Broadcast a message over a loudspeaker, and you can't be sure who will hear it. But whisper the message into the friend's ear, and you can be sure it got through. Cells follow a similar strategy when they transmit signals with reactive oxygen species (ROS), as Chen et al. show. By positioning the sender and recipient molecules near each other, cells ensure efficient communication.
ROS are best known as destructive byproducts of metabolism that might cause aging. But cells also use the molecules to carry messages. The mystery is how cells direct ROS to their targets, since some ROS can diffuse throughout the cell, potentially reacting with any molecules they encounter.
Proximity is the key, Chen et al. found. They tracked down the signal-relaying molecule NADPH oxidase 4 (Nox4), which produces the ROS hydrogen peroxide. The protein was stationed in the endoplasmic reticulum near another protein called PTP1B, which slows division of endothelial cells by turning down the epidermal growth factor receptor (EGFR). The team showed that Nox4 was oxidizing and shutting down adjacent PTP1B molecules. Using an antioxidant that homes in on the ER, for instance, the team could block EGFR signaling, indicating that oxidation of PTP1B had been prevented. An antioxidant that remains in the cytoplasm, however, had no effect on the receptor. The results suggest that by keeping Nox4 and PTP1B close together in the ER, cells make it easier for ROS signals to travel between them. One question the researchers now want to answer is what activates Nox4 in the first place.