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Organization, dynamics and mechanoregulation of integrin-mediated cell–ECM adhesions

Abstract

The ability of animal cells to sense, adhere to and remodel their local extracellular matrix (ECM) is central to control of cell shape, mechanical responsiveness, motility and signalling, and hence to development, tissue formation, wound healing and the immune response. Cell–ECM interactions occur at various specialized, multi-protein adhesion complexes that serve to physically link the ECM to the cytoskeleton and the intracellular signalling apparatus. This occurs predominantly via clustered transmembrane receptors of the integrin family. Here we review how the interplay of mechanical forces, biochemical signalling and molecular self-organization determines the composition, organization, mechanosensitivity and dynamics of these adhesions. Progress in the identification of core multi-protein modules within the adhesions and characterization of rearrangements of their components in response to force, together with advanced imaging approaches, has improved understanding of adhesion maturation and turnover and the relationships between adhesion structures and functions. Perturbations of adhesion contribute to a broad range of diseases and to age-related dysfunction, thus an improved understanding of their molecular nature may facilitate therapeutic intervention in these conditions.

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Fig. 1: Integrin conformational dynamics at integrin-mediated adhesions.
Fig. 2: Cataloguing the molecular components of integrin adhesion complexes.
Fig. 3: Molecular organization of integrin adhesion complexes.
Fig. 4: Molecular-scale mechanoregulation of integrin adhesion complexes.

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Acknowledgements

P.K. acknowledges funding support from the Mechanobiology Institute intramural fund and the Singapore Ministry of Education Academic Research Fund Tier 2 (MOE2019-T2-2-014) and Tier 3 (MOE-T3-2020-0001). D.A.C. acknowledges funding support from the National Institutes of Health (NIH) (R01GM134148 and R01GM138411).

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Correspondence to Pakorn Kanchanawong or David A. Calderwood.

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Glossary

RGD ligands

Amino acid motifs comprising tripeptide arginine, glycine and aspartate that serve as an integrin binding site in extracellular matrix (ECM) proteins such as fibronectin and vitronectin.

Basement membrane

A sheet of extracellular matrix (ECM) rich in laminins and type IV collagen to which epithelial and endothelial layers adhere. The basement membrane (sometimes termed the basal lamina) forms a barrier between tissues and provides a structural support and important signalling cues to epithelial and endothelial cells.

FERM domain

The band 4.1, ezrin, radixin and moesin domain is found in various cytoskeletal-associated proteins, and typically contains three subdomains (F1, F2 and F3) arranged in a cloverleaf formation.

Conformation-specific monoclonal antibodies

Antibodies that recognize the specific conformation of target proteins and, thus, can serve as reporters for the protein activation state or to selectively stabilize certain conformational states; for example, antibodies that recognize activated α5β1 integrin.

Phosphoinositides

Membrane phospholipids with phosphorylated inositol headgroups, for example PIP2 (phosphatidyl inositol 4,5-bisphosphate) and PIP3 (phosphatidyl inositol 3,4,5-trisphosphate), recognized by different protein domains and important in signalling, vesicular trafficking and cellular compartmentalization.

Yeast two-hybrid screens

A genetic screening method that relies on the modular domain organization of transcription factors, designed to identify binary protein–protein interactions between a specific ‘bait’ protein and a library of ‘prey’ proteins. In yeast cells, the ‘bait’ protein fused to a transcription factor DNA-binding domain is co-expressed with the library of ‘prey’ proteins fused to a transcriptional activation domain such that when ‘bait’ and ‘prey’ proteins interact the transcription factor is reconstituted, driving expression of target genes enabling selection of interacting clones and identification of ‘prey’ by DNA sequencing.

Mass spectrometry proteomics

An analytical technique allowing the identification of proteins in complex samples on the basis of the mass to charge ratios of charged fragments.

Src

A family of multi-domain signalling and adaptor proteins containing a tyrosine kinase domain, an Src homology 2 (SH2) domain which binds phosphorylated tyrosine and an SH3 domain which binds the proline-rich peptide motif.

p130Cas

(130-kDa Crk-associated substrate (Cas)). An important scaffold protein encoded by the BCAR1 (breast cancer anti-oestrogen resistance 1) gene. p130Cas contains numerous phosphorylation sites for Src-family kinases (SFK) and serine/threonine kinases, a proline-rich region, an Src homology 3 (SH3) domain and binding sites to numerous integrin adhesion complex (IAC) components such as focal adhesion kinase (FAK), paxillin and kindlin.

