Cell adhesion . Desmosome . Epidermal differentiation . AFM force spectroscopy . Invasion and metastasis
Cell-cell adhesion is critical for the development and function of complex multicellular organisms. Intercellular adhesive complexes and dedicated adhesion molecules sense the cellular environment through their adhesive function and serve as scaffolds for intracellular signaling molecules, shaping cellular behavior by regulating a multitude of intracellular signaling pathways. This is necessary to provide and adapt crucial functions such as strong tissue integrity, polarity and differentiation, individual and collective cell migration, tissue repair and many more. Not surprisingly, alterations in cell-cell adhesion are the cause of or contribute to a variety of devastating diseases, ranging from cancer to skin blisters (pemphigus diseases), and cardiomyopathies (arrhythmogenic cardiomyopathy).
We focus on desmosomes, cadherin-based, highly structured junctional complexes. These are present throughout the majority of epithelial and some non-epithelial tissues.They are especially abundant in tissues exposed to a high degree of mechanical load such as the epidermis, the myocardium or the intestinal epithelium. In desmosomes, clusters of specific desmosomal cadherins connect with their counterparts on the neighboring cell and are intracellularly anchored to the intermediate filament cytoskeleton through a set of adapter molecules referred to as plaque proteins. This design provides both flexibility and resistance by establishing a cytoskeletal network throughout entire tissues.
Despite their significance, surprisingly little is known about the mechanisms underlying desmosomal adhesion.
Our aim is to
- understand the basic regulation of desmosomal function and turnover,
- identify contributions of desmosomes and cell-cell adhesion to fundamental cellular processes,
- clarify desmosomal dysregulation in disease to facilitate more tailored treatment approaches.
As examples, we identified that desmosomal molecules sequester and modulate the function of signaling molecules in an adhesion-dependent “outside-in” manner, which is a crucial pathomechanism in the disease pemphigus vulgaris. Vice versa, the adhesive properties of desmosomes are tuned in an “inside-out” fashion by keratins and their ability to regulate signaling molecules.
Our models cover in vitro, cell culture-based as well as murine and human in vivo and ex vivo approaches. We use a set of biophysical techniques to characterize cell-cell adhesion down to single molecule levels, such as AFM force spectroscopy on living cells and fluorescence-based live imaging assays. We combine these with more conventional biochemical and genetic experiments to bring these results in a broader context.