© BioMed Central Ltd 2007
Published: 1 June 2007
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© BioMed Central Ltd 2007
Published: 1 June 2007
The integrins are a superfamily of cell adhesion receptors that bind to extracellular matrix ligands, cell-surface ligands, and soluble ligands. They are transmembrane αβ heterodimers and at least 18 α and eight β subunits are known in humans, generating 24 heterodimers. Members of this family have been found in mammals, chicken and zebrafish, as well as lower eukaryotes, including sponges, the nematode Caenorhabditis elegans (two α and one β subunits, generating two integrins) and the fruitfly Drosophila melanogaster (five α and one β, generating five integrins). The α and β subunits have distinct domain structures, with extracellular domains from each subunit contributing to the ligand-binding site of the heterodimer. The sequence arginine-glycine-aspartic acid (RGD) was identified as a general integrin-binding motif, but individual integrins are also specific for particular protein ligands. Immunologically important integrin ligands are the intercellular adhesion molecules (ICAMs), immunoglobulin superfamily members present on inflamed endothelium and antigen-presenting cells. On ligand binding, integrins transduce signals into the cell interior; they can also receive intracellular signals that regulate their ligand-binding affinity. Here we provide a brief overview that concentrates mostly on the organization, structure and function of mammalian integrins, which have been more extensively studied than integrins in other organisms.
Human integrin subunits
Gene accession number
Protein accession number
CD49b, α2 subunit of very late antigen 2 (VLA-2)
GTA, CD41, GP2B, HPA3, CD41b, GPIIb
CD49c, α3 subunit of VLA-3
CD49d, α4 subunit of VLA-4
CD49e, fibronectin receptor alpha
CD103, human mucosal lymphocyte antigen 1α
CD11a (p180), lymphocyte function-associated antigen 1 (LFA-1) α subunit
Mac-1, CD11b, complement receptor 3 (CR3) subunit
CD51, MSK8, vitronectin receptor α (VNRα)
CD11c, CR4 subunit
Fibronectin receptor β, CD29, MDF2, MSK12
Leukocyte cell adhesion molecule, CD18, CR3 subunit, CR4 subunit
CD61; GP3A; GPIIIa, platelet glycoprotein IIIa
The cytoplasmic tails of human integrin subunits are less than 75 amino acids long (the β4 tail is an exception at a length of approximately 1,000 amino acids, which includes four fibronectin type III repeats). There is striking homology among the β-subunit cytoplasmic tails, but the α-subunit tails are highly divergent except for a conserved GFFKR motif next to the transmembrane region, which is important for association with the β tail. A large number of cytoskeletal and signaling proteins have been reported to bind to β cytoplasmic tails and some have been found to interact with specific α tails. Most integrin β tails contain one or two NPxY/F motifs (where x is any amino acid) that are part of a canonical recognition sequence for phosphotyrosine-binding (PTB) domains, which are protein modules present in a wide variety of signaling and cytoskeletal proteins. Phosphorylation of the tyrosine (Y) in the NPxY/F motif may represent a mode of regulating integrin interactions with other proteins at the cytoplasmic face of the plasma membrane. The integrin tails recruit several proteins, such as talin, that bind actin filaments, and thus form a connection to the cytoskeleton, a connection that is essential for most, if not all, integrin-mediated functions. The structural basis for talin's unique ability to activate integrins through PTBs has been defined . Structural data on integrins are mostly derived from mouse and human and the structural basis for the activation of integrins through their cytoplasmic domains in other species is not yet known.
Integrins function as traction receptors that can both transmit and detect changes in mechanical force acting on the extracellular matrix. In mammals, some integrins are limited to certain cell types or tissues: αIIbβ3 to platelets; α6β4 to keratinocytes; αEβ7 to T cells, dendritic cells and mast cells in mucosal tissues; α4β1 to leukocytes; α4β7 to a subset of memory T cells; and the β2 integrins to leukocytes. Other integrins are widely distributed, such as αVβ3, which is expressed on endothelium. The RGD sequence in fibronectin was originally identified as an integrin-binding motif  and this and related sequences in extracellular matrix molecules do act as integrin-binding motifs in vivo. However, integrins also recognize many non-RGD sequences in their ligands, such as the tripeptide LDV in the immunoglobulin superfamily member vascular cell adhesion molecule 1 (VCAM-1), which is expressed on inflamed endothelium and is bound by α4β1. This pattern of integrin recognition and activation appears to be conserved among most mammals studied.
