Merlin casts spell on proliferation protein

The tactic that the protein Merlin uses to prevent tumors isn't magical, but it is unique, as Curto et al. report on page 893. The protein locks up a growth-inducing receptor in the membrane so that it can't broadcast its signals. The results suggest a possible way to combat some hard-to-treat cancers.

Like its mythological namesake, Merlin is powerful and mysterious. Its gene, NF2, goes awry in several cancers. But researchers didn't know how Merlin checks cell proliferation. Some evidence pointed to an interaction with the epidermal growth factor receptor (EGFR), which spurs cells to divide. In fruit flies, for example, the Merlin and EGFR pathways intersect.

To determine whether Merlin targets EGFR, the researchers compared the receptor's activity in normal cells and cells lacking Merlin. As the culture dish became crowded, the normal cells shut down EGFR signaling and stopped dividing. But in the Merlin-deficient group, EGFR remained active even as cells piled up.

Stimulated EGFR exits the surface of the membrane and enters the cell; many researchers think this step is crucial for signal transmission. In cells missing Merlin, Curto et al. found, EGFR intake continued even as culture density increased. But internalization stopped in cells that made Merlin, and EGFR was shunted into the most insoluble part of the membrane. That discovery indicates that, when cells feel crowded, Merlin incarcerates EGFR so that it can't transmit further growth-promoting messages.

As contact between cells is known to spur Merlin expression, the results also help clear up the long-standing mystery of how cells stop dividing when they touch each other, a phenomenon called contact inhibition.

Tumors that arise because of NF2 defects often sprout in the spinal cord or brain and can be hard to remove. The work suggests that EGFR blockers, some of which are already on the market, might attack these growths.