Product Code Database
Integrins are transmembrane receptors that help cell–cell and cell–extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, organization of the intracellular cytoskeleton, and movement of new receptors to the cell membrane. The presence of integrins allows rapid and flexible responses to events at the cell surface ( e.g. signal to initiate an interaction with coagulation factors).
Several types of integrins exist, and one cell generally has multiple different types on its surface. Integrins are found in all animals while integrin-like receptors are found in plant cells.
Integrins work alongside other proteins such as , the immunoglobulin superfamily cell adhesion molecules, and , to mediate cell–cell and cell–matrix interaction. Ligands for integrins include fibronectin, vitronectin, collagen and laminin.
| + alpha | ||
| CD49a | VLA1 | |
| CD49b | VLA2 | |
| CD49c | VLA3 | |
| CD49d | VLA4 | |
| CD49e | VLA5 | |
| CD49f | VLA6 | |
| ITGA7 | FLJ25220 | |
| ITGA8 | ||
| ITGA9 | RLC | |
| ITGA10 | PRO827 | |
| ITGA11 | HsT18964 | |
| ITGAD | FLJ39841 | |
| ITGAE | HUMINAE | |
| CD11a | LFA1A | |
| CD11b | MAC-1 | |
| ITGAV | VNRA, MSK8 | |
| CD41 | GPIIb | |
| CD11c |
| + beta | ||
| CD29 | FNRB, MSK12, MDF2 | |
| CD18 | LFA-1, MAC-1, MFI7 | |
| CD61 | GP3A, GPIIIa | |
| CD104 | ||
| ITGB5 | FLJ26658 | |
| ITGB6 | ||
| ITGB7 | ||
| ITGB8 |
Variants of some subunits are formed by differential RNA splicing; for example, four variants of the beta-1 subunit exist. Through different combinations of the α and β subunits, 24 unique mammalian integrins are generated, excluding splice- and glycosylation variants.
Integrin subunits span the cell membrane and have short cytoplasmic domains of 40–70 amino acids. The exception is the beta-4 subunit, which has a cytoplasmic domain of 1,088 amino acids, one of the largest of any membrane protein. Outside the cell membrane, the α and β chains lie close together along a length of about 23 nanometre; the final 5 nm N-terminus of each chain forms a ligand-binding region for the ECM. They have been compared to lobster claws, although they don't actually "pinch" their ligand, they chemically interact with it at the insides of the "tips" of their "pinchers".
The molecular mass of the integrin subunits can vary from to . Beta subunits have four cysteine-rich repeated sequences. Both α and β subunits bind several divalent . The role of divalent cations in the α subunit is unknown, but may stabilize the folds of the protein. The Ion in the β subunits are more interesting: they are directly involved in coordinating at least some of the ligands that integrins bind.
Integrins can be categorized in multiple ways. For example, some α chains have an additional structural element (or "domain") inserted toward the N-terminal, the alpha-A domain (so called because it has a similar structure to the A-domains found in the protein von Willebrand factor; it is also termed the α-I domain). Integrins carrying this domain either bind to (e.g. integrins α1 β1, and α2 β1), or act as cell-cell adhesion molecules (integrins of the β2 family). This α-I domain is the binding site for ligands of such integrins. Those integrins that don't carry this inserted domain also have an A-domain in their ligand binding site, but this A-domain is found on the β subunit.
In both cases, the A-domains carry up to three divalent cation binding sites. One is permanently occupied in physiological of divalent cations, and carries either a calcium or magnesium ion, the principal divalent cations in blood at median concentrations of 1.4 mM (calcium) and 0.8 mM (magnesium). The other two sites become occupied by cations when ligands bind—at least for those ligands involving an acidic amino acid in their interaction sites. An acidic amino acid features in the integrin-interaction site of many ECM proteins, for example as part of the amino acid sequence Arginine-Glycine-Aspartic acid ("RGD" in the one-letter amino acid code).
The X-ray crystal structure obtained for the complete extracellular region of one integrin, αvβ3, shows the molecule to be folded into an inverted V-shape that potentially brings the ligand-binding sites close to the cell membrane. Perhaps more importantly, the crystal structure was also obtained for the same integrin bound to a small ligand containing the RGD-sequence, the drug cilengitide. As detailed above, this finally revealed why divalent cations (in the A-domains) are critical for RGD-ligand binding to integrins. The interaction of such sequences with integrins is believed to be a primary switch by which ECM exerts its effects on cell behaviour.
The structure poses many questions, especially regarding ligand binding and signal transduction. The ligand binding site is directed towards the C-terminal of the integrin, the region where the molecule emerges from the cell membrane. If it emerges orthogonality from the membrane, the ligand binding site would apparently be obstructed, especially as integrin ligands are typically massive and well cross-linked components of the ECM. In fact, little is known about the angle that membrane proteins subtend to the plane of the membrane; this is a problem difficult to address with available technologies. The default assumption is that they emerge rather like little lollipops, but there is little evidence for this. The integrin structure has drawn attention to this problem, which may have general implications for how membrane proteins work. It appears that the integrin transmembrane helices are tilted (see "Activation" below), which hints that the extracellular chains may also not be orthogonal with respect to the membrane surface.
