Transient Frictional Slip between Integrin and the ECM in Focal Adhesions under Myosin II Tension

Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA.
Current biology: CB (Impact Factor: 9.57). 07/2010; 20(13):1145-53. DOI: 10.1016/j.cub.2010.05.049
Source: PubMed


The spatiotemporal regulation of adhesion to the extracellular matrix is important in metazoan cell migration and mechanosensation. Although adhesion assembly depends on intracellular and extracellular tension, the biophysical regulation of force transmission between the actin cytoskeleton and extracellular matrix during this process remains largely unknown.
To elucidate the nature of force transmission as myosin II tension is applied to focal adhesions, we correlated the dynamics of focal adhesion proteins and the actin cytoskeleton to local traction stresses. Under low extracellular tension, newly formed adhesions near the cell periphery underwent a transient retrograde displacement preceding elongation. We found that myosin II-generated tension drives this mobility, and we determine the interface of differential motion, or "slip," to be between integrin and the ECM. The magnitude and duration of both adhesion slip and associated F-actin dynamics is strongly modulated by ECM compliance. Traction forces are generated throughout the slip period, and adhesion immobilization occurs at a constant tension.
We have identified a tension-dependent, extracellular "clutch" between integrins and the extracellular matrix; this clutch stabilizes adhesions under myosin II driven tension. The current work elucidates a mechanism by which force transmission is modulated during focal adhesion maturation.

Download full-text


Available from: Margaret L Gardel, Aug 15, 2014
  • Source
    • "Without further analysis, it is impossible to ascertain whether the adhesion plaques are actually undergoing translocation or treadmilling. However, Arp2/3 inhibition reduces the coupling of adhesion plaques to the ECM to result in gross FA movements only typically seen during adhesion assembly [25] and disassembly [26]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Here we demonstrate that Arp2/3 regulates a transition between mesenchymal and amoeboid protrusions in MCF10A epithelial cells. Using genetic and pharmacological means, we first show Arp2/3 inhibition impairs directed cell migration. Arp2/3 inhibition results in a dramatically impaired cell adhesion, causing deficient cell attachment and spreading to ECM as well as an 8-fold decrease in nascent adhesion assembly at the leading edge. While Arp2/3 does not play a significant role in myosin-dependent adhesion growth, mature focal adhesions undergo large scale movements against the ECM suggesting reduced coupling to the ECM. Cell edge protrusions occur at similar rates when Arp2/3 is inhibited but their morphology is dramatically altered. Persistent lamellipodia are abrogated and we observe a markedly increased incidence of blebbing and unstable pseuodopods. Micropipette-aspiration assays indicate that Arp2/3-inhibited cells have a weak coupling between the cell cortex and the plasma membrane, and suggest a potential mechanism for increased pseudopod and bleb formation. Pseudopods are not sensitive to reduced in formin or myosin II activity. Collectively, these results indicate that Arp2/3 is not necessary for rapid protrusion of the cell edge but plays a crucial role in assembling focal adhesions required for its stabilization.
    Full-text · Article · Jun 2014 · PLoS ONE
  • Source
    • "Rac1 and Cdc42 activation at the leading edge drives the initial formation of small adhesions in an actin polymerization-dependent mechanism [23], [54]. RhoA is also localized to the leading edge and is activated spatiotemporally ahead of Rac1, but in contrast promotes the formation of contractile stress fibers resulting in the formation of large, long-lived FAs [32], [30], [56], [57]. CdGAP knockdown led to the formation of small FAs independent of matrix rigidity, suggesting that FAs in cdGAP RNAi-treated cells may have failed to mature due to decreased RhoA activity and/or the failure to activate downstream RhoA effectors such as ROCK or non-muscle myosin IIA. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Motile cells are capable of sensing the stiffness of the surrounding extracellular matrix through integrin-mediated focal adhesions and migrate towards regions of higher rigidity in a process known as durotaxis. Durotaxis plays an important role in normal development and disease progression, including tumor invasion and metastasis. However, the signaling mechanisms underlying focal adhesion-mediated rigidity sensing and durotaxis are poorly understood. Utilizing matrix-coated polydimethylsiloxane gels to manipulate substrate compliance, we show that cdGAP, an adhesion-localized Rac1 and Cdc42 specific GTPase activating protein, is necessary for U2OS osteosarcoma cells to coordinate cell shape changes and migration as a function of extracellular matrix stiffness. CdGAP regulated rigidity-dependent motility by controlling membrane protrusion and adhesion dynamics, as well as by modulating Rac1 activity. CdGAP was also found to be necessary for U2OS cell durotaxis. Taken together, these data identify cdGAP as an important component of an integrin-mediated signaling pathway that senses and responds to mechanical cues in the extracellular matrix in order to coordinate directed cell motility.
    Full-text · Article · Mar 2014 · PLoS ONE
  • Source
    • "However, these movements are on a very short, sub-micron spatial scale, and so we do not include them in the model. Adhesions are multi-component protein complexes, whose content and properties depend on many factors and on the stage of their dynamics [5] [36] [37]. However, the detailed morphological cycle of adhesion maturation and turnover is beyond the scope of the current study, as there is little understanding of respective mechanical changes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: All parts of motile cells, including the plasma membrane, have to translocate in the direction of locomotion. Both directed intracellular membrane transport coupled with polarized endo- and exocytosis and fluid flow in the plane of the plasma membrane can contribute to this overall plasma membrane translocation. It remains unclear how strong a force is required to generate this flow. We numerically solve Stokes equations for the viscous membrane flow across a flat plasma membrane surface in the presence of transmembrane proteins attached to the cytoskeleton and find the membrane tension gradient associated with this flow. This gradient is sensitive to the size and density of the transmembrane proteins attached to the cytoskeleton and can become significant enough to slow down cell movement. We estimate the influence of intracellular membrane transport and actin growth and contraction on the tension gradient, and discuss possible 'tank tread' flow at ventral and dorsal surfaces.
    Full-text · Article · Jan 2014 · PLoS ONE
Show more