JCB_201706052 4271..4286

The plasma membrane of higher eukaryotic cells serves as a platform for transmitting and processing extracellular and intracellular information (Grecco et al., 2011). In addition, the plasma membrane and the associated cell cortex can also act as an excitable medium capable of lateral signal propagation (Iglesias and Devreotes, 2012; Wu et al., 2013; Bement et al., 2015; Barnhart et al., 2017; Miao et al., 2017; van Haastert et al., 2017). The underlying network architecture of a typical excitable medium is based on a component that controls its own activity by coupled self-amplifying and self-inhibiting mechanisms (Murray, 2002; Iglesias and Devreotes, 2012). A time delay in the self-inhibiting mechanism makes such systems more robust with regard to kinetic parameters of the underlying signaling network (Stricker et al., 2008). If an excitable system is stimulated above a certain threshold, it generates a maximal response followed by an insensitive, refractory period. With spatial coupling, for example via diffusion, such systems can generate propagating wave fronts of excited signal activity (Iglesias and Devreotes, 2012). Excitable systems are a key element in the development of multicellular organisms and current models of chemotaxis. In this context, signaling networks that are centered on the Rho GTPases RhoA, Rac1, or Cdc42 are thought to serve a role in exploratory processes such as cortical excitability to direct cleavage furrow positioning in mitotic and meiotic oocytes (Bement et al., 2015), cortical instabilities in the actomyosin cortex of the Caenorhabditis elegans embryo (Nishikawa et al., 2017), or protrusion dynamics in small migrating cells, including Dictyostelium discoideum and neutrophils (Xiong et al., 2010; Iglesias and Devreotes, 2012; Tang et al., 2014; Yang et al., 2016). However, cell migration in larger cell types is thought to be more complex, involving coordinated cell protrusion and contraction (Burnette et al., 2011). Although several studies show that excitable signal transduction networks can control cell protrusion (Xiong et al., 2010; Iglesias and Devreotes, 2012; Tang et al., 2014; Yang et al., 2016; Barnhart et al., 2017; Miao et al., 2017; van Haastert et al., 2017), the role of excitability in controlling subcellular contractility is less clear. In nonmuscle cells, cell contraction is driven by actomyosin dynamics downstream of a signal pathway, including the small GTPase RhoA, Rho kinase 1 (ROCK1) Rho GTPase-based signaling networks control cellular dynamics by coordinating protrusions and retractions in space and time. Here, we reveal a signaling network that generates pulses and propagating waves of cell contractions. These dynamic patterns emerge via self-organization from an activator–inhibitor network, in which the small GTPase Rho amplifies its activity by recruiting its activator, the guanine nucleotide exchange factor GEF-H1. Rho also inhibits itself by local recruitment of actomyosin and the associated RhoGAP Myo9b. This network structure enables spontaneous, self-limiting patterns of subcellular contractility that can explore mechanical cues in the extracellular environment. Indeed, actomyosin pulse frequency in cells is altered by matrix elasticity, showing that coupling of contractility pulses to environmental deformations modulates network dynamics. Thus, our study reveals a mechanism that integrates intracellular biochemical and extracellular mechanical signals into subcellular activity patterns to control cellular contractility dynamics. An excitable Rho GTPase signaling network generates dynamic subcellular contraction patterns