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Integrins as biomechanical sensors of the microenvironment

Abstract

Integrins, and integrin-mediated adhesions, have long been recognized to provide the main molecular link attaching cells to the extracellular matrix (ECM) and to serve as bidirectional hubs transmitting signals between cells and their environment. Recent evidence has shown that their combined biochemical and mechanical properties also allow integrins to sense, respond to and interact with ECM of differing properties with exquisite specificity. Here, we review this work first by providing an overview of how integrin function is regulated from both a biochemical and a mechanical perspective, affecting integrin cell-surface availability, binding properties, activation or clustering. Then, we address how this biomechanical regulation allows integrins to respond to different ECM physicochemical properties and signals, such as rigidity, composition and spatial distribution. Finally, we discuss the importance of this sensing for major cell functions by taking cell migration and cancer as examples.

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Fig. 1: Distinct levels of integrin regulation.
Fig. 2: Force regulates integrin properties.
Fig. 3: Integrins mediate response to extracellular matrix (ECM) signals such as force, rigidity and ligand distribution.
Fig. 4: Integrin-mediated regulation of cell migration.

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Acknowledgements

The authors thank H. Hamidi for critical reading of the manuscript and text editing. This work was supported by the Spanish Ministry of Economy and Competitiveness (BFU2016-79916-P), the European Commission (H2020-FETPROACT-01-2016-731957), the Generalitat de Catalunya (2017-SGR-1602), Obra Social ‘La Caixa’ and the ICREA Academia programme of ICREA (to P.R.-C.), and ERC Consolidator grant 615258 and an Academy of Finland grant (to J.I.). The Institute for Bioengineering of Catalonia is the recipient of a Severo Ochoa Award of Excellence from the MICINN.

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Nature Reviews Molecular Cell Biology thanks C. Ballestrem and V. Weaver for their contribution to the peer review of this work.

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Correspondence to Johanna Ivaska or Pere Roca-Cusachs.

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Glossary

Type I transmembrane proteins

Proteins that span the cell membrane through a single transmembrane α-helix, with the N terminus on the extracellular side of the membrane.

RGD motif

A peptide sequence consisting of arginine, glycine and aspartate. It is found in extracellular matrix molecules such as fibronectin and vitronectin and it serves as a binding site for integrins.

Tetraspanins

Membrane-spanning proteins involved in the formation of specific membrane microdomains that have a role in numerous cellular processes, including cell adhesion, signalling and membrane trafficking. They have four transmembrane α-helices and two extracellular loops with a conserved Cys-Cys-Gly amino acid motif, as well as two other conserved cysteine residues.

Adaptor protein

In the context of integrin adhesions, an adaptor protein is any of the several different types of recruited protein that directly or indirectly link integrins to actin.

Talin

A high molecular weight protein (~270 kDa) that links the integrin β-subunit to actin filaments and promotes the assembly of focal adhesions. It consists of an amino-terminal head region with the F0 and FERM domains, a flexible rod domain and a carboxy-terminal dimerization sequence.

Nascent adhesions

Clusters of activated integrin molecules with sizes smaller than 1 µm. They either undergo fast disassembly or they progress to mature focal adhesions.

Focal adhesions

Nascent adhesions mature to focal adhesions on tension generated by actomyosin contractility or external forces. This leads to protein recruitment, and a change in shape from dotted to larger, elongated structures.

Kindlin

A family of proteins (kindlins 1, 2 and 3) involved in integrin-mediated cell signalling, acting as linkers between the actin cytoskeleton and integrins.

Focal adhesion kinase

(FAK). A tyrosine kinase that is involved in the activation and growth of focal adhesions and has a key role in motility and cell survival.

Lectins

Proteins that bind to carbohydrates with high specificity. They are involved in cell adhesion, cell–cell interaction and cell recognition.

Elastic strain

On application of force to stretch a material, the strain is the change in length divided by the original length. If it is elastic, it will revert to zero when force stops being applied.

