▲ FIGURE 19-29 Role of signal-transduction pathways in cell locomotion and the organization of the cytoskeleton.
Extracellular signals are transmitted across the plasma membrane by receptors specific for different factors. One set of growth factors induces actin polymerization at the leading edge through a Rac- and Cdc42-dependent pathway (left); another set of factors acts downstream through a Rho-dependent pathway to migration of cells into the wound and the formation of focal adhesions and stress fibers to close the wound.
An important aspect of locomotion is how movement is coordinated in response to different stimuli. For example, the assembly of the branched actin network at the membrane is enhanced by the action of several signaling pathways and their adapter proteins. The branching activity of the Arp2/3 complex is activated by an adapter protein, WASp, under the control of the Cdc42 GTPase. In addition, as discussed previously, the hydrolysis of PIP2 by phospholipase C releases profilin, cofilin, and gelsolin from the membrane. In another pathway, inositol 1,4,5-trisphosphate (IP3), a by-product of PIP2 hydrolysis, stimulates the release of Ca2+ ions from the endoplasmic reticulum into the cytosol; this increase in Ca2+ ions activates myosin II and the severing activity of gelsolin. These parallel pathways thus stimulate both actin severing and filament growth, thereby increasing actin turnover (Figure 19-29, right).
induce the assembly of focal adhesions and cortical contraction (center). Adhesion of a cell to the extracellular matrix triggers a parallel signaling pathway that induces the activation of profilin, cofilin, and gelsolin (right). Triggering of this pathway activates phospholipase C (PLC), which hydrolyzes PIP2 in the membrane. The subsequent increase in cytosolic Ca2+ stimulates actin turnover.
movements. For example, leukocytes are guided by a tripep-tide secreted by many bacterial cells. In the development of skeletal muscle, a secreted protein signal called scatter factor guides the migration of myoblasts to the proper locations in limb buds (Chapter 22).
Despite the variety of different chemotactic molecules— sugars, peptides, cell metabolites, cell-wall or membrane lipids—they all work through a common and familiar mechanism: binding to cell-surface receptors, activation of intra-cellular signaling pathways, and re-modeling of the cyto-skeleton through the activation or inhibition of various actin-binding proteins. The central question is, How do cell-surface receptors detect as small as a 2 percent difference in the concentration of chemotactic molecules across the length of the cell? To direct cell migration, an external chemoat-tractant gradient must somehow induce internal gradients that lead to polarization of the actin cytoskeleton.
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