Cell polarity is the asymmetric distribution of cellular and membrane components, making one side of the cell different from the other. This polarity is essential to many processes such as embryogenesis, axon migration, glucose transport across epithelial cells, and directional cell migration. A migrating cell responds to intracellular or extracellular signals via molecular cascades that reorganize the actin cytoskeleton to establish this polarity. In these cells, the Rho family proteins Cdc42, Rac, and Rho, are the key players in this signaling cascade and help establish the cell front and rear. These Rho proteins are small GTPases that act as molecular switches, shifting between inactive and active states.

Establishing the Cell Front

The cell front (or leading edge) is established by the activation of Cdc42 and Rac proteins. Here, the binding of stimulants to G-protein coupled receptors activates secondary messengers, such as PIP3 and G-proteins 12/13. Because PIP3 is membrane-bound, it can only activate its targets, Cdc42 and Rac, on one side of the cell, which becomes the leading edge. Activated Cdc42 promotes actin nucleation and filament formation via the Wasp-Arp 2/3 pathway, resulting in filopodia formation. Similarly, activated Rac triggers actin branching by the Arp 2/3 complex via the WAVE pathway, resulting in lamellipodial protrusions. Thus the leading edge is polarized to form membrane protrusions that push the cell forward.

Establishing the Cell Rear

Rho proteins, such as RhoA in vertebrates, are the key mediators in establishing the cell rear at the opposite end. The activated G-proteins 12/13 diffuse through the cytoplasm and activate these Rho proteins. Rho activation triggers formins and Rho-dependent kinase (ROCK). While formins promote parallel actin bundling to form stress fibers, ROCK promotes myosin contraction that pulls the cell rear in the direction of migration. Additionally, Rac and Rho inhibit each other, and this negative feedback stabilizes the cell's polarity.