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Integrins: An Overview of Structural and Functional Aspects


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Integrins are heterodimeric transmembrane receptors that mediate cell-adhesion.1 With their extracellular head region, most integrins bind extracellular matrix (ECM) glycoproteins such as laminins and collagens in basement membranes or connective tissue components like fibronectin. Others bind counterreceptors on neighboring cells, bacterial polysaccharides, or viral coat proteins. Through all these interactions integrins mediate stable adhesion to basement membranes, the formation of extracellular matrices and migration on such matrices, the formation of platelet aggregates, the establishment of intercellular junctions in the immune system, and bacterial and viral entry during infectious diseases. Furthermore, integrin-mediated adhesion modulates signaling cascades in control of cell motility, survival, proliferation, and differentiation. Here, a brief overview of basic structure/function aspects of integrins is given with the aim of providing background information for the following chapters in this book.

The History of Integrins

Intercellular cohesion is critical for the structural organization and intercellular communication within multicellular organisms. The origin of cell adhesion precedes multicellularity: genes encoding cadherin and C-type lectin domains were discovered in the genome of choanoflagellates, a group of metazoa-related protozoa.2 The integrin family emerged in metazoa, which appeared during evolution over 600 million years ago. In the most ancient living animals - the sponges, no cadherins have been detected and sponge cell aggregation is mediated by an extracellular proteoglycan matrix. The receptor that binds to this matrix also contains the typical integrin-binding motif, RGD (see below). Indeed, α and β integrin subunits have been cloned from sponges and RGD peptides block sponge cell aggregation.3 Some early metazoan must have evolved a laminin-binding integrin and an RGD-binding integrin, both of which have been preserved throughout metazoan evolution.1 In the nematode Caenorhabditis elegans, one β subunit (termed βpat3) and two a subunits (termed αina1 and αpat2) form two integrins (Table 1). In the fruit fly Drosophila melanogaster, five integrins are formed through combination of one β subunit (termed βPS) with five α subunits (termed αPS1 through 5). With vertebrate evolution, the integrin family has expanded considerably. Many different laminin and RGD-binding integrins evolved and a new group of integrins appeared that have an extra inserted I-domain (see below) in the extracellular region and that contain the receptors for fibrillar collagens and the leukocyte-specific β2 integrins. Ultimately, sequencing of the human genome has identified as many as 18 α and 8 β subunits, from which 24 different functional integrins are currently known to be formed in humans.4,5

Table 1. Integrins and their ligands.

Table 1

Integrins and their ligands.

Structural Aspects of Integrins

Integrins are formed through noncovalent association of two type I transmembrane glycoproteins, the α- and the β subunit. The extracellular parts are approximately 700 amino acids for α - and 1000 amino acids for β subunits and form elongated stalks and a globular ligand-binding head region6 (Fig. 1). The part of the a subunit that forms the globular head region and participates in ligand binding consists of seven repeats of about 60 amino acids that fold into a seven-bladed β propeller structure similar to the trimeric G protein β subunit.7 About half of the integrin a subunits has an insertion termed the I-domain within the β-propeller, which directly participates in ligand binding and appears closely related to the trimeric G protein α subunit and small G proteins.8 All integrin β subunits contain an “I-like domain” in the globular head region that also participates in ligand binding, perhaps most importantly in integrins lacking α I-domains. I domains contain a “metal ion-dependent adhesion site” (MIDAS) and I-like domains contain a structurally similar metal-binding motif. In analogy to small G proteins, where GTP hydrolysis leads to altered coordination of a Mg2+ ion causing conformational changes and loss of effector protein interaction, integrin ligand binding alters the coordination of the metal ion and shifts the I-domains from a closed to an open conformation. This process is thought to increase the affinity for ligand and to cause adhesion strengthening. 8

Figure 1. Structural aspects of integrins.

Figure 1

Structural aspects of integrins. A) Schematic drawing of integrin α and β subunits indicating basic structural units discussed in the text. B) Cartoon of inactive (i), activated (ii), and clustered integrins (iii). The exact nature of (more...)

