Function and regulation of the Arp2/3 complex during cell migration in diverse environments

Abstract

As the first de novo actin nucleator discovered, the Arp2/3 complex has been a central player in models of protrusive force production via the dynamic actin network. Here, we review recent studies on the functional role of the Arp2/3 complex in the migration of diverse cell types in different migratory environments. These findings have revealed an unexpected level of plasticity, both in how cells rely on the Arp2/3 complex for migration and other physiological functions and in the intricate modulation of the Arp2/3 complex by other actin regulators and upstream signaling cascades.

Figure 1. Cells use different actin networks for migration

The plasticity underlying the regulation of the actin machinery allows cells to adapt to diverse migratory environments. The migration of fibroblasts and other cell types on 2D surfaces is characterized by the formation of broad lamellipodia at the leading edge (upper left). These structures are composed of Arp2/3-mediated branched actin networks. In confined environments or in the absence of the Arp2/3 complex, many cell types generate filopodial structures of bundled linear actin filaments generated by formins (upper right). Properties of the extracellular matrix and inputs from upstream signaling pathways can mediate a switch between these different actin machineries. However, it is likely that cells migrating in diverse 3D environments in vivo use a combination of actin nucleators in order to fine-tune their cytoskeletal networks (lower center); these nucleators have been shown to both cooperate with and antagonize each other, depending on environmental context. Competition for free actin monomers, influenced by profilin, can modulate the balance between Arp2/3- and formin-mediated actin polymerization. Likewise, competition between formins, Ena/VASP, capping protein, profilin, and even NPFs for free barbed ends can influence the length and structure of the actin filaments. Thus, the migration machinery can be thought of as a spectrum, and cells can shift along this continuum from one mode to the next depending on regulatory protein concentrations, genetic factors or environmental cues. It should be noted that this Figure does not include contractility- or pressure-based modes of migration, such as blebbing or lobopodia.