Ligand-binding specificities of human integrins
Laminin, collagen, thrombospondin, E-cadherin, tenascin
Laminin, thrombospondin, uPAR
Thrombospondin, MAdCAM-1, VCAM-1, fibronectin, osteopontin, ADAM, ICAM-4
Fibronectin, osteopontin, fibrillin, thrombospondin, ADAM, COMP, L1
Laminin, thrombospondin, ADAM, Cyr61
Tenascin, fibronectin, osteopontin, vitronectin, LAP-TGF-β, nephronectin
Tenascin, VCAM-1, osteopontin, uPAR, plasmin, angiostatin, ADAM , VEGF-C, VEGF-D 
LAP-TGF-β, fibronectin, osteopontin, L1
ICAM, iC3b, factor X, fibrinogen, ICAM-4, heparin
ICAM, iC3b, fibrinogen, ICAM-4, heparin, collagen 
ICAM, VCAM-1, fibrinogen, fibronectin, vitronectin, Cyr61, plasminogen
Fibrinogen, thrombospondin,, fibronectin, vitronectin, vWF, Cyr61, ICAM-4, L1, CD40 ligand 
Fibrinogen, vitronectin, vWF, thrombospondin, fibrillin, tenascin, PECAM-1, fibronectin, osteopontin, BSP, MFG-E8, ADAM-15, COMP, Cyr61, ICAM-4, MMP, FGF-2 , uPA , uPAR , L1, angiostatin , plasmin , cardiotoxin , LAP-TGF-β, Del-1
Osteopontin, BSP, vitronectin, CCN3 , LAP-TGF-β
LAP-TGF-β, fibronectin, osteopontin, ADAM
MAdCAM-1, VCAM-1, fibronectin, osteopontin
Upon binding an extracellular ligand, integrins generate an intracellular signal and, conversely, their functioning can be regulated by signals from within the cell . They serve as transmembrane links between extracellular contacts (other cells or the extracellular matrix) and the actin microfilaments of the cytoskeleton, whose behavior integrins also regulate and modulate. Many different proteins on the cytoplasmic side of the membrane, such as talin, vinculin, and ERM (ezrin, radixin, moesin) actin-binding proteins, act as linker proteins to connect the cytoplasmic domains of integrins to the cytoskeleton, resulting in complex interactions . Extracellular ligation of integrins triggers a large variety of signal transduction events that modulate cell behaviors such as adhesion, proliferation, survival or apoptosis, shape, polarity, motility, haptotaxis, gene expression, and differentiation, mostly through effects on the cytoskeleton.
Phenotypes of deletions of integrin subunits in the mouse
Defects in bone healing and reduced tumor angiogenesis
Reduced branching morphogenesis and platelet adhesion
Kidney, lung, and skin defects
Placental and heart defects
Mesodermal and vascular defects
Epidermal detachment, defect in neurogenesis
Chylothorax (defect in lymphatic drainage)
Embryonic and perinatal lethal
Neutrophil adhesion and degranulation
Reduced T-cell response and T-cell phenotypic changes
Fails to gastrulate
Leukocyte adhesion deficiency
Accelerated age-related blindness
Inflammation in skin and lungs
Gut-associated lymphocyte defects
Embryonic and perinatal lethal
The cytoskeletal adaptor protein talin has been proposed to play a role in regulating integrin affinity. Binding of the talin head region to the integrin β cytoplasmic tail causes dissociation of the α and β tails and induces a conformational change in the extracellular region that increases its affinity for its ligand . Two models have been proposed for this change in affinity. In both, the inactive integrin is in a bent conformation, with the headpiece facing the membrane. In the 'deadbolt model' the bent conformation is maintained in an activated integrin, but piston-like movements of the transmembrane regions cause sliding of the extracellular stalks of the α and β subunits, which disrupts the interaction between the headpiece and the β stalk just beyond the membrane (the deadbolt) . In the 'switchblade model', dissociation of the α and β cytoplasmic and transmembrane regions leads to dislocation of an epidermal growth factor (EGF)-like repeat in the β stalk, which causes the head region to extend outwards in a switchblade-like movement . In both models, these proposed events correlate within seconds with integrin 'activation', leading to conformational changes in the ligand-binding pocket of the headpiece that increase its affinity for ligand.
The affinity directly regulates the nature of the ligand binding and appears to tune the degree and kinetics of cell adhesion. In leukocytes, for instance, αLβ2 in an intermediate-affinity state will interact with its ligand on endothelium to help decelerate the leukocytes, which roll slowly along the vessel wall but do not arrest (Figure 4a). Conversion of αLβ2 to the high-affinity state by intracellular signals from other receptors mediates their complete arrest (Figure 4b) and signals cell polarization and leukocyte movement across the post-capillary venule wall into the inflamed tissue .
