JAM-C (green) loosens cell junctions (red) to increase blood vessel permeability.

Most cell junction proteins increase endothelial cell–cell adhesion. But junction adhesion molecule-C (JAM-C), despite its sticky name, loosens vascular endothelial cell connections, thus allowing increased blood vessel permeability.

Increasing the permeability of small blood vessels is essential for new vessels to form and for leukocytes to escape the circulation and enter surrounding tissues during inflammation and tissue repair. Permeability is thought to be controlled by tight junctions between neighboring cells. Most tight junction components promote cell–cell adhesion and thus reduce permeability. But Orlova et al. (page 2703) show that the tight junction protein JAM-C does the opposite—it promotes permeability. Indeed JAM-C is the first junctional molecule reported to behave this way.

Using dye tracking, the team showed that knocking down JAM-C reduced endothelial permeability both in vitro and in vivo. The permeability-promoting effect of JAM-C was not on tight junctions themselves, but rather on a different type of cell–cell junction called adherens junctions, which contain the adhesion protein VE-cadherin. Knocking down JAM-C led to increased adhesion between VE-cadherin molecules at cell junctions. Such increased interaction is thought to trigger, via junction-associated factors, a series of steps that ultimately promotes actin depolymerization—thus further reducing permeability, as cells are unable to contract and pull apart. Consistent with this theory, knocking down JAM-C also reduced intracellular actin polymerization.

That a molecule from one type of junction can promote permeability by acting on another type of junction was surprising. The team found, however, that JAM-C increased endothelium permeability whether located at the cell junctions or diffusely distributed in the cytoplasm, indicating that JAM-C might be a signaling as well as structural protein, though the authors have yet to investigate this possibility.

One of the many more typical tight junction molecules that reduce vessel permeability is JAM-A, a closely related family member of JAM-C. How two such structurally similar junction molecules can have opposing effects on blood vessel permeability remains to be determined.