A matter of give and take

Many surfaces within the body are lined with tightly interconnected sheets of epithelial cells, with individual cells tethered to one another via complexes known as adherens junctions (AJs).

These sheets undergo considerable reorganization during embryonic development and wound healing; accordingly, AJs are not merely ‘cellular staples’, but appear to provide an important mechanism for monitoring adjacent cells. “I imagine that cells confirm whether their neighbors are alive and have the same adhesion molecules by ‘pulling’ adjacent cells through AJs,” explains Shigenobu Yonemura, of the RIKEN Center for Developmental Biology in Kobe. “Dead cells cannot pull back, and thus would not be recognized as members of the epithelial cell sheet.”

Yonemura’s team has uncovered evidence that AJs counter tensions generated through intercellular interactions via their associations with cytoskeletal actin filaments, spotlighting a potentially important association between AJ component á–catenin and the actin-binding protein vinculin1. By further exploring the relationship between these two proteins, his team has now achieved a breakthrough in understanding AJ-mediated force detection2.

The researchers identified a vinculin-binding region in the middle of á-catenin, but also identified a second segment of the protein that actively inhibits this interaction. At one end, á-catenin also contains an actin-binding region, and Yonemura and colleagues found that this association appears to be essential for relieving this self-inhibition, suggesting that the á-catenin–vinculin interaction is force-dependent.

Subsequent experiments enabled the team to construct a model in which á-catenin is normally collapsed like an accordion, with the inhibitory domain masking the vinculin binding site. However, increased tension extends the protein and exposes this site, enabling further interactions with the cytoskeleton that effectively counter the force pulling against a given AJ. The result is essentially a ‘tug of war’ between cells, with the integrity of the epithelium hanging in the balance.

If accurate, this model offers a simple explanation for how epithelial cells can react rapidly to rearrangements in their local environment. “The central part of the mechanism involves the protein structure of á-catenin—no enzymatic reaction is required,” says Yonemura. “Because of this, sensing and response take place at the same time and place.”

His team is now designing experiments to confirm this á-catenin rearrangement in response to applied force, but Yonemura believes they may have potentially uncovered a broadly relevant model for cellular communication. “Because the mechanism is so simple, I think that it could be fundamental and used among a wide variety of cells,” he says.

The corresponding author for this highlight is based at the Electron Microscope Laboratory, RIKEN Center for Developmental Biology

Journal information

1. Miyake, Y., Inoue, N., Nishimura, K., Kinoshita, N., Hosoya, H. & Yonemura, S. Actomyosin tension is required for correct recruitment of adherens junction components and zonula occludens formation. Experimental Cell Research 312, 1637–1650 (2006)

2. Yonemura, S., Wada, Y., Watanabe, T., Nagafuchi, A. & Shibata, M. á-Catenin as a tension transducer that induces adherens junction development. Nature Cell Biology 12, 533–542 (2010)