Tanioku Kihei Memorial Lecture
Invited Review Article
Discriminating roles of desmosomal cadherins: Beyond desmosomal adhesion

https://doi.org/10.1016/j.jdermsci.2006.10.006Get rights and content

Summary

The desmosomal cadherins, which include desmogleins and desmocollins, are Ca2+-dependent adhesion molecules that cooperate to make up the adhesive core of intercellular junctions known as desmosomes. The roles of desmosomal cadherins in epidermal integrity and as targets in human cutaneous disease have been well established. However, the molecular basis of these disorders is still poorly understood, due in part to a lack of fundamental knowledge about the organization of the adhesive interface and molecular machinery that dictates the proper presentation of desmogleins and desmocollins on the cell surface. Further, the diversity of the desmosomal cadherin family, and their individualized expression patterns within complex tissues, suggests that these adhesion molecules may have differentiation-specific functions that transcend their roles in intercellular adhesion. Here we will review the most recent data from our own group and others that are beginning to unveil the diverse properties and functions of this complex family of adhesion molecules.

Section snippets

Introduction to the cadherin family and desmosomal cadherin subfamilies

The desmosomal cadherins belong to the larger cadherin superfamily which also includes classic cadherins, protocadherins, FAT family cadherins, seven pass transmembrane cadherins, and T-cadherin [1]. With the exception of T-cadherin, which is associated with the plasma membrane via a glycosylphosphatidylinositol (GPI)-anchor, the cadherins are single pass transmembrane proteins that possess an extracellular domain containing varied numbers of ∼110 amino acid motifs involved in adhesion and

Desmosomal cadherin gene structure

The human desmosomal cadherin family consists of four Dsg isoforms (Dsg1–4) and three Dsc isoforms (Dsc1–3), each of which is a product of a separate gene [6], [7], [8] (Fig. 2). The genomic organization of Dsgs and Dscs is similar to that of classic cadherins, suggesting evolution from a common ancestor through multiple gene duplication and divergent evolutionary events [6]. The DSC and DSG subfamilies are clustered together on opposite sides of a central region on chromosome 18. This

Regulation of desmosomal cadherin expression

The Dsg and Dsc isoforms are expressed in a tightly regulated cell type- and differentiation-specific manner (Fig. 3). Dsc2 and Dsg2 are expressed ubiquitously in all tissues that contain desmosomes [27], [28] and can be found in simple epithelia, as well as in the heart myocardium and basal layer of complex epithelia [27], [28], [29], [30]. The expression of Dsc/Dsg3 and Dsc/Dsg1 is, in contrast, restricted to certain stratified, squamous epithelia. In such tissues, these two isoform pairs are

Human disease

Long before the specific plasma membrane targets in pemphigus were identified, the existence of this autoimmune blistering disease was cited as evidence that desmosomes and desmosomal glycoproteins function in intercellular adhesion. Although other potential molecular targets in pemphigus have been proposed [43], it is now widely held that circulating autoantibodies directed against the desmosomal cadherins Dsg3 and Dsg1 cause acantholysis (splitting between cells) and consequent epidermal

Assembly and disassembly: regulating the balance of cell surface expression of desmosomal cadherins in homeostasis and disease

Although desmosomes are highly resilient structures and biochemically extremely insoluble, these organelles are also dynamically remodeled during differentiation, wound healing and in certain diseases such as pemphigus and tumor metastasis. This remodeling is likely to occur at least in part through alterations in the balance of desmosome assembly and disassembly. Early biochemical studies demonstrated that, following biosynthesis, Dsg first enters a detergent soluble pool and then becomes

Recent insights into signaling roles for desmosomal cadherins and their associated proteins

Over the past decade, classic cadherins have been revealed as adhesion receptors at the intersection of chemical and mechanical signaling pathways [5]. Not only is cadherin function modulated by intracellular signals, but cadherins themselves also participate in signaling by regulating the activity of growth factor receptors and the associated armadillo protein, β-catenin. Recent evidence suggests that desmosomal cadherins also participate in bi-directional signaling involving known kinase