The integrin cytoplasmic tails are less than 75 amino acids in length (the β4 tail forms an exception with its length of approximately 1000 amino acids containing 4 fibronectin type III repeats). There is a striking homology between the β cytoplasmic tails but the α cytoplasmic tails are highly divergent, except for a conserved GFFKR motif next to the transmembrane region that is important for association with the β tail.9 A large number of cytoskeletal and signaling proteins has been reported to bind to β cytoplasmic tails and some have been found to interact with specific α tails. Most β tails contain an NPxY motif, which can potentially bind a wide variety of cytoskeletal and signaling proteins that contain a PTB-domain.10 Furthermore, tyrosine phosphorylation in the NPxY motif may represent a mode of regulation of integrin interactions at the cytoplasmic face. By recruiting several proteins that bind actin filaments, the cytoplasmic tails mediate the integrin-cytoskeletal connection, which is essential for most, if not all, integrin mediated functions (see below for further details).

Finally, alternative mRNA splicing in the extracellular as well as in the intracellular regions gives rise to variant forms of several α and β subunits.11 There is evidence that these variants can differ in ligand specificity or in their effect on signal transduction pathways. The selection for certain splice variants in specific cell types at specific stages of differentiation points to important functional differences. For instance, the switch to α7A and β1D variants that accompanies terminal differentiation of skeletal muscle cells probably reflects the need for a stronger interaction with laminin and a stronger connection to the cytoskeleton to be able to support muscle contraction.12

Extracellular Ligands and Lateral Associations

Most integrins bind to components of the ECM such as laminins, collagens, and fibronectin (Table 1). Many of the ECM proteins share a common integrin-binding motif, Arg-Gly-Asp (RGD), which is present in fibronectin, vitronectin, fibrinogen, and many others. Integrin-binding to laminins and collagens occurs at other recognition motifs, though cryptic RGD sites may become accessible after proteolytic cleavage of those proteins. Some integrins bind to counter receptors present on other cells, such as members of the ADAM (a disintegrin and metalloprotease) family or immunoglobulin-type receptors such as ICAM (intercellular adhesion molecule) and VCAM (vascular cell adhesion molecule) that are expressed on leukocytes and endothelial cells. Finally, bacterial polysaccharides and an increasing number of viruses are known to bind to integrins.

Various physical and functional interactions of integrins with other transmembrane receptors have been described. Some 11 integrins, in particular the laminin-binding integrins, associate with members of the tetraspanin family. It appears that such interactions do not modulate integrin-mediated adhesion but rather, that they affect the ability of cells to spread, migrate, and undergo morphological changes.13 In addition, integrins can functionally interact with cell surface proteoglycans termed syndecans and they can transactivate receptor tyrosine kinases (see below for details).

Regulation of Integrin-Mediated Adhesion

For many biological processes, most notably hemostasis and immunity, it is important that integrin-mediated adhesion can be regulated. The number of integrin-ligand bonds can be regulated through changes in cellular shape, lateral diffusion of integrins in the membrane, and integrin clustering; aspects that can be controlled through cytoskeletal organization. Additionally, the intrinsic affinity of individual integrins for their ligands can be regulated from within the cell, a process referred to as “inside-out signaling”.5 Early studies on platelets had shown that thrombin binding to its receptor leads to a very rapid increase in fibrinogen binding by aIIbβ3. Since then, it has become clear that the α and β cytoplasmic tails are required to maintain integrins in the inactive state, that they associate with each other, and that this association is disrupted upon treatment with agonists known to cause integrin activation.14

One key player in regulation of integrin affinity appears to be the cytoskeletal adaptor talin. Binding of the talin head region to the integrin β cytoplasmic tail causes dissociation of the cytoplasmic tails and induces a conformational change in the extracellular region that increases integrin affinity.15-17 How dissociation of the cytoplasmic tails leads to conformational changes all the way to the ligand-binding head domain is a subject of intense study. Based on electron microscopy, mutational analysis, structural analysis, and functional studies two models have been proposed. In the “switchblade model” inactive integrins are in a “bent” conformation with the head region facing the membrane. Dissociation of the cytoplasmic and transmembrane regions (e.g., upon talin binding) leads to dislocation of an EGF-like repeat in the β stalk, which causes the head region to extend upward in a switchblade-like motion.7,18 In the “deadbolt model” the bent conformation is maintained in activated integrins but piston-like movements of the transmembrane regions (e.g., in response to talin binding) cause sliding of the stalks, which disrupts an interaction between the head region and the β stalk just above the membrane (the “deadbolt”).19,20 In both models, the described events during integrin activation ultimately cause conformational changes in the ligand-binding pocket of the head region that increase affinity for ligand.

