Pushing protons out of a cell's leading edge prompts a positive feedback loop for polarity, according to a new report by Frantz et al.
An important polarity protein in numerous cell types is a Rho GTPase called Cdc42, which transduces signals to the cytoskeleton to maintain polarized growth. Now, Frantz and colleagues show that Cdc42 also maintains polarity during fibroblast migration.
Migration is thought to be regulated by intracellular pH. The team found that Cdc42 caused an increase in intracellular pH by activating a sodium/hydrogen exchanger called NHE1, which drives protons out of the cell.
This increase in pH was necessary to activate Cdc42 at the leading edge of the cell. The pH increase was needed to bring Cdc42's activator, a guanine nucleotide exchange factor (GEF), to the membrane, allowing the GEF to pass a new GTP to Cdc42 for hydrolysis.
The team is currently investigating what kicks off this positive feedback loop for polarity. They are also intrigued that, given the pH dependency of GEF activity, numerous cell signaling pathways that also require GEFs and GTPases might be regulated by proton flux.