Prospects for the future

In summary, Dscs and Dsgs have emerged as adhesion molecules that, like classic cadherins, are at the crossroads of mechanical and chemical signaling pathways. In the future, additional studies to discern adhesion-dependent and -independent functions of these protein complexes will help to clarify their involvement in tissue-specific signaling. It seems likely that such functions are coordinated by associated regulatory proteins that bind to the unique desmosomal cadherin tails, such as kinases

Acknowledgements

The authors are grateful to the entire Green Laboratory for their efforts in generating the data from our lab that were discussed in this report, and to our colleagues in the desmosome field for their contributions to the science discussed here and their collegiality throughout the years. Thanks go also to Spiro Getsios for critical reading of the manuscript. KJG was supported by grants R01AR43380, R01AR41836, R01CA122151 and project #4 of P01DE12328, and the J.L. Mayberry Endowment.

Rachel L. Dusek graduated summa cum laude from Illinois Wesleyan University with a B.A. in Biology in 1997. She entered the Integrated Graduate Program in the Life Sciences at Northwestern University in 1999, where she worked in the laboratory of Dr. Kathleen J. Green studying desmosomal cadherins and their role in epithelial intercellular adhesion, as well as alternative functions for desmosomal components in modulating keratinocyte apoptosis and tissue morphogenesis. She earned her Ph.D. in

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    Rachel L. Dusek graduated summa cum laude from Illinois Wesleyan University with a B.A. in Biology in 1997. She entered the Integrated Graduate Program in the Life Sciences at Northwestern University in 1999, where she worked in the laboratory of Dr. Kathleen J. Green studying desmosomal cadherins and their role in epithelial intercellular adhesion, as well as alternative functions for desmosomal components in modulating keratinocyte apoptosis and tissue morphogenesis. She earned her Ph.D. in Cancer Biology in 2005. Currently she is a postdoctoral scholar at Stanford University, where she is applying her background and interest in epithelial and desmosome biology toward advanced training in cancer biology and mouse genetics.

    Kathleen J. Green graduated with Distinction in Biology from Pomona College in 1977 and went on to obtain a Ph.D. in Cell and Developmental Biology at Washington University in St. Louis in 1982. After postdoctoral training in Cell Biology at Northwestern University Medical School, Dr. Green joined the faculty of the Pathology and Dermatology Departments where she is currently the Joseph L. Mayberry Professor of Pathology and Toxicology. Dr. Green's research program is directed toward elucidating the structure and function of epithelial adhesion molecules and adhesive structures in tissue morphogenesis and differentiation, as well as in pathological processes such as cancer, autoimmune and inherited disease. Green's work was instrumental in the discovery of the plakin gene family, and helped facilitate the identification of human diseases resulting from mutations in desmoplakin, which plays a critical role in integrity of the epidermis and heart.

    A fellow of the American Association for the Advancement of Science, Green was a Keith Porter Fellow and has been a recipient of two faculty research awards from the American Cancer Society, a Johnson and Johnson Focused Giving Award, and a March of Dimes Basil O’Connor Starter Scholar Award. She was awarded the 2002 William Montagna Lectureship from the Society for Investigative Dermatology and was the Odland Lecturer at the University of Washington in Seattle in 2005. Dr. Green has served on the Program Committees for the Society for Investigative Dermatology and the American Society for Cell Biology, and as chair of the NIH-General Medicine A1 Study Section. She was on the Board of Directors of the Society for Investigative Dermatology from 2001 to 2006. Green was Chair of the Gordon Conferences on Intermediate Filaments and on Epithelial Differentiation and Keratinization. She is a member of Faculty 1000, an Associate Editor of the Journal of Investigative Dermatology and serves as editor for the The Journal of Cell Science.

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