Scientists led by Sergey Troyanovsky, PhD, professor of Dermatology and of Cell and Developmental Biology, have uncovered new intracellular mechanisms promoting cell-cell adhesion, a process disrupted in a variety of skin and inflammatory diseases, according to a recent study published in the Journal of Cell Biology.  

Cadherins are essential cell-cell adhesion proteins that help connect cells into tissue by forming adherens junctions, which appearances are extensively differ depending on the type of cells and even on their location within a cell-cell contact. Defects in these interactions can contribute to the manifestation of disease, but the mechanisms which underlie this structural differentiation of adherens junctions have remained unknown, until now.  

Using advanced microscopy and cell imaging techniques to study cells deficient in alpha-catenin, a protein that links cadherins to the actin cytoskeleton, the scientists discovered that two delta-catenin family proteins — p120 and plakophilin 4 (pkp4) — bind intracellular regions of classical cadherins and contribute to the differentiation of adherens junctions.  

Specifically, p120 drives adherens junctions variation through interactions between alpha-catenin and actin filaments to promote cell-cell adhesion. Alternatively, pkp4 drives variation through a mechanism independent of alpha-catenin and generates lateral adherens junctions, which provide mechanical support to the cell.  

“What we found the most surprising is that these junctions are organized by very specific mechanisms: p120 is specific for apical and basal junctions but pkp4, which is a very similar protein from the same family, activates this totally different pathway for which alpha-catenin is not needed at all,” said Troyanovsky, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. 

The findings demonstrate that delta-catenins regulate the variation of adherens junctions through regulating the balance between different assembly pathways.  

“We believe that these junctions are involved in cell-cell signaling because to signal between the cells, two membranes of cells should be very close together. Adherins junctions somehow keep this membrane close together to permit communication with signaling molecules between these two neighboring cells,” Troyanovsky said. 

Going forward, Troyanovsky said his team aims to investigate similar underlying mechanisms of the differentiation of desmosomes, which help maintain the mechanical and structural integrity of tissue.  

Farida Korobova, PhD, research assistant professor of Cell and Developmental Biology, was a co-author of the study.  

The work was supported by the National Institute of Health Grants AR070166 and GM148571.