Extracellular Matrix Rigidity Causes Strengthening of Integrin–Cytoskeleton Linkages

Choquet, Daniel; Felsenfeld, Dan P.; Sheetz, Michael P.

doi:10.1016/s0092-8674(00)81856-5

Cited by 1,159 publications

(1,022 citation statements)

References 47 publications

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“…It has been shown that forces exerted on focal adhesions stretch the receptor-ligand bonds and aid the growth of adhesions (15). The softer ECMs undergo larger deformation and thus lead to greater distances between receptors and ligands, which in turn is thought to impair adhesion bond formation (16).…”

Section: Cell-ecm Adhesion Dynamicsmentioning

confidence: 99%

Scattering of Cell Clusters in Confinement

Pathak

2016

Biophysical Journal

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Epithelial-to-mesenchymal transition (EMT) enables scattering of cell clusters and disseminates motile cells to distant locations in vivo during embryonic development and cancer metastasis. Both stiffness and topography of the extracellular matrix (ECM) have been shown to influence EMT. In this work, we examine how the integrity of epithelial cell clusters is regulated by subcellular forces, protrusions, and adhesions for varying ECM inputs, such as stiffness, topography, and dimensionality. Our model simulates multicell networks of defined sizes and shapes in ECMs of varied stiffness and geometry. The integrity of cell clusters is dictated by cell-cell junctions, which depend on subcellular forces and adhesion dynamics within each cell of the cluster. Our simulations demonstrate an enhanced dissociation of cell-cell junctions in stiffer and more confined three-dimensional (3D) environments, consistent with experimental findings. In narrow channels, the cell edges parallel to the axis of channels lose their cell-cell junctions more readily than those oriented in the perpendicular direction. The inhibition of protrusive activity and cell polarity disables confinement-dependent cell scattering. Here, cell adhesion and spreading along channel walls is found to be essential for scattering. The model also predicts that two-dimensional (2D) confinement of clusters restricts cell spreading and simultaneously blunts the confinement-sensitive cell scattering. This new, to our knowledge, multiscale model integrates molecular adhesion dynamics, subcellular forces, cellular deformation, and macroscale mechanical properties of the ECM to predict the state of cell clusters of defined shapes and sizes. The predictions made by our model not only match experimental findings from a number of experimental setups, but also provide a new conceptual framework for understanding mechanosensitive cell scattering and EMT.

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Section: Cell-ecm Adhesion Dynamicsmentioning

confidence: 99%

Scattering of Cell Clusters in Confinement

Pathak

2016

Biophysical Journal

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“…87 Integrins are mechanoreceptors, able to sense substrate rigidity via periodic contraction of the integrinassociated cytoskeleton. 88 This results in the recruitment of additional cytoskeletal elements to strengthen the interaction, 89 which themselves are sensitive to the presence of mechanical force. 90 Lack of tensional forces may compromise the ability of integrins to mediate productive signaling into the cell, particularly among signaling events that are dependent upon the cytoskeleton.…”

Section: Signaling Cascades and The Integrin Rheostatmentioning

confidence: 99%

Integrins as a distinct subtype of dependence receptors

Stupack

2005

Cell Death Differ

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In the absence of their cognate ligand, dependence receptors trigger programmed cell death. This function is the defining feature of dependence receptors, which include members of several different protein families. The integrins are a family of heterodimeric receptors for extracellular matrix (ECM) proteins, mediating cell anchorage and migration. Integrins share characteristics with dependence receptors, and integrin binding to substrate ECM ligands is essential for cell survival. Although integrins do not conform in all characteristics to the established definitions of dependence receptors, alterations in the expression of integrins and their ligands during physiological and pathological events, such as wound healing, angiogenesis and tumorigenesis, do regulate cell fate in a ligand-dependent manner. This biosensory function of integrins fits well with our current concept of dependence receptor action, and thus integrins may rightly be considered to comprise a distinct subclass of dependence receptor.

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“…Various micromechanical techniques have been established during the last few years to measure local elastic moduli or the stress-strain relationship of whole cells including micropipette aspiration techniques [12][13][14], atomic force microscopy [15], optical tweezers [16,17], or cell poking with glass rods [18]. Based on these techniques, the elastic properties of cell envelopes, whole nucleated cells and erythrocytes have been extensively studied [1,19].…”

Section: Introductionmentioning

confidence: 99%

Active mechanical stabilization of the viscoplastic intracellular space of Dictyostelia cells by microtubule–actin crosstalk

Heinrich

Sackmann²

2006

Acta Biomaterialia

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The micro-viscoelasticity of the intracellular space of Dictyostelium discoideum cells is studied by evaluating the intracellular transport of magnetic force probes and their viscoelastic responses to force pulses of 20-700 pN. The role of the actin cortex, the microtubule (MT) aster and their crosstalk is explored by comparing the behaviour of wild-type cells, myosin II null mutants, latrunculin A and benomyl treated cells. The MT coupled beads perform irregular local and long range directed motions which are characterized by measuring their velocity distributions (P(v)). The correlated motion of the MT and the centrosome are evaluated by microfluorescence of GFP-labelled MTs. P(v) can be represented by log-normal distributions with long tails and it is determined by random sweeping motions (v $ 0.5 lm/s) of the MTs (caused by tangential forces on the filament ends coupled to the actin cortex) and by intermittent bead transports parallel to the MTs (v max $ 1.5 lm/s). The tails are due to spontaneous filament deflections (with speeds up to 10 lm/s) attributed to pre-stressing of the MT by local cortical tensions, generated by dynactin motors generating plus-end directed forces in the MTs. The viscoelastic responses are strongly non-linear and are mostly directed opposite or perpendicular to the force, showing that the cytoplasm behaves as an active viscoplastic body with time and force dependent drag coefficients. Nano-Newton loads exerted on the soft MT are balanced by traction forces arising at the MT ends coupled to the actin cortex and the centrosome, respectively. The mechanical coupling between the soft microtubules and the viscoelastic actin cortex provides cells with high mechanical stability despite the softness of the cytoplasm.

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Extracellular Matrix Rigidity Causes Strengthening of Integrin–Cytoskeleton Linkages

Cited by 1,159 publications

References 47 publications

Scattering of Cell Clusters in Confinement

Scattering of Cell Clusters in Confinement

Integrins as a distinct subtype of dependence receptors

Active mechanical stabilization of the viscoplastic intracellular space of Dictyostelia cells by microtubule–actin crosstalk

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