Dynamics of the actin cytoskeleton mediates receptor cross talk: An emerging concept in tuning receptor signaling

Abstract

Recent evidence implicates the actin cytoskeleton in the control of receptor signaling. This may be of particular importance in the context of immune receptors, such as the B cell receptor, where dysregulated signaling can result in autoimmunity and malignancy. Here, we discuss the role of the actin cytoskeleton in controlling receptor compartmentalization, dynamics, and clustering as a means to regulate receptor signaling through controlling the interactions with protein partners. We propose that the actin cytoskeleton is a point of integration for receptor cross talk through modulation of protein dynamics and clustering. We discuss the implication of this cross talk via the cytoskeleton for both ligand-induced and low-level constitutive (tonic) signaling necessary for immune cell survival.

Figure 1.

General principles of the regulation of submembranous actin structures by various actin-binding proteins. Carefully regulated balance of filament polymerization, depolymerization, bundling, and capping together with contractility and regulated connections to the plasma membrane lead to different properties of actin-based structures, such as actin cortex, lamellipodia, and filopodia. Classical examples of actin-binding proteins that convey these activities are illustrated. The actin cortex is a relatively stable mesh-like network of interconnected and contractile filaments that are physically linked with the membrane and aligned under it in a juxtaposed manner. At the leading edge of the cell, lamellipodia are highly dynamic structures where branched filaments are aligned perpendicular to the membrane and push it forward. Filopodia, also found in the leading edge, are finger-like structures, where long and straight filaments are bundled together to protrude the membrane outward.

Figure 2.

Examples of proteins connecting the plasma membrane to the actin cytoskeleton. (top left) ERM proteins (Neisch and Fehon, 2011). (bottom left) Protein 4.1-ankyrin-spectrin network (Baines, 2010; Baines et al., 2014). (top right) Septins (Gilden et al., 2012; Bridges and Gladfelter, 2015). (middle right) Filamins (Lin et al., 2001; Stossel et al., 2001; Beekman et al., 2008; Zhou et al., 2010). (bottom right) Myosin 1 (McConnell and Tyska, 2010).

Figure 3.

Model of the nanoscale organization of IgM and IgD at the B cell surface. Schematic diagram illustrating IgM (blue) and IgD (red) nanoclusters at the surface of B cells based on super-resolution STORM analysis reported in Mattila et al. (2013). A heterogeneity of clusters is present from monomers to small clusters of varying size and number of molecules. Dashed circles on the right show zoomed-in view of nanoclusters in box outlined. Based on a mean cluster size with radius of ∼70 nm and considering the surface area of the cell and the number of BCR at the cell surface, we calculated a theoretical estimate of receptor density within nanoclusters and depict an average IgM cluster and a high-density IgD cluster, as IgD was found to be significantly more densely packed than IgM nanoclusters. Inset box on left depicts a model of the actin cytoskeleton (green) in relation to nanoclusters based on electron tomography data from Morone et al. (2006). Diagram is to scale.

Figure 4.

BCR nanoclusters are brought together to form signaling BCR microclusters. (A) En-face view of the cell–cell contact showing nanoclusters of BCR and CD19 are brought together to form signaling microclusters. Some microclusters contain only IgM, some contain only IgD, and some contain both IgM and IgD as shown in Depoil et al. (2008). Note that not all BCRs form microclusters; monomers and nanoclusters of BCR not in microclusters are shown as semitransparent. (B) Side view of cell–cell contact showing actin and ERM proteins are reorganized to form a fence around BCR microclusters as shown in Treanor et al. (2011). These signaling microclusters lead to localized reorganization of actin that will release unengaged monomers/nanoclusters of BCR from the actin-defined diffusion barrier providing a positive feedback loop to amplify BCR signaling.

Figure 5.

Actin dynamics as a mechanism of integrating receptor cross talk. We propose that the actin cytoskeleton provides a mechanism to integrate environmental stimuli through modification of receptor organization and dynamics and, consequently, protein–protein interactions regulating receptor signaling. In the context of B cells, alterations in the actin cytoskeleton induced through non–BCR-signaling pathways are able to tune BCR activation through increased BCR diffusion dynamics and thus the probability that the BCR will encounter CD19. Changes in actin dynamics could be induced, for example, through innate immune receptors such as TLRs, as recently shown by Freeman et al. (2015), or through other environmental stimuli such as cytokines and chemokines. A recent study showed that BAFFR signaling leads to phosphorylation of Igα/β subunits and subsequent activation of the kinase Syk (Schweighoffer et al., 2013); perhaps this is caused by BAFFR-induced changes in the cytoskeleton and increased interaction between BCR and CD19. This integration of environmental stimuli via actin dynamics could result in priming of BCR and increased BCR sensitivity for ligand. It could also offer perspective on tonic BCR signaling as periodic spatiotemporal changes in the cytoskeleton could modulate BCR–CD19 interactions and initiate localized ligand-independent signaling.