The relative importance of conformational changes versus clustering in priming cells for adhesion versus post-ligand binding adhesion strengthening remains controversial.21,22 In this respect, mutations in the β3 transmembrane region that cause constitutive αIIbβ3 activation have been reported to enhance the tendency of the β3 subunit to form homo-oligomers in one study but not in another, leaving open the question if clustering may in fact be a critical component of integrin activation.23,24

Integrin-Containing Adhesions

Integrin-engagement triggers the formation of membrane extensions that are required for cell spreading on ECM surfaces, for migration of cells into sheets of other cells, or for engulfment of particles or pathogens by phagocytic cells. Activation of Rho GTPases, the enzymes controlling the actin cytoskeleton, is involved in this process.25 Ultimately, ligands, integrins, cytoskeletal proteins, and signaling molecules assemble in high local concentrations as aggregates on each side of the plasma membrane, forming “cell-matrix adhesions” in the case of integrins binding to ECM proteins26 or forming complex intercellular junctions such as the “immunological synapse” in the case of leukocyte β2 integrins binding to counter receptors on other cells.27 In contrast to the initial ligand-driven adhesion complexes, the formation of these more elaborate structures requires integrin-cytoskeletal linkage and is driven by cytoskeletal remodeling. Indeed, Rho family GTPases control the formation of these integrin-containing adhesions.28

The vast majority of integrins connect with filamentous (F)-actin in cell-matrix adhesions via cytoskeletal adaptor proteins such as talin, vinculin, paxillin, and others26,29 (see below for details). In 2-dimensional culture systems these come in various flavors: cells can form “focal complexes” (small adhesions found in membrane protrusions of spreading and migrating cells), “focal adhesions” (larger adhesions connected by F-actin stress fibers that are derived from focal complexes in response to tension), and “fibrillar adhesions” (elongated adhesions associated with fibronectin matrix assembly)30 (Fig. 2). In 3-dimensional cultures and in vivo, components of these structures coorganize in a mixed type of cell-matrix adhesions.31 In osteoclasts, macrophages, some epithelial cells, and Rous sarcoma-transformed cells exceptional cell-matrix adhesions are found, termed “podosomes”. These adhesions have been described mainly in vitro and consist of highly dynamic, dot-shaped F-actin-rich contacts whose function is not completely understood.32 Finally, a unique type of cell-matrix adhesions, termed “hemidesmosomes”, is formed by basal keratinocytes in the skin. Here, the unusually long cytoplasmic tail of the β4 subunit connects α6β4 not to the actin cytoskeleton but, instead, to the keratin cytoskeletal system. This association is not mediated by the proteins found in other cell-matrix adhesions (e.g., talin) but by a specialized protein complex including plectin, BP180, and BP230.33

Figure 2. Cell-matrix adhesions.

Figure 2

Cell-matrix adhesions. Immunofluorescence images showing four different types of cell-matrix adhesions. Arrows indicate clustering of paxillin in focal adhesions (upper left); tensin in fibrillar adhesions (upper right); activated Src in podosomes (lower (more...)

The Integrin-Cytoskeleton Connection

Integrin function largely depends on the connection of integrins to the cytoskeleton.34 The integrin cytoplasmic tails connect to the F-actin filaments through an exquisitely regulated multiprotein complex (Fig. 3). Some important players in this complex are discussed here:

Figure 3. Integrin-F-actin connections.

Figure 3

Integrin-F-actin connections. Schematic drawing of the various connections from integrin cytoplasmic tails to the actin cytoskeleton. Proteins involved in F-actin binding are underlined; those playing a regulatory role are indicated in small fonts.


Talin is an antiparallel homodimeric actin cross-linking protein that can bind to integrin tails with the FERM domain in its globular head region and with a second, low affinity binding site in the tail.35 The FERM domain also contains binding sites for F-actin and focal adhesion kinase (FAK). The talin tail region contains a conserved actin-binding site and multiple binding sites for vinculin. Through these interactions talin plays an important role in the assembly of cell-matrix adhesions. Talin knockout mice are embryonic lethal and undifferentiated talin null ES cells fail to assemble cell-matrix adhesions.36,37 Cell-matrix-adhesion formation is restored following ES cell differentiation, which may be explained by the existence of a talin-2 gene or by the usage of alternative integrin/actin binding proteins such as α-actinin or filamin. Biophysical studies have established that talin forms the initial link between microclusters of αvβ3 and the actin cytoskeleton.38 The talin head FERM domain binds and activates PIPKIγ and thereby increases the local production of PIP2.39,40 PIP2 in turn may activate several proteins present in adhesions, including talin resulting in reinforcement of the cytoskeletal linkage. Talin can be cleaved by the calcium-dependent protease calpain, which is important for the turn-over of cell-matrix adhesions.41 Thus, besides its role in inside-out signaling discussed above, talin is also at the center of a multimolecular complex that connects integrins to the actin cytoskeleton.