Cortical microtubule stabilizing complex

(CMSC). A micrometre-sized, patch-like, multi-protein complex localized in proximity to focal adhesions (FAs) and containing LL5β, liprins and ELKS adaptor proteins. Responsible for tethering microtubules at the cell cortex and linking them to FAs via KANK.

Micelle

A particle suspension usually formed by segregation of a hydrophobic moiety in a lipid-like molecule away from the aqueous phase. The dimensions of micelle particles can be precisely determined by the molecular structure of the lipid, thus close-packing of micelle particles can be applied to achieve patterning at the nanoscale.

Supported lipid bilayers

An experimental platform using fluid biological membranes formed on glass substrates to facilitate imaging-based study of membrane-dependent processes.

Fluorescence anisotropy

A measurement of the fluorescence emission intensity differences along different polarization axes which can be used to estimate molecular orientation.

GPI-anchored proteins

Peripheral membrane proteins that are anchored to the extracellular leaflet of the plasma membrane via post-translational modification that conjugate the protein C terminus with a polysaccharide linkage to GPI membrane lipid.

Lipid rafts

Relatively ordered lateral domains (10–200 nm) in the plasma membranes that are enriched in cholesterol and sphingolipids.

Syndecan

A family of homodimeric transmembrane proteoglycans that serve as receptors to the extracellular matrix (ECM) and growth factors via their extracellular glycosaminoglycan chains, and which contain small cytoplasmic domains with interaction sites for Src and Fyn tyrosine kinases and the PDZ (Post-synaptic-density-95/disc large tumour suppressor/zonula occludens 1) protein–protein interaction domain.

Tetraspanin

A family of transmembrane proteins containing four transmembrane helices that can be organized into tetraspanin-enriched microdomains (TEMs), a sub-micrometre plasma membrane domain enriched with tetraspanins and cholesterol as well as associated membrane proteins such as integrins, and which form direct protein–protein interactions with a wide range of proteins including multiple integrins.

Immuno-electron microscopy

An electron microscopy technique for localizing proteins in ultrastructure, in which specific biomolecules are identified using antibodies conjugated with electron-dense nanoparticles.

Atomic force microscopy

An imaging and micro-manipulation technique which is based on cantilever-mounted mechanical probe tips, whereby laser-based measurement of the cantilever deflection allows high-precision measurement of physical topography or mechanical properties of the specimens.

Cryo-electron tomography

An imaging technique in which 3D ultrastructural organization of cryogenically frozen specimens is determined from computation reconstruction of a series of electron micrographs taken at various angles.

VASP

(Vasodilator stimulated phosphoprotein). VASP or Ena and their homologues Mena and EVL (Ena/Vasp-like) are tetrameric proteins known to promote barbed-end actin polymerization. In addition to actin and associated proteins, binding partners of VASP include zyxin, vinculin, Abl kinase and Src kinase.

α-Actinin

A family of actin-binding proteins containing four isoforms in mammals (α-actinin 1 to α-actinin 4) which form antiparallel dimers that crosslink actin filaments.

Cryptic vinculin binding sites

An amphipathic α-helix with high binding affinity to the vinculin head domain that is sterically sequestered by a folded protein tertiary structure, but which can be exposed upon mechanically induced protein conformational changes.

Pleckstrin homology domain

A protein domain with a binding site for phosphatidylinositol glycolipid which confers the targeting ability to various cellular membrane compartments.

Glycocalyx

A carbohydrate-rich biopolymer matrix associated with the exterior plasma membrane that plays important roles in cellular protection, cell–cell signalling, adhesion and recognition.

Arp2/3

A heteroheptameric protein complex that promotes the formation of branched actin networks through filamentous actin nucleation and branching activities.

Formin

A family of proteins that promote processive actin polymerization leading to the linear elongation of filamentous actin; examples include diaphanous formins (mDia1–mDia3).

Mechanically activated ion channels

Transmembrane protein pores whose opening for specific ion conductance directly depends upon mechanical force, and which include calcium channels such as the Piezo family, members of the transient receptor potential (TRP) superfamily such as TRPV4 and potassium channels such as TREK1, TREK2 and TRAAK. Additionally, certain ligand-gated or voltage-dependent ion channels, such as Kv1.1, Nav1.5 and Hv1, have been shown to be modulated by mechanical force.

Calpain

A calcium-dependent protease that cleaves specific sites in numerous integrin adhesion complex (IAC) components such as talin, focal adhesion kinase (FAK) and paxillin.

