(A) Myosin II bipolar filaments bind to actin filaments in the lamellipodial meshwork and cause network contraction. The myosin-driven reorientation of the actin filaments forms an actin bundle that recruits more myosin II and helps generate the contractile forces required for retraction of the trailing edge of the moving cell. (B) A fragment of the large lamellipodium of a keratocyte can be separated from the main cell body either by surgery with a micropipette or by treating the cell with certain drugs. Many of these fragments continue to move rapidly, with the same overall cytoskeletal organization as the intact keratocytes. Actin (blue) forms a protrusive meshwork at the front of the fragment. Myosin II (pink) is gathered into  a band at the rear. (From A. Verkhovsky et al., Curr. Biol. 9:11–20, 1999. With permission from Elsevier.) edge of a migrating cell to advance, protrusion of the membrane must be followed by adhesion to the substratum at the front. Conversely, in order for the cell body to follow, contraction must be coupled with de-adhesion at the rear of the cell. The processes contributing to migration are therefore tightly regulated in space and time, with actin polymerization, dynamic adhesions, and myosin contraction being employed to coordinate movement. Myosin II operates in at least two ways to assist cell migration. The first is by helping to connect the actin cytoskeleton to the substratum through integrin-mediated adhesions. Forces generated by both actin polymerization and myosin activity create tension at attachment sites, promoting their maturation into focal adhesions, which are dynamic assemblies of structural and signaling proteins that link the migrating cell to the extracellular matrix (see Figure 19–59). A second mechanism involves bipolar myosin II filaments, which associate with the actin filaments at the rear of the lamellipodium and pull them into a new orientation—from nearly perpendicular to the leading edge to almost parallel to the leading edge. This sarcomere-like contraction prevents protrusion, and it pinches in the sides of the locomoting lamellipodium, helping to gather in the sides of the cell as it moves forward (Figure 16–81).
Actin-mediated protrusions can only push the leading edge of the cell forward if there are strong interactions between the actin network and the focal adhesions that link the cell to the substrate. When these interactions are disengaged, polymerization pressure at the leading edge and myosin-dependent contraction cause the actin network to slip back, resulting in a phenomenon known as retrograde flow (Figure 16–82).
The traction forces generated by locomoting cells exert a significant pull on the substratum. By growing cells on a surface coated with tiny flexible posts, the force exerted on the substratum can be calculated by measuring the deflection of each post from its vertical position (Figure 16–83). In a living animal, most crawling cells move across a semiflexible substratum made of extracellular matrix, which can be deformed and rearranged by these cell forces. Conversely, mechanical tension or stretching applied externally to a cell will cause it to assemble stress fibers and focal adhesions, and become more contractile. Although poorly understood, this two-way mechanical interaction between cells and their physical environment is thought to help vertebrate tissues organize themselves.
Cell Polarization Is Controlled by Members of the Rho Protein Family
Cell migration requires long-distance communication and coordination between one end of a cell and the other. During directed migration, it is important that the front end of the cell remain structurally and functionally distinct from the back end. In addition to driving local mechanical processes such as protrusion at the front and retraction at the rear, the cytoskeleton is responsible for coordinating cell shape, organization, and mechanical properties from one end of the cell to the other, a distance that is typically tens of micrometers for animal cells.