Figure 16–85 The contrasting effects of Rac and Rho activation on actin organization. (A) Activation of the small GTPase Rac leads to alterations in actin accessory proteins that tend to favor the formation of actin networks, as in lamellipodia. Several different pathways contribute independently. Rac-GTP activates members of the WASp protein family, which in turn activate actin nucleation and branched web formation by the Arp 2/3 complex. In a parallel pathway, Rac-GTP activates a protein kinase, PAK, which has several targets including the web-forming cross-linker filamin, which is activated by phosphorylation, and the myosin light chain kinase (MLCK), which is inhibited by phosphorylation. Inhibition of MLCK results in decreased phosphorylation of the myosin regulatory light chain and leads to myosin II filament disassembly and a decrease in contractile activity. In some cells, PAK also directly inhibits myosin II activity by phosphorylation of the myosin heavy chain (MHC). (B) Activation of the related GTPase Rho leads to nucleation of actin filaments by formins and increases contraction by myosin II, promoting the formation of contractile actin bundles such as stress fibers. Activation of myosin II by Rho requires a Rho-dependent protein kinase called Rock. This kinase inhibits the phosphatase that removes the activating phosphate groups from myosin II light chains (MLC); it may also directly phosphorylate the myosin light chains in some cell types. Rock also activates other protein kinases, such as LIM kinase, which in turn contributes to the formation of stable contractile actin filament bundles by inhibiting the actin depolymerizing factor cofilin. A similar signaling pathway is important for forming the contractile ring necessary for cytokinesis (see Figure 17–44).
5 µm neutrophil Gi G12/13 Rho PI(3,4,5)P3 Rac Rac dominates, polymerization (protrusion) Rho dominates, actin–myosin contraction chemoattractant receptor bacterium back front (A) (B) then activates the Arp 2/3 complex leading to lamellipodial protrusion. Through an unknown mechanism, accumulation of the polarized actin web at the leading edge causes further local enhancement of PI3K activity in a positive feedback loop, strengthening the induction of protrusion. The PI(3,4,5)P3 that activates Rac cannot diffuse far from its site of synthesis, since it is rapidly converted back into PI(4,5)P2 by a constitutively active lipid phosphatase. At the same time, binding of the chemoattractant ligand to its receptor activates another signaling pathway that turns on Rho and enhances myosin-based contractility. The two processes directly inhibit each other, such that Rac activation dominates in the front of the cell and Rho activation dominates in the rear (Figure 16–86B). This enables the cell to maintain its functional polarity with protrusion at the leading edge and contraction at the back.
Nondiffusible chemical cues attached to the extracellular matrix or to the surface of cells can also influence the direction of cell migration. When these signals activate receptors, they can cause increased cell adhesion and directed actin polymerization. Most long-distance cell migrations in animals, including neuralcrest-cell migration and the travels of neuronal growth cones, depend on a combination of diffusible and nondiffusible signals to steer the locomoting cells or growth cones to their proper destinations.