Gαi3 (yellow) clusters at the leading edge (arrows) of a crawling cell.

Missing links aren't just for paleontologists. Ghosh et al. report what might be the long-sought connection between cell surface receptors and the direction in which cells crawl.

Nearby food and growth factors galvanize a cell. At the section of the membrane nearest the stimulus, activity of the signaling molecule Akt cranks up and actin elongates into stress fibers essential for crawling. The cell then pushes forward this part of its membrane, the leading edge. Surface receptors first detect the stimulus, and then trigger G proteins, which pass the signal on. What scientists don't know is how cells confine the molecular action to the leading edge. The team suspected it might involve an intermediary, the protein GIV, which can latch onto G proteins and stimulate Akt.

To find out, Ghosh et al. investigated the interaction between GIV and a G protein component known as Gαi3. If Gαi3 is absent, the team found, actin doesn't extend, Akt activity doesn't rev up, and cells are stuck. Gαi3 homes in on the leading edge, and it appears to drag GIV along with it. In cells lacking Gαi3, GIV collects near the Golgi apparatus instead of dispersing to the edge of the cell. Gαi3 might even instigate a positive feedback loop because it presents GIV to Akt to be switched on; GIV can then further amplify Akt activity.

GIV and Gαi3 also help macrophages and tumor cells migrate, the team found. By ferrying GIV to the leading edge, Gαi3 might ensure that only one portion of the membrane undergoes the changes required for movement.

Ghosh, P., et al.
J. Cell Biol.