The cytoskeleton:
Function and regulation by Rho GTPases

The actin cytoskeleton plays a central role in a variety of cellular processes like motility, cytokinesis, cell-to-cell and cell-susbstrate interactions and intracellular transport. All these processes are made possible through remodelling of diverse F-actin structures arising by interactions among actin filaments and regulatory components. Actin-binding proteins contribute to the structural organization of the actin cytoskeleton by filament crosslinking (e.g. filamin, a-actinin) or bundling (e.g. villin, fimbrin), some anchor cytoskeletal structures to the plasma membrane, nuclear envelope or cell-to-cell adhesion sites (e.g. spectrin, interaptin, plectin), others, such as the myosins, mediate movement of cargoes along F-actin tracks.
The signaling pathways that lead to remodeling of the microfilament system in response to a variety of stimuli constitute an active research field. In particular investigations on the the role of small GTPases of the Rho family have led to a better understanding of the mechanisms that underlie nucleation of actin polymerization and formation of branched networks of microfilaments at the leading edge of motile cells. The current model of the mechanism of action of these proteins is presented below.


The dendritic nucleation model of actin dynamics at the leading edge of motile cells.
Actin (blue circles) at the leading edge of migrating cells is organized in a branched network (blue polymers), with the fast growing barbed ends of the filaments pointing toward the membrane. Polymerization occurs at the free barbed ends, and as it does, the force generated by the rapid growth of the actin network leads to protrusion of the membrane.
The initiation of new filaments relies on Arp2/3 complex (red circles), activated by a protein such as SCAR or WASP (green rectangles) in response to a variety of signals. The branching morphology is generated by the binding of Arp2/3 complex to the sides of preexisting filaments.
(Adapted from Higgs, H. N. and Pollard, T. D. 2001. Regulation of actin filament network formation through ARP2/3 complex:
activation by a diverse array of proteins. Annu. Rev. Biochem., 70, 649-676)