Cell directions get confused when the front cannot communicate with the back (bottom).

Chemoattractants cause neutrophils to polarize by triggering competing signaling pathways that promote “frontness” and “backness” at opposite poles of the cell. On page 437, Van Keymeulen et al. report that the two responses are not independent. Instead, frontness signals do double duty by reinforcing backness on the cell's other side.

The chemoattractant fMLP activates receptors that stimulate two different G proteins, Gi and G12/G13. At the front of the neutrophil, Gi increases PIP3 accumulation and turns on Rac and CDC42, causing actin polymers to form a pseudopod. G12/13 stimulates RhoA activity, which causes the back of the cell to contract. The two responses exclude each other locally to produce a single front and a single back, rather than multiple “frontlets” and “backlets” scattered over the cell surface.

Van Keymeulen et al. discovered the key to this tricky balancing act by treating cells with inhibitors of PIP3 synthesis. As expected, the inhibitors impaired frontness responses. They prevented fMLP-dependent activation of Cdc42, reduced activation of Rac, and rendered pseudopods transient, small, and unstable.

Surprisingly, pseudopod multiplicity was found all around the cell periphery because of reduced fMLP-dependent RhoA activity at the back of the cell. Activation of RhoA not only depended on G12/G13, but also required components of the frontness response, including elevated PIP3 and Cdc42 activity.

Thus the polarized neutrophil's ability to stabilize a single front and a single back depends on long-range augmentation of backness by the frontness program. Van Keymeulen et al. speculate that the long-range effect of frontness is mediated by Cdc42 regulation of microtubules, which extend preferentially to the back of polarized neutrophils.