Cells are pushed closer together by physical forces. In the lung, for instance, epithelial cells feel the pressure from underlying muscle tissue, particularly in asthmatic patients. The authors see that these forces do not change cellular volume. Rather, they squeeze out fluids from between neighboring cells.
The resulting close cellular proximity means that ligands that get secreted between cells are more concentrated and therefore more likely to activate signaling pathways. “Now there's less space for these things to bounce around in before they find a receptor,” says Tschumperlin.
Lung cells under mechanical stress phosphorylate ERK as a result of EGFR activation. The authors find that this phosphorylation is due to the HB-EGF ligand. Assuming that ligand secretion and diffusion rates are uniform, they calculate that ligand concentration is inversely proportional to the width of the space between cells. Putting their equation to the test, they found that stress, or an increase in ligand equivalent to that predicted from that stress, both activated ERK phosphorylation to the same extent.
“When we put our results together, it seemed so obvious that we had to go back to the literature to see why no one had suggested it before,” says Tschumperlin. “No proteins or molecules or channels sensitive to stress are needed. Cells just use the existing machinery, not directly changing any proteins, in a changing extracellular volume.”
This simple system may extend to any cell type that releases ligands into a restricted space. Proliferating cells that get more tightly packed during development, for example, might activate differentiation pathways at the right place and time. ▪