Grab your partner with both hands: cytoskeletal remodeling by Arp2/3 signaling

Abstract

The seemingly simple structure of the actin filament belies the elaborate signaling pathways that regulate its assembly and disassembly in eukaryotic cells. In retrospect, this signaling complexity should not be surprising. Actin regulates many dynamic cellular processes, including protein and organelle trafficking, establishment of cell polarity, directional migration, cellular traction, and the efficiency of endocytosis. Signaling events that coordinately control actin turnover during these processes must display a high degree of sophistication. Emerging data on an important regulator of actin dynamics, the actin-related protein 2 and 3 (Arp2/3) complex, suggest a model of how this may occur.

Fig. 1

Model of actin remodeling through Arp2/3 signaling. (A) Wiskott-Aldrich syndrome protein (WASP) and Wiskott-Aldrich verprolin homologous protein (WAVE) family members are held in an inactive conformation, which occludes the verprolin-cofilin-acidic region (VCA) domain. The actin-related protein 2 and 3 (Arp2/3) complex is also inactive and may be held in an inhibited state by other proteins, such as perinuclear binding protein and substrate for protein kinase C (PICK1). (B) WASP proteins are activated downstream of Cdc42. This causes an allosteric change that allows the VCA domain to bind and activate Arp2/3. Dimerization of WASP by proteins containing F-BAR [Fes-Cdc42-interacting protein 4 (CIP4) homology (FCH) bin-amphiphysin-Rvs] and SH3 (Src homology 3) domains causes hyperactivation of Arp2/3 by allowing two VCA domains to interact with each Arp2/3 complex. [Clustering of WASP by phosphatidyli-nositol biphosphate (PIP₂) brings VCA domains in close proximity and also leads to hyperactivation of Arp2/3.] Together, these inputs stimulate the polymerization of a new actin filament along the side of an existing filament at a fixed 70° angle. (C) Cortactin binds Arp2/3 through the N-terminal acidic (NtA) region and can stabilize the actin branchpoint as well as displace WASP and WAVE family proteins. (D) Coronin 1B and the phosphatase Slingshot replace Arp2/3 from the branchpoint. Coronin 1B–containing branches are positioned at variable angles from the existing actin filament compared with Arp2/3-containing branches (indicated by the double arrow). (E) Branches containing Coronin 1B and Slingshot are unstable and lead to the disassembly of the branched actin filament.