Two Distinct Actin Networks Mediate Traction Oscillations to Confer Focal Adhesion Mechanosensing

Abstract

Focal adhesions (FAs) are integrin-based transmembrane assemblies that connect a cell to its extracellular matrix (ECM). They are mechanosensors through which cells exert actin cytoskeleton-mediated traction forces to sense the ECM stiffness. Interestingly, FAs themselves are dynamic structures that adapt their growth in response to mechanical force. It is unclear how the cell manages the plasticity of the FA structure and the associated traction force to accurately sense ECM stiffness. Strikingly, FA traction forces oscillate in time and space, and govern the cell mechanosensing of ECM stiffness. However, precisely how and why the FA traction oscillates is unknown. We developed a model of FA growth that integrates the contributions of the branched actin network and stress fibers (SFs). Using the model in combination with experimental tests, we show that the retrograde flux of the branched actin network promotes the proximal growth of the FA and contributes to a traction peak near the FA’s distal tip. The resulting traction gradient within the growing FA favors SF formation near the FA’s proximal end. The SF-mediated actomyosin contractility further stabilizes the FA and generates a second traction peak near the center of the FA. Formin-mediated SF elongation negatively feeds back with actomyosin contractility, resulting in central traction peak oscillation. This underpins the observed FA traction oscillation and, importantly, broadens the ECM stiffness range over which FAs can accurately adapt to traction force generation. Actin cytoskeleton-mediated FA growth and maturation thus culminate with FA traction oscillation to drive efficient FA mechanosensing.

Mechanosensing during directed cell migration requires dynamic actin polymerization at focal adhesions

“…Previous studies demonstrated that cells respond to the mechanical demands of the local microenvironment by dynamically altering their actin cytoskeleton at focal adhesions (FAs; Choquet et al, 1997;Butcher et al, 2009). In agreement with these findings, mathematical and experimental modeling suggested that the acto-myosin cytoskeleton at FAs mediates an oscillating traction force required for mechanically directed motility, the directional movement toward a mechanical stimulus (Plotnikov et al, 2012;Wu et al, 2017). However, the mechanisms that regulate these FA cytoskeletal dynamics and the distinctive role they play in mechanosensing, mechanically directed motility, and durotaxis have yet to be elucidated.…”

Talin – the master of integrin adhesions

“…However, focal adhesions do not display this behaviour, but rather increase their traction force monotonically as the stiffness increases (Ghibaudo et al, 2008). This finding suggests that there is a mechanism that reinforces the clutch so that it can operate at higher traction force, which turns out to require both talin and vinculin (Elosegui-Artola et al, 2016; see also new computational model from Wu et al, 2017).…”

Traction forces control cell-edge dynamics and mediate distance-sensitivity during cell polarization

“…They are believed to drive cell motion, shape changes, and extracellular matrix remodeling [1][2][3]. However, most of the traction force analysis has been performed on stationary cells, investigating forces at the level of individual focal adhesions or linking them to static cell parameters such as area and edge curvature [4][5][6][7][8][9][10]. It is not well understood how traction forces are related to shape changes and motion, e.g.…”