Like talin, α-actinin is an antiparallel homodimeric actin cross-linking protein that can bind directly to integrin cytoplasmic tails or link integrins to the actin cytoskeleton indirectly through vinculin.42 α-actinin is not dedicated to integrins but it also interacts with ICAMs, cadherins, syndecans, and other receptors. Four α-actinin isoforms exist in humans of which two are restricted to striated muscle. The interactions of α-actinin can be regulated by phospholipids and calcium and it may regulate cell-matrix adhesion disassembly in motile cells: it recruits MEKK1, a regulator of calpain, which in turn cleaves several cell-matrix adhesion components thereby regulating adhesion disassembly.42,43


An alternative direct interaction from integrin cytoplasmic tails to F-actin can be mediated by filamins. In contrast to the antiparallel dimers talin and α-actinin, filamins are parallel homodimeric proteins that bind actin with their head domain and organize the actin cytoskeleton in a loose network.44,45 With their rod domain they bind to transmembrane receptors including integrins and to Rho GTPases and several other proteins. The relative efficiencies of talin versus filamin-binding affect the ability of integrins to promote cell migration: mutations in the β1 cytoplasmic tail that increase binding to filamin-A inhibit membrane protrusion and cell migration whereas mutations in the β7 cytoplasmic tail that decrease binding to filamin-A have the opposite effect.46


Vinculin consists of a globular head domain that can bind talin and α-actinin and a tail region that can bind F-actin and paxillin.35,47 Like for talin, vinculin's interactions can be regulated by PIP2 binding. Vinculin folds into an autoinhibited conformation through interactions between the head and the tail region. PIP2 binding transiently weakens this interaction as does F-actin binding to the vinculin tail, causing exposure of binding sites in the head region for talin and α-actinin. The open conformation of vinculin may be stabilized by binding to multiple proteins, which are concentrated in cell-matrix adhesions.48,49 Vinculin knockout mice are embryonic lethal but this may be related to its function in cell-cell junctions as well as cell-matrix adhesions.50 Vinculin null fibroblasts have few, small cell-matrix adhesions with an unusual high turnover rate and these cells are highly motile, suggesting that vinculin plays an important role in assembly of cell-matrix adhesions, although this does not hold through for all cell types and it is noteworthy that deletion of vinculin has no obvious effects in Drosophila.35,50,51 The ability of vinculin to control the interaction between FAK and paxillin appears to be important in this regulation.52

ILK, PINCH, and Parvins

Integrin-linked kinase (ILK) was originally identified as a Ser/Thr kinase that binds integrin cytoplasmic tails.53 Deletion of the ILK gene in mice causes peri-implantation lethality but based on genetic studies in flies and worms it seems that the kinase function of ILK is dispensable for normal development.54-56 The major ILK null phenotype is an adhesion/polarization defect due to abnormal F-actin organization.56 The C-terminal part of ILK that contains the putative kinase domain can bind paxillin and a family of F-actin-binding proteins identified in different laboratories under different names, together termed “parvins”.34 The N-terminal part of ILK contains 4 ankyrin repeats and a PH domain and it can bind PINCH1 and PINCH2, two adaptor proteins, which, in turn mediate interactions with several proteins involved in organization of the actin cytoskeleton.57 Thus, this multiprotein complex can bind and regulate the actin cytoskeleton through multiple pathways.


