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Cell adhesion: integrating cytoskeletal dynamics and cellular tension

Key Points

  • Cell migration affects all morphogenetic processes and contributes to numerous diseases, including cancer and cardiovascular disease.

  • Cell migration begins with protrusion of the cell membrane, followed by the formation of new adhesions at the cell front that link the actin cytoskeleton to the substratum, generation of traction forces that move the cell forwards and disassembly of adhesions at the cell rear.

  • Cells exhibit a continuum of migration modes that are determined by several factors, among the most important being substrate compliance and the intrinsic contractility of the cells.

  • The steps in the migration cycle — assembly, maturation and disassembly — are tightly coupled to actin polymerization and organization, and actin–myosin contraction, which are in turn regulated by Rho GTPases and protein Tyr kinases.

  • Adhesion dynamics are regulated by complex feedback loops with Rho proteins and a poorly understood reciprocity between Rac and Rho activation that is mediated through the action of guanine nucleotide exchange factors and GTPase-activating proteins.

  • Adhesions provide cells with the ability to sense the mechanical properties of the substratum and subsequently modulate myosin II activity, integrin clustering, adhesion size and composition, and downstream signalling. It is likely that myosin II is regulated by changes in integrin signalling mediated by a feedback loop that connects adhesion, contractility and signalling through Rho GTPases.

Abstract

Cell migration affects all morphogenetic processes and contributes to numerous diseases, including cancer and cardiovascular disease. For most cells in most environments, movement begins with protrusion of the cell membrane followed by the formation of new adhesions at the cell front that link the actin cytoskeleton to the substratum, generation of traction forces that move the cell forwards and disassembly of adhesions at the cell rear. Adhesion formation and disassembly drive the migration cycle by activating Rho GTPases, which in turn regulate actin polymerization and myosin II activity, and therefore adhesion dynamics.

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Figure 1: Structural elements of a migrating cell.
Figure 2: Myosin II and adhesion maturation and turnover.
Figure 3: Models for the assembly of nascent adhesions.
Figure 4: Adhesion maturation and Rho GTPase activation.

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Acknowledgements

The authors wish to acknowledge the help of M. Vicente-Manzanares and C. Choi in the preparation of the figures and C. Choi for making the supplementary movie. The authors acknowledge support from the Cell Migration Consortium (U54 GM64346), NCI CA40042 (to J.T.P), NIGMS-GM23244 (to A.R.H) and GM47214 (to M.A.S).

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Correspondence to J. Thomas Parsons.

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Supplementary information Movie S1

GFP–paxillin adhesion dynamics in migrating CHO K1 cells. (MOV 10644 kb)

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FURTHER INFORMATION

The Cell Migration Consortium

Glossary

Blebbing cell

A cell that extends a round, dynamic process from the its membrane.

Substrate compliance

A measure of the elasticity of the material to which cells adhere and is related to the distance a material deforms under force. It is the inverse of stiffness and is given in units of 1 per Pascal.

Extracellular matrix

The fibrillar material made of collagens, laminin, fibronectin or other glycoproteins, and proteoglycans, which forms a solid substratum under or around cells in vivo and in culture.

Lamellipodium

A broad, flat protrusion at the leading edge of a cell that moves owing to actin polymerization that is generally induced by Rac activation.

Filopodium

A long, thin protrusion at the periphery of cells and growth cones. Filopodia are composed of F-actin bundles and are often induced by the activation of CDC42.

Actomyosin

A complex of myosin and actin filaments. Activation of the myosin motor leads to shortening of the filaments and subsequent cellular movements.

Guanine nucleotide exchange factor

A protein that activates specific small GTPases by catalysing the exchange of bound GDP for GTP.

GTPase-activating protein

A protein that inactivates small GTP-binding proteins, including Ras and Rho family members, by increasing their rate of GTP hydrolysis.

TIRF

(Total internal reflection fluorescence). A microscope exploiting evanescent wave excitation of the thin region (100 nm) at the contact area between a specimen and the glass coverslip (of a distinct refractive index). It provides improved signal to noise ratios for the observation of events near the coverslip–water interface.

Lamellum

A distinct region of dense actin behind the lamellipodium.

Three-dimensional matrix

(3D matrix). Cells that migrate on top of a thin layer of ECM are considered to be in 2D, whereas cells that are inside and surrounded by ECM on all sides are considered to be in 3D.

Osteoclast

A mesenchymal cell with the capacity to differentiate into bone tissue.

ARP2/3

A complex consisting of seven subunits, including the actin-related proteins ARP2 and ARP3, that, on activation by WASP-family proteins, binds to the sides of existing actin filaments and nucleates the growth of new filaments to form a dendritic network.

Retrograde flow

The movement of actin filaments or other cell components from the cell edge towards the centre, generally driven by actin polymerization at the leading edge.

Transverse arc

A bundle of actin filaments that forms parallel to the leading edge and undergoes retrograde movement towards the cell centre.

Barbed end

The fast-polymerizing end of an actin filament, which is defined by the arrowhead- shaped decoration of actin filaments with myosin fragments.

Computational multiplexing

A mathematical method to correlate multiple time-dependent variables obtained during time-lapse imaging of cells.

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Parsons, J., Horwitz, A. & Schwartz, M. Cell adhesion: integrating cytoskeletal dynamics and cellular tension. Nat Rev Mol Cell Biol 11, 633–643 (2010). https://doi.org/10.1038/nrm2957

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