Although the crystal structure changed surprisingly little after binding to cilengitide, the current hypothesis is that integrin function involves changes in shape to move the ligand-binding site into a more accessible position, away from the cell surface, and this shape change also triggers intracellular signaling. There is a wide body of cell-biological and biochemical literature that supports this view. Perhaps the most convincing evidence involves the use of antibody that only recognize integrins when they have bound to their ligands, or are activated. As the "footprint" that an antibody makes on its binding target is roughly a circle about 3 nm in diameter, the resolution of this technique is low. Nevertheless, these so-called LIBS (Ligand-Induced-Binding-Sites) antibodies unequivocally show that dramatic changes in integrin shape routinely occur. However, how the changes detected with antibodies look on the structure is still unknown.
A prominent function of the integrins is seen in the molecule GpIIb/IIIa, an integrin on the surface of blood (thrombocytes) responsible for attachment to fibrin within a developing blood clot. This molecule dramatically increases its binding affinity for fibrin/fibrinogen through association of platelets with exposed collagens in the wound site. Upon association of platelets with collagen, GPIIb/IIIa changes shape, allowing it to bind to fibrin and other blood components to form the clot matrix and stop blood loss.
Cell attachment to the ECM is a basic requirement to build a multicellular organism. Integrins are not simply hooks, but give the cell critical signals about the nature of its surroundings. Together with signals arising from receptors for soluble growth factors like VEGF, EGF, and many others, they enforce a cellular decision on what biological action to take, be it attachment, movement, death, or differentiation. Thus integrins lie at the heart of many cellular biological processes. The attachment of the cell takes place through formation of cell adhesion complexes, which consist of integrins and many cytoplasmic proteins, such as talin, vinculin, paxillin, and alpha-actinin. These act by regulating such as FAK (focal adhesion kinase) and Src kinase family members to phosphorylate substrates such as p130CAS thereby recruiting signaling adaptors such as CRK. These adhesion complexes attach to the actin cytoskeleton. The integrins thus serve to link two networks across the plasma membrane: the extracellular ECM and the intracellular actin filamentous system. Integrin α6β4 is an exception: it links to the keratin intermediate filament system in epithelial cells.
Focal adhesions are large molecular complexes, which are generated following interaction of integrins with ECM, then their clustering. The clusters likely provide sufficient intracellular binding sites to permit the formation of stable signaling complexes on the cytoplasmic side of the cell membrane. So the focal adhesions contain integrin ligand, integrin molecule, and associate plaque proteins. Binding is propelled by changes in free energy. As previously stated, these complexes connect the extracellular matrix to actin bundles. Cryo-electron tomography reveals that the adhesion contains particles on the cell membrane with diameter of 25 +/- 5 nm and spaced at approximately 45 nm. Treatment with Rho-kinase inhibitor Y-27632 reduces the size of the particle, and it is extremely mechanosensitive.
One important function of integrins on cells in tissue culture is their role in cell migration. Cells adhere to a substrate through their integrins. During movement, the cell makes new attachments to the substrate at its front and concurrently releases those at its rear. When released from the substrate, integrin molecules are taken back into the cell by endocytosis; they are transported through the cell to its front by the endocytic cycle, where they are added back to the surface. In this way they are cycled for reuse, enabling the cell to make fresh attachments at its leading front. The cycle of integrin endocytosis and recycling back to the cell surface is important for migrating cells and also during animal development.
The repertoire of integrins expressed on a particular cell can specify the signaling pathway due to the differential binding affinity of ECM ligands for the integrins. The tissue stiffness and matrix composition can initiate specific signaling pathways regulating cell behavior. Clustering and activation of the integrins/actin complexes strengthen the focal adhesion interaction and initiate the framework for cell signaling through assembly of adhesomes.
Depending on the integrin's regulatory impact on specific receptor tyrosine kinases, the cell can experience:
Knowledge of the relationship between integrins and receptor tyrosine kinase has laid a foundation for new approaches to cancer therapy. Specifically, targeting integrins associated with RTKs is an emerging approach for inhibiting angiogenesis.
| [[Collagen]]s, [[laminin]]s | |||
| Collagens, laminins | |||
| Laminin-5 | |||
| [[Fibronectin]], VCAM-1 | |||
| MAD-CAM1 | |||
| fibronectin and [[proteinase]]s | |||
| laminins | |||
| laminins | |||
| ICAM-1, ICAM-2 | |||
| Blood plasma]] proteins, ICAM-1 | |||
| fibrinogen, fibronectin | |||
| [[vitronectin]], [[osteopontin]], fibrinogen | |||
| [[vitronectin]], fibronectin, fibrinogen, [[osteopontin]], Cyr61, [[thyroxine]], [[TETRAC]] | |||
| [[vitronectin]], osteopontin, and adenovirus | |||
| [[fibronectin]]; TGFβ1+3 | |||
| [[fibronectin]]; TGFβ1+3 | |||
| α6β4 | Epithelial cells | Laminin |
Beta-1 integrins interact with many alpha integrin chains. Gene knockouts of integrins in mice are not always lethal, which suggests that during embryonal development, one integrin may substitute its function for another in order to allow survival. Some integrins are on the cell surface in an inactive state, and can be rapidly primed, or put into a state capable of binding their ligands, by cytokines. Integrins can assume several different well-defined shapes or "conformational states". Once primed, the conformational state changes to stimulate ligand binding, which then activates the receptors — also by inducing a shape change — to trigger outside-in signal transduction.
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