Glycocalyx

A meshwork surrounding the cell membrane of many eukaryotic cells and bacteria. It consists of carbohydrates (mostly proteoglycans and glycoproteins) that extend out of the cell membrane.

Fluid-phase endocytosis

Continuous and non-specific uptake of extracellular fluid. This form of endocytosis is not mediated by a specific receptor.

BAR protein

A protein with a BAR (BIN/amphiphysin/RVS) domain. The special banana-shaped conformation of BAR domain dimers creates a pocket of positive charges that could mediate phospholipid binding and curvature sensing or induction.

Cell traction forces

Forces that the contractile action of the actomyosin cytoskeleton in cells exert on a substrate measured per unit area.

Caveolae

Small (~50–100 nm) invaginations of the plasma membrane rich in cholesterol. They are shaped by different proteins, of which the caveolin protein family are the principal components.

Lipid rafts

Subdomains of the plasma membrane rich in cholesterol and glycosphingolipids that are resistant to solubilization by non-ionic detergents. They are thought to serve as protein and signalling hubs.

Fibrillar adhesions

Cell–extracellular matrix adhesion sites rich in α5β1 integrin and tensin. They are located towards the cell centre and usually form along extracellular matrix fibrils.

Stress fibres

Actin bundles rich in non-muscle myosin II and α-actinin. They have an important role in force transmission and cellular contractility in non-muscle cells.

MRTFA

A transcription coactivator whose nuclear translocation is regulated by the balance between F-actin and G-actin in the cell cytoplasm. When not bound to G-actin, it translocates to the nucleus, where it regulates gene expression on association with serum response factor.

YAP/TAZ

Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are the two mammalian orthologues of Drosophila melanogaster Yorkie. Both proteins are regulated by mechanical signals and the Hippo pathway. In response to mechanical stimulation of the cells or on inhibition of the Hippo pathway, YAP and TAZ translocate to the nucleus, where they can regulate gene expression through their binding to transcription factors of the TEAD family.

Linker of nucleoskeleton and cytoskeleton (LINC) complex

A protein complex that links the inner nuclear lamina with the cytoskeleton. It has important roles in cell migration, nuclear mechanosensing and nuclear positioning.

Basement membrane

A sheet-like extracellular matrix structure rich in laminin, collagen IV and nidogen. It acts as a barrier between parenchymal cells and connective tissue.

Neural crest cells

A multipotent group of cells arising at the border between the neural plate and non-neural ectoderm. After gastrulation, they become specified and undergo a process of epithelial–mesenchymal transition during neurulation, migrating to form distinct cell populations in different tissues.

Carcinomas

Cancers that originate in epithelial tissues such as the skin or in tissues that line or cover internal organs. There are different types of carcinoma, including squamous and basal cell carcinomas, adenocarcinomas, melanomas, papillomas and ductal carcinomas.

Convergent extension

A process of collective cell movement during embryonic development by which tissues undergo elongation over one axis and narrowing over the other axis.

Interstitial

Internal to a tissue but not specific to a particular structure.

Mesenteric basement membrane

A set of connective tissues that attaches the intestine to the abdominal wall. It contains blood vessels, nerves, lymph nodes and fat.

Urokinase plasminogen activator receptor

(uPAR). A glycosylphosphatidylinositol-anchored cell membrane receptor that acts as a receptor for urokinase plasminogen activator. The binding of urokinase plasminogen activator to its receptor is instrumental for the activation of plasminogen to plasmin — an important blood protease implicated in blood clot resolution, which has also been shown to degrade extracellular matrix and has been linked to cancer progression.

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Kechagia, J.Z., Ivaska, J. & Roca-Cusachs, P. Integrins as biomechanical sensors of the microenvironment. Nat Rev Mol Cell Biol 20, 457–473 (2019). https://doi.org/10.1038/s41580-019-0134-2

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