Proton antiporters

Integral membrane proteins that regulate intracellular pH by coupling the export of proton with the import of cations into cells. Examples include sodium–hydrogen antiporter 1 (NHE1).

Catch and slip bond

An intermolecular interface whose bond strength (typically measured as bond lifetime) varies as a function of force. With higher forces, slip bonds become weaker (that is, shorter lifetime) and catch bonds become stronger (that is, longer lifetime).

Actin retrograde flow

The motion of filamentous actin networks from the cell periphery inwards, which is observed in various adherent cells. Actin retrograde flow is generally considered to be driven by actin polymerization and influenced by plasma membrane tension and myosin II contractility.

FRET

(Förster resonance energy transfer). A process by which the energy of the excited state of a donor molecule is transferred to a nearby (typically <10 nm distance) acceptor molecule, which can be measured by observing fluorescence emission of the acceptor in response to the fluorescence excitation of the donor. Due to its sensitivity to molecular-scale changes in donor–acceptor proximity, the FRET principle is used in the design of a wide variety of biosensors (such as tension sensors, protein conformation sensors and enzymatic activity sensors).

Myotendinous junction

A contact zone between muscles and tendon consisting of highly involuted muscle cell plasma membrane and serving as the main force transmission interface.

Molecular clutch

A physical model describing mechanical force transmission between cell surface receptors through the flexible adaptor (or clutch) molecules that dynamically connect to actin or other cytoskeletal networks.

βPIX

A protein encoded by the ARHGEF7 gene, also known as p21-activated protein kinase exchange factor-β, which can interact with GIT dimers and activate Rac1 and Cdc42 through its GTP exchange factor activity.

GIT

GIT1 and GIT2 are related ARF GTPase activating proteins which form a stable complex with βPIX and play important roles in regulating small GTPase signalling.

LIM domain

A protein domain found in a family of integrin adhesion complex (IAC) proteins such as zyxin, paxillin and LIMD1 that is capable of selectively binding to actin filaments under mechanical tension, named after the LIN11, ISL1 and MEC3 proteins.

Durotaxis

Directional cell migration along a gradient of extracellular matrix (ECM) rigidity, typically towards regions of higher stiffness.

Intrinsically disordered regions

Polypeptide segments that lack ordered conformation. Intrinsically disordered regions play diverse and important roles in protein functions, including serving as flexible linkers between protein domains, forming ligand recognition sites and participating in liquid–liquid phase separation (LLPS).

Frustrated endocytosis

A modification of the classical clathrin-mediated endocytosis where a mechanical obstruction prevents endocytic structures from forming an invagination, resulting in long-lived, clathrin-coated, plasma membrane structures.

Fibrinogen

A blood clotting factor which is cleaved by thrombin to form fibrin, which forms blood clots.

Dystrophin-associated glycoprotein complex

A multi-protein complex found in various tissues that supports cell adhesion to laminin and linkage to the cytoskeleton. α-Dystroglycan binds laminin and associates with the transmembrane protein β-dystroglycan which engages the intracellular actin-binding adaptor protein dystrophin. Mutations in the complex are associated with muscular dystrophies and cardiomyopathies.

Cystic fibrosis transmembrane conductance regulator

(CFTR). A transmembrane glycoprotein functioning as a chloride channel. Mutations in the CFTR gene cause cystic fibrosis and leukocyte adhesion deficiency (LAD) type IV.

Poikiloderma

A skin condition characterized by patches or hyperpigmentation or hypopigmentation associated with atrophy.

Latency-associated peptide

(LAP). The heavily glycosylated disulfide-linked dimer of the pro-peptide of the transforming growth factor-β (TGFβ) cytokine that binds TGFβ, preventing its interaction with its receptors.

Senescence

The proliferative arrest of cells during ageing or in response to various stimuli such as genome instability or DNA damage. Contributes to developmental morphogenesis, suppresses tumour formation and limits fibrosis, but in ageing cells reduces cellular functions and regenerative capacities.

Reactive oxygen species

(ROS). By-products of oxidative respiration by mitochondria such as hydrogen peroxide that play important roles in normal cellular processes including cell signalling and migration. Excess ROS production gives rise to oxidative stress and damages cellular structure.

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Kanchanawong, P., Calderwood, D.A. Organization, dynamics and mechanoregulation of integrin-mediated cell–ECM adhesions. Nat Rev Mol Cell Biol (2022). https://doi.org/10.1038/s41580-022-00531-5

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