Paxillin and its three related family members Hic-5, leupaxin, and PaxB are adaptor proteins that recruit multiple signaling intermediates to cell-matrix adhesions.58 Paxillin contains four double zinc-finger motifs termed LIM domains in its C-terminal half, two of which are required for its localization in cell-matrix adhesions. It is not known which protein recruits paxillin in cell-matrix adhesions although direct binding to the α4 cytoplasmic tail has been demonstrated.59 The N-terminal half of paxillin contains 5 LDxLLxxL (LD) motifs, which can bind vinculin, FAK, ILK, paxillin kinase linker (PKL), and α-parvin.60,61 Paxillin can be phosphorylated on serine/threonine as well as on tyrosine (e.g., by FAK and Src), the latter generating SH2-binding sites that recruit the Src inhibitor, Csk and the SH2-SH3 adaptor protein, Crk. In turn, Crk couples to several signaling pathways including those in control of actin cytoskeletal organization.62,63 Thus, paxillin brings together various regulatory pathways that control the dynamics of cell-matrix adhesions and the organization of the actin cytoskeleton.64,65


Tensin is an actin filament cross-linking protein that localizes in cell-matrix adhesions and can bind the NPXY motif of integrin β tails through its PTB domain. Tensin comprises a multi-gene family, including the tensin1, tensin2, tensin3, and cten genes.66 While most tensin family members are widely expressed, cten expression is restricted to epithelial cells in a few tissues, most notably the prostate. Tensin1 is important for proper kidney function and muscle regeneration while tensin3 is important for normal development of bone, lung, and intes- tine.67,68 Tensin family members can be phosphorylated on tyrosine in response to growth factors and they can interact with other phosphotyrosine-containing proteins through their C-terminal SH2 domains (there is also a C-terminal PTB domain but apparently this does not bind tyrosine phosphorylated proteins).66 Thus, tensin may represent an important signal integrator in cell-matrix adhesions. Two parts of the molecule can direct tensin localization to cell-matrix adhesions: the N-terminus through the actin-binding region and the C-terminus through the PTB domain. Although the cellular function of the different tensin members remains largely unclear, it has been implicated in fibronectin fibrilogenesis and tensin1 and 2 can promote cell migration, which requires cell-matrix adhesion targeting and phosphotyrosine-binding.69,70


Focal adhesion kinase is a tyrosine kinase whose activity is tightly regulated by cell adhesion but also by RTK signaling and oncogenes.71 FAK localizes in cell-matrix adhesions through binding of its C-terminal “focal-adhesion targeting” region to paxillin and other, less-well characterized interactions. Clustering of integrins triggers the phosphorylation of Tyr397. Though FAK-mediated effects have been found to be independent of its kinase domain, this Tyr397 recognition site is essential for most, if not all functions of FAK. It forms a regulated binding site for Src and other SH2-containing proteins such as the p85 subunit of PI 3-kinase.72 FAK-associated Src phosphorylates multiple other cell-matrix adhesion proteins as well as other tyrosine residues in FAK. FAK also binds the SH3 domain of the adaptor protein p130Cas, which, like paxillin, controls actin cytoskeletal organization through Crk.73 FAK can also bind growth factor receptors and nonreceptor tyrosine kinases through its N-terminal FERM domain to regulate cell migration.74,75 Thus, the FAK-Src complex may be a central regulator of adhesion dynamics in response to changes in the ECM and growth factor signaling. Indeed, fibroblasts deficient in FAK or Src family kinases show defects in cell-matrix adhesion turnover and cell motility.65,76,77

Biological Processes Involving Integrins

Matrix Assembly

Integrins participate in the assembly of various types of ECM. In the case of basement membranes, β1 integrins cooperate with the dystroglycan receptor to promote synthesis and polymerization of laminin chains into a multivalent network in which subsequently, collagen and other components are incorporated78 (Fig. 4). Fibronectin-rich matrices are essential structures for cell migration during embryogenesis and wound healing.79 The functional interaction of integrins with syndecans is important for fibronectin matrix assembly,80 with α5β1 being the typical integrin involved although other integrins can compensate to some extent for its absence.81,82 The high efficiency with which α5β1 promotes fibronectin matrix assembly may be related to the fact that binding of fibronectin through α5β1 efficiently stimulates the activity of RhoA,83 a Rho GTPase that stimulates actomyosin-driven contractility, which is required for fibronectin fibrillogenesis.84

Figure 4. Functional implications of integrin-mediated adhesion.

Figure 4

Functional implications of integrin-mediated adhesion. Schematic drawing of roles for integrins in ECM assembly, intracellular signaling pathways, and cell migration. See text for details.

