External Signals and Various Signaling Pathways Coordinate Events That Lead to Cell Migration

A striking feature of a moving cell is its polarity: a cell has a front and a back. When a cell makes a turn, a new leading lamellipodium or pseudopodium forms in the new direction.

If these extensions form in all directions, as in myosin I ameba mutants, then the cell is unable to pick a new direction of movement. To sustain movement in a particular direction, a cell requires signals to coordinate events at the front of the cell with events at the back and, indeed, signals to tell the cell where its front is. In this section, we present several examples of how external signals activate cell migration and control the direction of movement.

Activation of Filopodia, Membrane Ruffles, and Stress Fibers by Growth Factors Certain growth factors in a fresh wound stimulate a quiescent cultured fibroblast to grow and divide by forming filopodia and lamellipodia at its leading edge and later to assemble stress fibers and focal adhesions. Similar signal-induced events are thought to take place in the wound-healing response of fibroblasts in vivo, the development of cells in embryos, and the metastasis of cancer cells. These events require the polymerization of actin filaments, the activation of myosin molecules, and the assembly of actin bundles and networks. The cytoskeletal rearrangements that are a part of the wound-healing response of fibroblasts include intracellular signaling pathways directed by Rac, Rho, and Cdc42, all Ras-like molecules belonging to the GTPase superfamily of switch proteins. These pathways are activated by the binding of growth factors to receptor tyrosine kinases, a class of cell-surface receptors described in Chapter 13.

The roles of Ras-related proteins were revealed by simple microinjection experiments. When Rac was microin-jected into a fibroblast, the membrane immediately started to form upward projections called ruffles; focal adhesions and stress fibers formed 5-10 minutes later. Injection of an inactive form of Rac inhibited all reorganization of the actin cytoskeleton when growth factors were added to the cell. When Rho, rather than Rac, was injected, it mimicked the mitogenic effects of lysophosphatidic acid (LPA), a chemokine in serum and a potent stimulator of platelet aggregation. Both Rho and LPA induced the assembly of stress fibers and focal adhesions within 2 minutes but did not induce membrane ruffling.

These findings lead to a model in which extracellular factors trigger Ras-linked signal-transduction pathways that activate actin polymerization at the leading-edge membrane as an early event and the formation of focal adhesions as a later event (Figure 19-29). If this model is correct, then the inhibition of stress-fiber assembly should not affect membrane ruffling. To test the model, Rac and ADP-ribosylase, an enzyme that inactivates Rho by covalently attaching ADP to it, were co-injected into a fibroblast. As predicted, membrane ruffles were formed, but the assembly of stress fibers was blocked. These observations suggest that Rho-dependent events such as stress-fiber formation are "downstream" of control by Rac. The results of later experiments in which Cdc42 was microinjected into fibroblasts showed that this protein controlled an earlier step, the formation of filopodia. Thus the sequence of events in wound healing begins with the participation of filopodia and lamellipodia during the

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