During migration, microtubule polymerization at the leading edge leads to increased Rac GTPase activity and the formation of lamellipodia via actin polymerization. Conversely, microtubule depolymerization in the cell body activates Rho and leads to myosin contractility. Now, it seems that a guanine nucleotide exchange factor (GEF) is “the missing link between microtubule activation and RhoGTPase regulation of the actin cytoskeleton,” according to Bokoch.
Bokoch found that GEF-H1 activates Rho GTPase, but only when the exchange factor is not associated with microtubules. Disassembly of microtubules in the cell body of a migrating cell frees GEF-H1, which activates Rho to promote myosin contractility and actin stress fiber formation. The assembly of microtubules at the leading edge leads to low GEF-H1 activity, and therefore low Rho activity, allowing lamellipodial assembly.
GEF-H1 exchange activity is specific to Rho. Bokoch speculates, however, that a similar mechanism may regulate Rac activity. A different exchange factor could be activated by microtubule binding, up-regulating Rac at leading edge of the cell.
According to Bokoch, microtubule-regulated GEFs could be involved in more than just cell motility. They may promote growth cone stability during axonal pathfinding, or regulate Rho activity and actin assembly during cell division, when microtubules direct positioning of the division furrow. ▪