The interconnected cytoskeleton is crucial for cell migration. Although movement is driven primarily by actin polymerization and myosin contractility, septins and intermediate filaments also participate. For example, vimentin intermediate filament networks associate with integrins at focal adhesions, and vimentin-deficient fibroblasts display impaired mechanical stability, migration, and contractile capacity. Furthermore, disruption of linker proteins that connect different cytoskeletal elements, including several plakins and KASH proteins, leads to defects in cell polarization and migration. Thus, interactions among cytoplasmic filament systems, as well as mechanical linkage to the nucleus, are required for complex, whole-cell behaviors such as migration.
Cells also use microtubules to help organize persistent movement in a specific direction. In many locomoting cells, the position of the centrosome is influenced by the location of protrusive actin polymerization. Activation of receptors on the protruding front edge of a cell might locally activate dynein motor proteins that move the centrosome by pulling on its microtubules. Several effector proteins downstream of Rac and Rho modulate microtubule dynamics directly: for example, a protein kinase activated by Rac can phosphorylate (and thereby inhibit) the tubulin-binding protein stathmin (see Panel 16–4), thereby stabilizing microtubules.
Figure 16–86 Neutrophil polarization and chemotaxis. (A) The pipette tip at the right is leaking a small amount of the bacterial peptide formyl-Met-Leu-Phe, which is recognized by the human neutrophil as the product of a foreign invader. The neutrophil quickly extends a new lamellipodium toward the source of the chemoattractant peptide (top). It then extends this lamellipodium and polarizes its cytoskeleton so that contractile myosin II is located primarily at the rear, opposite the position of the lamellipodium (middle). Finally, the cell crawls toward the source of the peptide (bottom). If a real bacterium were the source of the peptide, rather than an investigator’s pipette, the neutrophil would engulf the bacterium and destroy it (see also Figure 16–3 and Movie 16.14). (B) Binding of bacterial molecules to G-protein-coupled receptors on the neutrophil stimulates directed motility. These receptors are found all over the surface of the cell, but are more likely to be bound to the bacterial ligand at the front. Two distinct signaling pathways contribute to the cell’s polarization. At the front of the cell, stimulation of the Rac pathway leads, via the trimeric G protein Gi, to growth of protrusive actin networks. Second messengers within this pathway are short-lived, so protrusion is limited to the region of the cell closest to the stimulant. The same receptor also stimulates a second signaling pathway, via the trimeric G proteins G12 and G13, that triggers the activation of Rho. The two pathways are mutually antagonistic. Since Rac-based protrusion is active at the front of the cell, Rho is activated only at the rear of the cell, stimulating contraction of the cell rear and assisting directed movement. (A, from
O.D. Weiner et al., Nat. Cell Biol. 1:75–81, 1999. With permission from Macmillan Publishers Ltd.)