It has been proposed that on binding extracellular ligands, mammalian integrins cluster in the membrane and transduce signals to the interior of the cell (outside-in signaling; Figure 4b). Extracellular ligand binding induces conformational changes, including the outward swing of the hybrid domain, separation of the α and β 'leg' domains (Figure 3b), and separation of the transmembrane domains, that lead to the interaction of the cytoplasmic tails with intracellular signaling molecules . These include enzymes (for example, the focal adhesion kinase/c-Src, and the small GTPases Ras and Rho) and adaptors (for example, Cas/Crk and paxillin) that assemble within dynamic adhesion structures, including focal adhesions that bind cells to the extracellular matrix and podosomes (small foot-like extensions of plasma membrane) [15, 19]. In this manner, the affinity of an integrin and its valence in binding ligands such as intercellular adhesion molecule-1 (ICAM-1) regulate the extent of outside-in signaling at the site of focal adhesive contacts (Figure 4). These contacts are active sites that transduce information such as the density of extracellular ligand or the magnitude and direction of extracellular forces on the cell. Integrins can also be activated from the outside by the binding of divalent cations to the metal-ion-binding sites in the I and I-like domains in the α and β subunits, respectively.
Binding of RGD-containing peptides or related compounds to a site in the headpiece of the integrin heterodimers has been shown in crystal structures of αVβ3 [4, 5] and αIIbβ3 . The binding site is composed of the β-propeller domain of the α subunit and the I-like domain of the β subunit. The original crystal structure of integrin αVβ3 revealed a bent conformation of the head region associated with low affinity for ligand [4, 5]. It was therefore proposed that the bent form does not bind ligand or carry out outside-in signaling and that activated integrins have an extended form (see the switchblade model described above). Interestingly, it has been shown that the bent form of αVβ3 can still bind to fibronectin  (see the deadbolt model described above). Several intermediate forms of integrin conformation have been postulated that confer ligand-binding affinities and a different activation and cell adhesion status from either the bent or the extended forms .
The interaction of integrins with their ligands is a major target for the development of therapeutic drugs. A humanized anti-β3 antibody (abciximab) that blocks the binding of platelet integrin αIIbβ3 to fibrinogen has been used in the clinic to prevent thrombosis . A humanized anti-α4 antibody (natalizumab) that can block the α4β1-VCAM interaction or the α4β7-mucosal addressin cell adhesion molecule (MAdCAM) interaction on mucosal endothelium has been tested in clinical trials. Natalizumab blocks leukocyte trafficking across the blood-brain barrier and thereby moderates inflammation in multiple sclerosis . Anti-α4 antibody is also effective in clinical trials in ameliorating inflammatory bowel diseases, for example, Crohn's disease. Many RGD-based low-molecular-weight integrin antagonists have been developed and some of them have been approved as therapeutics (for example, eptifibatide and tirofiban as inhibitors of αIIbβ3 to reduce platelet aggregation and the formation of blood clots) . As more becomes known about the relationship between integrin three-dimensional structure and how this regulates affinity for ligand and signaling into the cell, antagonists can be designed that stabilize a specific conformation, thereby promoting or blocking specific intercellular adhesion functions.
Integrins are transmembrane molecules that are essential for both embryonic development and immunological function by binding to a wide variety of ligands, including extra-cellular matrix molecules and members of the immunoglobulin superfamily. Their capacity to specifically recognize particular amino-acid motifs and regulate binding affinity to them lies in their heterodimeric structure. This molecular design incorporates a remarkable ability to direct conformational changes initiated at the cytoplasmic domain, and also to signal extracellular ligand binding back to the inside of the cell. Much of our current knowledge of the myriad of functions attributed to ligand binding of a particular αβ pair comes from gene knockout studies in mouse or from rare hereditary disorders in humans. Only a handful of crystal structures of integrins bound to their ligands have been solved. From these data it appears that small variations in the particular structure or charge of a ligand (that is, down to single atoms) can strongly influence the binding affinity and the capacity of the integrin to maintain a conformation that signals back into the cell. This implies that ligand binding can influence allosteric changes in the integrin, which in turn dictate how the integrin reports on the environment in which the cell finds itself. Thus, integrins serve as both sensors of their molecular surroundings and effectors that conduct motile forces exerted by the cell's cytoskeleton and from the dynamic environment (that is, shear forces within blood vessels). We are just beginning to understand the structural and chemical basis of this sensor-effector system. A particularly exciting development is the discovery of small molecules that bind tightly to the ligand-binding pocket or to other domains and allosterically stabilize integrin conformations that promote or antagonize binding. For instance, small molecules have been discovered that can allosterically tune conformations of αLβ2 that favor low, intermediate, and high-affinity binding. In this manner, it is possible to steer the adhesive response of a leukocyte in a blood vessel to promote tethering and rolling, firm arrest, or no binding at all. It may be possible to apply such small molecules as therapeutics either to promote leukocyte recruitment at sites of infection or to block their accumulation in chronic inflammatory diseases such as in rheumatoid arthritis and psoriasis. As more knowledge accumulates relating amino-acid sequence to common structural motifs associated with the allosteric control of ligand recognition and outside-in signaling to the cytoplasm, it will become possible to design small molecules that target these critical domains.
Additional data are available online with this article: Additional data file 1 contains tables of the integrin subunits present in the mouse, chicken, zebrafish, nematodes, Xenopus laevis, and D. melanogaster.