How is stress fiber assembly regulated?2018-02-06T10:24:19+08:30

How is stress fiber assembly regulated?

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 [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].

The microtubule and intermediate filament networks play a key role in regulating the global deposition pattern of the actin filaments; therefore, they will also influence actin filament production and membrane protrusion dynamics [50] (reviewed in [51][52][53][54][55]).

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