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CHEMOTACTIC SIGNALING PATHWAYS IN NEUTROPHILS: FROM RECEPTOR TO ACTIN ASSEMBLY

Hematology Division, Harvard Medical School, Brigham and Women's Hospital, LMRC 301, 221 Longwood Avenue, Boston, MA 02115;

View larger version (145K): [in a new window]   Figure 1. Neutrophil morphology. Phase micrograph of an fMLP-activated neutrophil (bar = 5 µm) with an electron micrograph of leading lamella of an fMLP-activated neutrophil demonstrating the highly branched actin filament network (bar = 500 nm).

View larger version (36K): [in a new window]   Figure 2. Activation cycle of small GTPases of the Ras superfamily. Small GTPases of the Ras superfamily cycle between a GTP-bound active and a GDP-bound inactive state. GTPase Activating Proteins (GAPs) enhance the slow intrinsic GTPase activity of small GTPases. Guanosine Dissociation Inhibitors (GDIs) inhibit dissociation of GDP from the GDP-bound form of these proteins, whereas Guanosine Exchange Factors (GEFs) enhance this process.

View larger version (96K): [in a new window]   Figure 3. Regulation of actin filament elongation in migrating neutrophils. Panel A illustrates the activity of the Arp2/3 complex in generating new filament ends. Two mechanisms have been proposed. In the top of the panel, Arp2/3 complex binds to the side of the filament with a characteristic 70° angle and nucleates the growth of a new filament with a free high-affinity end. In a separate model, the Arp2/3 complex binds to an existing high-affinity filament end and nucleates the growth of a new filament. Panel B illustrates the mechanism of uncapping, in which phosphoinositide lipids, illustrated with black head-groups within the phospholipid bilayer, stimulate the dissociation of an actin filament capping protein from the high-affinity end of the actin filament. This filament is then free to elongate. In panel C, we have tried to integrate these activities, as well as the activity of actin cross-linking proteins, to generate the structures found at the leading edge of a motile cell. In all panels, actin filaments are generated from the assembly of actin monomer in gray, the Arp2/3 complex is a collection of multi-component gray ovals, and the capping proteins are open circles.

View larger version (23K): [in a new window]   Figure 4. Summary. A schematic outline of the known signaling elements that link chemotactic receptors and actin assembly in neutrophils. It is recognized that each arrow could represent multiple elements in the signaling path.