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  • Review Article
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The final steps of integrin activation: the end game

Key Points

  • Cell-directed changes in the ligand-binding affinity ('activation') of integrins regulate cell adhesion and migration, extracellular matrix assembly and mechanotransduction.

  • The final intracellular steps in integrin activation involve the binding of talins and/or kindlins to the β-integrin cytoplasmic domains. Interference with these binding events, or lack of these proteins, is associated with genetic defects in integrin activation, and can serve as potential therapeutic targets for various diseases.

  • The activation signal crosses the cell membrane by altering the interaction of the α- and β-integrin transmembrane domains. A recent structure of the αIIbβ3 integrin transmembrane domain reveals that the αβ-integrin association is stabilized by two distinct clasps. Disruption of one of these (the inner membrane clasp) by mutations, or by binding of talin to the β-integrin cytoplasmic domain, can lead to integrin activation.

  • RAP1 GTPase is an important signalling intermediate in integrin activation. Recent work shows that active RAP1 binds to RAP1–GTP-interacting adaptor molecule (RIAM), thereby inducing the formation of a RAP1–RIAM–talin complex that results in talin recruitment to the integrin and subsequent integrin activation.

Abstract

Cell-directed changes in the ligand-binding affinity ('activation') of integrins regulate cell adhesion and migration, extracellular matrix assembly and mechanotransduction, thereby contributing to embryonic development and diseases such as atherothrombosis and cancer. Integrin activation comprises triggering events, intermediate signalling events and, finally, the interaction of integrins with cytoplasmic regulators, which changes an integrin's affinity for its ligands. The first two events involve diverse interacting signalling pathways, whereas the final steps are immediately proximal to integrins, thus enabling integrin-focused therapeutic strategies. Recent progress provides insight into the structure of integrin transmembrane domains, and reveals how the final steps of integrin activation are mediated by integrin-binding proteins such as talins and kindlins.

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Figure 1: The structure of the αIIbβ3 integrin transmembrane complex enables inside–out signal transduction.
Figure 2: An affinity-capture method to study transmembrane domain interactions.
Figure 3: Activators, such as talins and kindlins, bind to integrins to cause their activation.
Figure 4: A road map from thrombin receptors to αIIbβ3 integrin activation.

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Acknowledgements

Researches quoted from our laboratories were supported by the National Institutes of Health. C.K. is the recipient of a postdoctoral fellowship from the American Institute for Cancer Research. We thank our colleagues for their understanding in cases where space limitations have forced us to cite or discuss their work less thoroughly than we would have liked to.

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DATABASES

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Kindler syndrome

LAD1

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Glossary

Valency

A term that refers to the number of chemical bonds between two atoms. Here it refers to the number of integrin-binding sites presented by a given adhesive ligand.

Microcluster

A loosely defined term that refers to a non-covalent oligomer of integrins on the cell surface that appears as a point source (that is, with a diameter < 100nm) in fluorescence microscopy.

Detergent micelle

A globular aggregate of amphipathic detergent in aqueous solution, with detergent hydrophilic ends facing outside and hydrophobic ends facing inside.

Förster resonance energy transfer

(FRET). A phenomenon in which one fluorophore (the donor) in its electronic excited state can transfer its energy to another fluorophore (the acceptor) in close proximity, so that excitation of the donor causes the acceptor to emit fluorescence. As the FRET only occurs when the distance between donor and acceptor is less than 10 nm, it is useful for monitoring interactions between two fluorophore-fused molecules.

Focal complex

A relatively small dot-like adhesion ( 1 m in width) mainly found in lamellipodia. It is a transient adhesion site during cell migration and can mature into a more stable focal adhesion.

Focal adhesion

A large (2–5 μ m in width), elongated, oval-shaped protein complex found on the cell periphery, which connects the actin cytoskeleton (F-actin bundle) to the ECM and provides strong integrin-dependent adhesion.

Immunological synapse

A cell–cell junction between a T lymphocyte and an antigen presenting cell during T lymphocyte activation.

Podosome

A type of ECM contact that is different from focal complexes and focal adhesions. Podosomes have a core actin filament surrounded by a ring structure of integrin adhesive complexes. They are shorter than other ECM contacts in depth ( 0.2–0.4 μ m) and are typically found in monocytic lineages.

Invadopodium

A type of ECM contact that is different from focal complexes and focal adhesions but similar to podosomes. Invadopodia can extend up to 8 μ m, associate with ECM-degrading enzymes and are seen in transformed fibroblasts or malignant cells.

Bioluminescence resonance energy transfer

A FRET-like phenomenon in which bioluminescence generated by luciferase (the donor) can excite a nearby fluorophore (the acceptor).

Image correlation spectroscopy

A method used to analyse molecular densities and rates of aggregation and diffusion of fluorescent molecules by autocorrelating the temporal (or spatial) fluctuation of intensities in confocal images.

Interferometric photoactivated localization microscopy

A recently developed fluorescent microscopy that provides 20 nm resolution in three dimensions, thus allowing single-molecule imaging.

Phospholipid bicelle

A planar disc-shaped particle made of a phospholipid mixture. The centre of the bicelle consists of two layers of phospholipids and the edge of the bicelle is covered by phospholipids with shorter lipid chains.

Microsomal membrane

A membrane vesicle that is generated by fragmentation of the endoplasmic reticulum.

Coiled coil

A protein structure generated by dimerization or multimerization of α-helices. These α-helices typically consist of repeats of two hydrophilic residues, followed by a hydrophobic residue that is buried into the binding interface in aqueous solution.

Pathological thrombosis

The formation of an occlusive mass of fibrin, platelets and leukocytes in a blood vessel, which results in diseases such as myocardial infarction and stroke.

PTB domain

(Phosphotyrosine binding domain). A protein domain that recognizes an Asn-Pro-X-Tyr motif that is found in most β-integrin tails.

FERM domain

(4.1 protein, ezrin, radixin and moesin homology domain). A common domain found in a number of proteins that mediate linkage of the cytoskeleton to the plasma membrane. The FERM domain often interacts with the cytoplasmic tail of transmembrane proteins.

Pleckstrin homology domain

A lipid-binding protein domain originally identified in Pleckstrin.

Mesenteric arteriolar thrombosis

Thrombosis that occurs in an arterial vessel of mesentery. Mesentery is the anatomical term indicating the layers of membrane that suspend the small intestine from the back wall of the abdomen.

Glanzmann thrombasthenia

A genetic bleeding disorder caused by a lack of αIIbβ3 integrin or by mutations that inhibit αIIbβ3 integrin function.

Amphipathic helix

An α-helix that contains hydrophilic amino acids on one side and hydrophobic amino acids on the other.

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Shattil, S., Kim, C. & Ginsberg, M. The final steps of integrin activation: the end game. Nat Rev Mol Cell Biol 11, 288–300 (2010). https://doi.org/10.1038/nrm2871

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