Mechanisms of integrin activation and trafficking

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Integrin adhesion receptors are essential for the normal function of most multicellular organisms, and defective integrin activation or integrin signaling is associated with an array of pathological conditions. Integrins are regulated by conformational changes, clustering, and trafficking, and regulatory mechanisms differ strongly between individual integrins and between cell types. Whereas integrins in circulating blood cells are activated by an inside-out-induced conformational change that favors high-affinity ligand binding, β1-integrins in adherent cells can be activated by force or clustering. In addition, endocytosis and recycling play an important role in the regulation of integrin turnover and integrin redistribution in adherent cells, especially during dynamic processes such as cell migration and invasion. Integrin trafficking is strongly regulated by their cytoplasmic tails, and the mechanisms are now being identified.

Highlights

Integrin activation mechanisms differ between individual integrins. ► Integrin activation mechanisms differ for non-adherent and adherent cells. ► Integrins in adherent cells are strongly regulated by trafficking mechanisms. ► It is unclear how the NxxY motifs in the β-cytoplasmic tails regulate integrin trafficking. ► The α-subunits are important regulators of integrin trafficking.

Introduction

Integrins are heterodimeric αβ transmembrane receptors that connect the extracellular matrix (ECM) to the cytoskeleton. In mammals, 18 α-subunits and eight β-subunits assemble into 24 different integrins, which bind collagens, laminins, or RGD-containing proteins. In addition, several integrins bind soluble ligands or cellular receptors (Figure 1). Many integrins are known to adopt low-affinity, intermediate-affinity, and high-affinity conformations, and these exist in a dynamic equilibrium with one another. An increase in the proportion of heterodimers adopting high-affinity conformations is termed integrin activation, and can be induced either by cytoplasmic events (‘inside-out’ activation; Figure 2A), or by extracellular factors (‘outside-in’ activation). Ligand-binding triggers integrin clustering (avidity), integrin connection to the cytoskeleton, and the formation of macromolecular adhesion complexes (Figure 2A). Moreover, integrin–ligand interactions induce a plethora of ‘outside-in’ events such as cell spreading and migration, ECM assembly, and the activation of several signal transduction pathways that regulate proliferation, survival, and gene expression [1]. Most integrins engage the actin cytoskeleton, and a range of integrin-containing actin-associated adhesive structures has been described, including focal complexes, focal adhesions (FAs), fibrillar adhesions (FBs), podosomes, and invadopodia [2] (Figure 2B). By contrast, integrin α6β4 connects to the intermediate filament system, and localizes to hemidesmosomes [3]. The relatively short α-cytoplasmic and β-cytoplasmic tails (13–70 amino acids, except for β4) contain docking sites for a variety of proteins that control integrin activation, recruitment to adhesion sites, and trafficking. Here, we discuss recent advances in our understanding of how these processes are regulated by integrin cytoplasmic tails, with emphasis on differences between adherent and non-adherent cells, and between individual integrins.

Section snippets

Integrin activation mechanisms

Integrin activation in non-adherent cells such as leukocytes and platelets is rapid, reversible, and tightly controlled, and this process is best-exemplified by the rapid enhancement of ligand-binding capacity of integrin αIIbβ3 following platelet activation with agonists such as thrombin. In resting platelets, the bent, low-affinity conformation of αIIbβ3 is stabilized by a ‘clasp’ formed between the GFFKR sequence in αIIb and the HDRxE motif in β3, most importantly a salt bridge between R995

Integrin cytoplasmic motifs and the regulation of integrin trafficking

Over the past years, it has been firmly established that integrin trafficking in adherent cells is important for integrin-dependent cell adhesion, spreading and migration, as well as cancer cell invasion. Integrin trafficking regulates FA disassembly, matrix turnover, and localized integrin redistribution to new adhesion sites, for example at the leading edge in migrating cells [31]. Trafficking mechanisms include the delivery of newly synthesized integrins via the biosynthetic-secretory

Conclusions

Our knowledge of the diverse mechanisms of integrin regulation has steadily increased over the years, and it is now clear that mechanisms of integrin activation and trafficking differ between different integrins and between cell types. Future work requires more focus on how integrin trafficking is regulated by the α-subunits and associated proteins, and by the two NPxY motifs in the β-subunits. Furthermore, the interplay between trafficking and activation merits further exploration, which will

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We apologise to all authors whose work has been omitted owing to space restrictions, and for not always citing primary literature. This study was funded by Cancer Research, UK (J.C.N.) and a grant from the Dutch Cancer Society (A.S.).

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