Article

Force as a Facilitator of Integrin Conformational Changes during Leukocyte Arrest on Blood Vessels and Antigen-Presenting Cells

Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Immunity (Impact Factor: 21.56). 02/2007; 26(1):17-27. DOI: 10.1016/j.immuni.2007.01.002
Source: PubMed

ABSTRACT

Integrins comprise a large family of cell-cell and cell-matrix adhesion receptors that rapidly modulate their adhesiveness. The arrest of leukocyte integrins on target vascular beds involves instantaneous conformational switches generating shear-resistant adhesions. Structural data suggest that these integrins are maintained in low-affinity conformations and must rapidly undergo conformational switches transduced via cytoplasmic changes ("inside-out" signaling) and simultaneous ligand-induced rearrangements ("outside-in"). This bidirectional activation is accelerated by signals from endothelial chemoattractants (chemokines). Recent studies predict that shear forces in the piconewton (pN) range per integrin can facilitate these biochemical switches. After extravasation, antigen recognition involves smaller internal forces from cytoskeletal motors and actin polymers forming the immune synapse. In this review, we address how forces facilitate allosteric integrin activation by biochemical signals. Evidence suggests that preformed cytoskeletal anchorage rather than free integrin mobility is key for force-enhanced integrin activation by chemokines and TCR signals.

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Available from: Michael L Dustin
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    • "The molecular mechanisms that underlie mechanosensing remain a topic of intense study (Moore et al., 2010). A number of studies suggest that integrins may serve as putative mechanosensors (Alon and Dustin, 2007). We find that Jurkat cells exhibit mechanosensitivity even without integrin engagement, suggesting that these mechanisms may be quite general. "
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    ABSTRACT: T-cells are critical for the adaptive immune response in the body. The binding of the T-cell receptor (TCR) with antigen on the surface of antigen presenting cells leads to cell spreading and signaling activation. The underlying mechanism of signaling activation is not completely understood. While cytoskeletal forces have been implicated in this process, the contribution of different cytoskeletal components and their spatial organization is unknown. Here, we use traction force microscopy to measure the forces exerted by Jurkat T-cells during TCR activation. Perturbation experiments reveal that these forces are largely due to actin assembly and dynamics with myosin contractility contributing to the development of force but not its maintenance. We find that Jurkat T-cells are mechanosensitive, with cytoskeletal forces and signaling dynamics both sensitive to the stiffness of the substrate. Our results delineate the cytoskeletal contributions to interfacial forces exerted by T-cells during activation. © 2014 by The American Society for Cell Biology.
    Full-text · Article · Dec 2014 · Molecular Biology of the Cell
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    • "Integrin activation can be induced by binding molecules inside the cell (inside-out activation) (Puklin-Faucher and Sheetz, 2009), or forces exerted by the ECM and transmitted through ligand (outside-in activation) (Takagi et al., 2002) and a subsequent propagation of conformational changes from the tail to head and head to tail domains, respectively. Some suggest that during cell adhesion, conformational changes are induced simultaneously by inside-out and outside-in signals, and expedited by forces transmitted through ligands (Alon and Dustin, 2007; Puklin-Faucher and Sheetz, 2009; Puklin-Faucher et al., 2006). Simulations by Puklin-Faucher et al. show acceleration in activation events from seconds to microseconds in the presence of mechanical forces (Puklin- Faucher et al., 2006). "

    Full-text · Dataset · Apr 2014
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    • "Integrin activation can be induced by binding molecules inside the cell (inside-out activation) (Puklin-Faucher and Sheetz, 2009), or forces exerted by the ECM and transmitted through ligand (outside-in activation) (Takagi et al., 2002) and a subsequent propagation of conformational changes from the tail to head and head to tail domains, respectively. Some suggest that during cell adhesion, conformational changes are induced simultaneously by inside-out and outside-in signals, and expedited by forces transmitted through ligands (Alon and Dustin, 2007; Puklin-Faucher and Sheetz, 2009; Puklin-Faucher et al., 2006). Simulations by Puklin-Faucher et al. show acceleration in activation events from seconds to microseconds in the presence of mechanical forces (Puklin- Faucher et al., 2006). "

    Full-text · Dataset · Apr 2014
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