Really outside signaling

Reactive oxygen species (ROS) such as hydrogen peroxide (H₂O₂) pose a potential chemical threat in cells, so it was surprising enough when they turned up as essential signaling components downstream of receptor activation. Now Garrett DeYulia, Juan Cárcamo, David Golde (Memorial Sloan-Kettering Cancer Center, New York, NY) and colleagues have found that H₂O₂ can be generated outside cells, independent of any intracellular events, by ligand binding to cytokine receptors.

The group had earlier seen that extracellular catalase, which breaks down H₂O₂, inhibited signaling through the GM-CSF receptor. They now find that ligand binding to this receptor increases the amount of extracellular H₂O₂. This occurs even when the cells are fixed before ligand addition or with a version of the receptor lacking intracellular signaling domains. H₂O₂ production was also evident with EGF binding to its receptor in the presence of an inhibitor of downstream signaling.

Extracellular destruction of H₂O₂ reduced signaling and cell survival downstream of GM-CSF binding. Addition of extracellular H₂O₂, by contrast, induced phosphorylation of downstream targets.

H₂O₂ makes a good second messenger—it is small, diffusible, and can be destroyed easily. It can also inactivate proteins such as phosphatases by oxidizing active site cysteine residues. How it is generated initially is a mystery. In intracellular ROS signaling the necessary electrons are supplied by NADPH oxidase, but outside the cell the only precedent is an unusual reaction between oxygen radicals and water catalyzed by antibodies. DeYulia and colleagues plan to mutate ligand and receptor residues to track down what parts of the proteins may be responsible for ROS generation.

Reference: