In many cases, including but not limited to cell migration, large-scale cytoskeletal coordination takes the form of the establishment of cell polarity, where a cell builds different structures with distinct molecular components at the front versus the back, or at the top versus the bottom. Cell locomotion requires an initial polarization of the cell to set it off in a particular direction. Carefully controlled cell-polarization processes are also required for oriented cell divisions in tissues and for formation of a coherent, organized multicellular structure. Genetic studies in yeast, flies, and worms have provided most of our current understanding of the molecular basis of cell polarity. The mechanisms that generate cell polarity in vertebrates are only beginning to be explored. In all known cases, however, the cytoskeleton has a central role, and many of the molecular components have been evolutionarily conserved.
The establishment of many kinds of cell polarity depends on the local regulation of the actin cytoskeleton by external signals. Many of these signals seem to converge inside the cell on a group of closely related monomeric GTPases that are members of the Rho protein family—Cdc42, Rac, and Rho. Like other monomeric GTPases, the Rho proteins act as molecular switches that cycle between an active GTP-bound state and an inactive GDP-bound state (see Figure 3–66). Activation of Cdc42 on the inner surface of the plasma membrane triggers actin polymerization and bundling to form filopodia. Activation of Rac promotes actin polymerization at the cell periphery, leading to the formation of sheetlike lamellipodial extensions. Activation of Rho promotes both the bundling of actin filaments with myosin II filaments into stress fibers and the clustering of integrins
Figure 16–82 Control of cell– substratum adhesion at the leading edge of a migrating cell. (A) Actin monomers assemble on the barbed end of actin filaments at the leading edge. Transmembrane integrin proteins (blue) help form focal adhesions that link the cell membrane to the substrate. (B) If there is no interaction between the actin filaments and focal adhesions, the actin filament is driven rearward by newly assembled actin. Myosin motors (green) also contribute to filament movement.
(C) Interactions between actin-binding adaptor proteins (brown) and integrins link the actin cytoskeleton to the substratum. Myosin-mediated contractile forces are then transmitted through the focal adhesion to generate traction on the extracellular matrix, and new actin polymerization drives the leading edge forward in a protrusion.
Figure 16–83 Traction forces exerted by a motile cell. (A) Tiny flexible pillars attached to the substratum bend in response to traction forces. (B) Scanning electron micrograph of a cell on a substratum coated with pillars that are 6.1 μm in height. Pillar deflections are used to calculate force vectors corresponding to inward pulling forces on the underlying substratum. (Adapted from J. Fu et al., Nat. Methods 7:733–736, 2010. With permission from Macmillan Publishers.) and associated proteins to form focal adhesions (Figure 16–84). These dramatic and complex structural changes occur because each of these three molecular switches has numerous downstream target proteins that affect actin organization and dynamics.