Mutating NHE1 results in either a back end that sticks (left) or a front end that has too many protrusions (right).

For a cell with signaling receptors distributed uniformly on its plasma membrane, deciding which direction to move in response to a stimulus is a serious problem. Earlier work traced this polarity decision to the amplification of phosphoinositide signaling at the cell's leading edge. But on page 1087, Denker and Barber follow the signal back one step further, to the highly conserved ion exchange protein NHE1. The exchanger appears to be necessary not only for defining the front and rear of the cell, but also for coordinating events at the two ends.

The authors previously found that NHE1 is not only a sodium proton exchanger, but also a plasma membrane anchor for the cytoskeleton. Both functions are needed for PI-3 kinase activation and localization of ion exchange at the leading edge of lamellipodia.

In fibroblasts expressing a mutant form of NHE1 that is defective in ion translocation but retains the ability to anchor the cytoskeleton and localize to lamellipodia, focal adhesions appear to form, but they are not properly remodeled or disassembled. The result is fan-shaped lamellipodia and elongated cell tails, and an inhibition of migration. Cells expressing a form of NHE1that is a functional ion transporter but defective in cytoskeletal anchoring and localization develop multiple pseudopodia extending in all directions, also slowing migration.Others have shown that migratory receptors stimulate ion transport by NHE1, which should increase cytoplasmic pH at the leading edge and possibly activate actin-regulating proteins such as ADF/cofilin and gelsolin. As yet, changes in pH have not been seen in migrating cells, perhaps because the available techniques for measuring pH lack the necessary resolution. And other questions remain. It is not clear, for example, what determines the initial localization of NHE1 to the leading edge, or what signal NHE1 generates at the front of a cell to regulate events at the rear. ▪