Cell Migration

Besides mediating stable adhesion, integrins play a crucial role in cellular motility.85 Cell migration is essential for embryonic development, immune responses, and tissue repair, whereas deregulated migration characterizes metastatic cancers. Migrating cells establish a polarized morphology: the lamellipodium at the front contains an actin cytoskeletal meshwork associated with stationary focal complexes, whereas at the rear, F-actin stress fibers connect large, inward sliding focal contacts.86 Stabilization of the lamellipodium requires integrin-mediated adhesion to the ECM or to other cells. By anchoring the actin cytoskeleton to the ECM in cell-matrix adhesions, integrins are also required for the generation of propulsive forces. It is presently unclear how spatial organization of the signals that control polarity of a migrating cell is established, but concentration of distinct protein complexes at sites of integrin-mediated adhesion at the front and at the rear may be involved. Moreover, different integrins promote distinct modes of motility and cells may alter their motile behavior by expressing different integrins.87


Integrin engagement can regulate intracellular signal transduction cascades that ultimately control differentiation, proliferation, and survival. For instance, for most cell types activation of the Raf—MEK—ERK signaling pathway is weak and transient when adhesion is perturbed but strong and sustained in the presence of integrin-mediated adhesion.88,89 Through clustering of activated forms of signaling proteins such as FAK, Src, p130Cas, ILK, and ERK26 cell-matrix adhesions may be the sites where amplification of signaling cascades takes place. It appears that oncogenes can uncouple this process of signal amplification from cell-anchorage: FAK activity is deregulated in transformed cells and the tyrosine kinase c-Abl phosphorylates paxillin in response to cell adhesion while its oncogenic variant, Bcr-Abl binds paxillin constitutively in a multi-phosphoprotein complex.71,90,91 Even mRNA and ribosomes can be found associated with cell-matrix adhesions suggesting that they may locally connect signal transduction to protein synthesis.92 Clustering and transactivation of PDGFR, EGFR, VEGFR and several other RTKs, is a more direct manner through which integrins can modulate RTK signaling. 93-95 Moreover, growth factors can be concentrated and modified by the ECM and integrin-mediated cell adhesion then allows their subsequent presentation to growth factor receptors.96 Finally, through cytoskeletal connections with the nucleus the distribution and the stability of cell-matrix adhesions may even be connected physically to nuclear shape, chromatin structure, and gene expression.97,98

Through its effect on multiple signal transduction cascades, integrin-mediated cell adhesion regulates the G1 phase of the cell cycle. Integrins cooperate with RTKs to stimulate the cyclin E-cdk2 activity that drives S-phase entry.99 Multiple different pathways have been described to connect integrins to G1 cell cycle progression but whichever pathway cells use, the organization of the actin cytoskeleton by integrins, is likely to be very important.100 Most adherent cell types also depend on integrin-mediated adhesion for survival (apoptosis in response to loss of adhesion has been termed “anoikis”). Integrin-mediated cell adhesion in 2-dimensional culture systems stimulates PI3K-mediated PKB/AKT activity which mediates survival signals101,102 and α6β4 ligation supports NF?B-mediated survival signals in 3-dimensional cultures of mammary epithelial cells.103 Integrins that are not ligand-bound can also trigger apoptosis of fully adherent cells by recruitment and activation of caspase-8104,105 suggesting that a given integrin expression profile renders a cell dependent on a specific ECM environment for its survival. Finally, integrins also regulate the expression of genes related to differentiation. The synthesis of milk proteins by mammary epithelial cells,106,107 the formation of contracting myotubes and expression of meromyosin by embryonic myoblasts,108 the production of inflammatory cytokines by monocytes,109 and the expression of involucrin in terminally differentiating keratinocytes110 are all controlled in vitro by integrin-mediated adhesion.

Concluding Remarks

Here, some general features of the structure and function of integrins has been discussed. In the next three chapters we will learn in more detail how integrins are critically involved in extracellular matrix assembly, cell migration, and how integrins modulate many intracellular signaling cascades. Subsequently, the rest of this book will discuss what we can learn from genetic studies and from human diseases about the roles of integrins and associated proteins in animal development and tissue function.


I thank Stephan Huveneers and Sandy Litjens for providing images of podosomes and hemidesmosomes, and Arnoud Sonnenberg for critical reading of the manuscript. Funded by the Dutch Cancer Society (grant NKI 2003-2858).


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