and E. Wieschaus. 1990. Cell. 63:549-560). In addition, PC12/Wnt-1 cells show elevated expression of E-cadherin and increased calcium-dependent cell-cell adhesion. These results imply evolutionary conservation of cellular responses to Wnt-1/wingless and indicate that in certain cell types Wnt-1 may act to modulate cell adhesion mechanisms

The desmosomal adhesive core is formed by four major components: desmoglein (Mr, 165,000), desmocollins I and II (Mr, 120,000 and 110,000, respectively), and a Mr 22,000 protein. Here, we report the cloning and sequencing of cDNAs encoding a bovine desmocollin. The open reading frame found in the longest cDNA, 5 kilobases, contains a region encoding a protein of 839 amino acids. The features of the deduced amino acid sequence imply that the mature 707-amino acid desmocollin is a type I transmembrane protein that is produced by proteolytic cleavage of an 810-amino acid precursor. The ectodomain of desmocollin contains repeats that show extensive sequence similarity to members of the cadherin family of calcium-dependent cell adhesion molecules. A comparison of the amino acid sequences of desmocollin, desmoglein, and the cadherins shows that although these intercellular junctional adhesion molecules share a consensus sequence in their adhesive domains that defines them as a family, several features, including the divergence in the sequence of their cytoplasmic tails, divide them into three distinct subtypes