Mechanisms of integrin activation and trafficking
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.).
References (51)
- et al.
Regulation of hemidesmosome disassembly by growth factor receptors
Curr Opin Cell Biol
(2008) - et al.
Integrin cytoplasmic tyrosine motif is required for outside-in alphaIIbbeta3 signalling and platelet function
Nature
(1999) - et al.
Kindlin-1 and -2 directly bind the C-terminal region of beta integrin cytoplasmic tails and exert integrin-specific activation effects
J Biol Chem
(2009) - et al.
Loss of Kindlin-1 causes skin atrophy and lethal neonatal intestinal epithelial dysfunction
PLoS Genet
(2008) - et al.
Integrins: masters and slaves of endocytic transport
Nat Rev Mol Cell Biol
(2009) - et al.
Talin controls the exit of the integrin alpha5beta1 from an early compartment of the secretory pathway
J Cell Sci
(2000) - et al.
Caveolin-1-dependent beta1 integrin endocytosis is a critical regulator of fibronectin turnover
J Cell Sci
(2008) - et al.
Clathrin mediates integrin endocytosis for focal adhesion disassembly in migrating cells
J Cell Biol
(2009) - et al.
Small GTPase Rab21 regulates cell adhesion and controls endosomal traffic of beta1-integrins
J Cell Biol
(2006) - et al.
Integrin structure, activation, and interactions
Cold Spring Harb Perspect Biol
(2011)
Molecular architecture and function of matrix adhesions
Cold Spring Harb Perspect Biol
Regulation of integrin activation
Annu Rev Cell Dev Biol
The structure of an integrin/talin complex reveals the basis of inside-out signal transduction
EMBO J
The tail of integrins, talin, and kindlins
Science
Loss of talin1 in platelets abrogates integrin activation, platelet aggregation, and thrombus formation in vitro and in vivo
J Exp Med
Talin is required for integrin-mediated platelet function in hemostasis and thrombosis
J Exp Med
Kindlin-3 is essential for integrin activation and platelet aggregation
Nat Med
Kindlin-3 is required for beta2 integrin-mediated leukocyte adhesion to endothelial cells
Nat Med
The insider's guide to leukocyte integrin signalling and function
Nat Rev Immunol
Beta integrin tyrosine phosphorylation is a conserved mechanism for regulating talin-induced integrin activation
J Biol Chem
In vivo beta1 integrin function requires phosphorylation-independent regulation by cytoplasmic tyrosines
Genes Dev
Genetic analysis of beta1 integrin “activation motifs” in mice
J Cell Biol
Focal adhesions are sites of integrin extension
J Cell Biol
Mechanically activated integrin switch controls alpha5beta1 function
Science
Demonstration of catch bonds between an integrin and its ligand
J Cell Biol
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