When Two Cells Meet at a Junction…
Adherens junctions (AJs) are protein complexes at the cell-cell interface that withstand mechanical forces and maintain tissue structure. They also regulate intracellular signaling for cell growth, division, and death. Functional AJs are therefore critical for morphogenesis and organogenesis. AJ dysfunctions can cause carcinoma invasion and metastasis. AJs also play an important role in how immune cells kill malignant cells and virally infected cells. AJs are formed and maintained by an intricate network of chemical and mechanical signals generated at the interface between two opposing cells. These interactions are associated with changes in actin cytoskeleton organization and clustering of cadherin molecules that constitute cell-cell adhesions. Investigating the causes and effects of these interactions and structural changes will help identify potent targets in cancer treatments and immunotherapies.
The cover for the February 15 Issue of Biophysical Journal is a snapshot from a simulation using a new biophysics-based computational model of cell-cell adhesion formation and maintenance. We present this model in our paper entitled “Cortical tension initiates the positive feedback loop between cadherin and F-actin.” In this paper, we systematically investigate how interactions between F-actin and cadherin regulate the development of intercellular adhesion.
The cover image panels depict the contact plane between two spherical cells in a cell doublet. The top panel is a snapshot of cadherin clustering at the contact plane. The red and green dots represent cadherins embedded in each opposing cell. These monomers diffuse and interact with other cadherins in the same plasma membrane to form small clusters. Blue dots represent cadherins from the two opposing cells binding across two cells through trans-dimerization. The bottom panel is a snapshot of the corresponding concentration of filamentous actin directly underneath the contact plane. Using the rainbow spectrum to map F-actin concentration, blue denotes low concentration, and red denotes high concentration. The snapshot depicts an asymmetry in the size of the cadherin clusters and the corresponding concentration of F-actin at the AJ. This reflects the observations in a cell-doublet experiment in which the cells experience shearing hydrodynamic flows. Our modeling shows how this asymmetry could arise by interrupting a positive feedback loop between F-actin density and cadherin clustering.
By simulating the biophysics and spatial patterning of cadherin clusters, we have gained a deeper understanding of how external mechanical stimuli drive adhesion remodeling. In future work, we will use our model to answer questions about how the positive feedback loop between F-actin and cadherins is hijacked by malignant and virally infected cells to escape immune response. Because cadherin plays important roles in many intracellular processes such as apoptosis and growth, we are also interested in studying what information can be gained about the physiological states of cells from these cell-cell adhesion patterns. Beyond fundamental understanding, we believe that addressing these questions about adhesion patterning will form the foundations of precision cellular therapies and tissue engineering technologies of the future.
- Qilin Yu, William R. Holmes, Jean P. Thiery, Rodney B. Luwor, and Vijay Rajagopal