Regulation of Stress Fiber Assembly
Regulation of Stress Fiber Assembly[Edit]
Tension-dependent actin polymerization and assembly of stress fibers is influenced by many factors (reviewed in [1, 2]), including differences in substrate composition [3], rigidity [4, 5, 6] (reviewed in [7]), cell membrane phospholipids [8], external force (reviewed in [9]), as well as by strength of the connection(s) between actin filaments and the adhesion sites [10, 11, 12] (reviewed in [13, 14]).
Each of these cues converges at the level of the Rho family of GTPases and their effector substrates (reviewed in [14, 15, 16, 17]). The activity of the Rho GTPases is finely regulated by GTPase activating proteins (GAPs), guanine nucleotide exchange factors (GEFs), and guanine nucleotide dissociation inhibitors (GDIs) [18] (reviewed in [19, 20]); however, actin-associated proteins such as synaptopodin can also block the degradation of RhoA and lead to stress fiber formation [21].
Stress fibers function to counter membrane tension and to keep the non-adherent regions of a cell straight [22]. Accordingly, the rate of actin assembly at the leading edge is directly dependent on the membrane tension: elevated tension lowers membrane protrusion and cell motility, regardless of whether the tension is applied externally (e.g., stretching) or internally (e.g., contraction of stress fibers) [23, 24, 25]. Furthermore, Rho GTPases recruit formins to initiate actin assembly from focal adhesions in a manner that is also force-dependent [17].
As tension regulates the dynamic assembly and disassembly of actin filaments [26], proteins that contribute to the structural integrity of the filaments will influence the physical transmission of forces across the network. α-actinin and filamin are enriched in arcs and stress fibers [27, 28, 29, 30, 31] and they are both known to alter the structural dynamics of the actin cytoskeleton (reviewed in [32, 33]). α-actinin recruits proteins that are important for mechanosensing in stress fibers (e.g., zyxin [34, 35]) and for stress fiber maintenance (e.g., CLP-36 [36], palladin [37]) whereas filamin links the filaments to cellular membranes and its degradation products may act as signaling molecules (reviewed in [33, 38]). Interestingly, the association of α-actinin with actin filaments and stress fibers is highly dynamic [17, 39, 40] and dynamic binding is essential for proper cell function [41]; this implies that any factors that manipulate the actin-binding properties of α-actinin or its association with actin filaments (e.g., Alix [42]; RIL [43]) will likely influence the formation of stress fibers.
Membrane curvature, cross-linking and bundling of F-actin at the leading cell edge is mediated by proteins containing IM/I-BAR domains such as IRSp53 (reviewed in [44]); these proteins interact with actin-associated proteins (e.g., synaptopodin) and components of the actin polymerizing module (e.g., Mena, WAVE) to regulate the protrusive dynamics and structure of the growing actin network [45, 46, 47, 48]. The relative expression level of IRSp53 influences stress fiber assembly: stress fibers are seen when IRSp53 levels are low, while overexpression causes their complete disassembly [49].