Integrin-Based Therapeutics in Diseases: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Igor Tvaroška.

Integrins are heterodimeric glycoproteins crucial to the physiology and pathology of many biological functions. As adhesion molecules, they mediate immune cell trafficking, migration, and immunological synapse formation during inflammation and cancer. The recognition of the vital roles of integrins in various diseases revealed their therapeutic potential. 

  • integrins
  • mechanism
  • cancer

1. Structure of Integrins

Integrins are membrane glycoproteins composed of α and β subunits that form a heterodimer. Both subunits consist of well-defined domains: a large extracellular domain (ectodomain) and a relatively short transmembrane domain with ~60 amino acids (aa). The exception is the β4 integrin [132][1] with ~1000 aa and cytoplasmic domain [20][2]. The integrin cytoplasmic domain modulates crucial cell processes by interacting with various skeletal proteins and intracellular signaling molecules [9][3]. Two subunits in integrin complexes are held together by non-covalent bonds and form a ligand-binding site on the top of the two subunits. The ectodomain of α-chain is larger than that of β-chain: ~ 940𠀓1120 aa vs. ~700 aa. An α subunit ectodomain consists of two calf domains, a tight, and a seven-bladed β-propeller. The β subunit consists of a β-tail domain, four epidermal growth factor (EGF) modules, a hybrid domain with the inserted βI domain, and a plexin-semaphorin-integrin (PSI) domain.
There are 18 different found α subunits (α1–α11, αv, αIIb, αD, αL, αM, αX, and αE) and eight found β subunits (β1–β8). Nine of eighteen α subunits, namely α1, α2, α10, α11, αD, αL, αM, αX, and αE, have inserted the αI domain between the second and third blade of the β-propeller, which is crucial for the formation of a ligand binding region. This region also contains a Metal Ion-Dependent Adhesion Site (MIDAS) containing divalent cations such as Mg2+, Ca2+, or Mn2+. In the other nine α subunits (α3–α9, αv, and αIIb), the αI domain is missing, and a βI domain from an α-propeller domain in the α subunit headpiece and the MIDAS in the β subunit are responsible for forming the ligand binding region. In this case, other metal ion sites were also found similar to βI MIDAS; of the two ADMIDAS (Adjacent to MIDAS) sites, one of them is called a synergistic metal ion-binding site (SYMBS). Twenty-four integrins were identified in humans and can be classified according to their ligand-binding properties (Figure 2b)  or tissue expression [8,15][4][5].

1.1. Glycosylation of Integrins

Glycan structures added to integrins by post-translational modifications contribute to their structural and functional diversity [133,134,135,136,137,138,139][6][7][8][9][10][11][12]. The glycosylation of proteins is a step-wise process carried out by glycosyltransferases. Glycosyltransferases (GTs) catalyze the transfer of glycosyl residue from a donor to an acceptor molecule [48][13]. The N- and O-glycosylations are the most frequent types of glycosylation. There are sufficient data linking aberrant glycosylation with pathological conditions, including chronic inflammation, immune diseases, cancer progression, and metastasis [48,140,141,142,143][13][14][15][16][17]. N-glycans presence is crucial for the association of both subunits into heterodimers, their stability, conformation, and interactions with ligands. For example, α5β1 and α3β1 integrins contain 14 and 12 N-glycosylation sites on α and β subunits, respectively. Their presence is crucial for interactions with fibronectin and laminin, mediating cell adhesion, migration, differentiation, and apoptosis [134][7]. However, from multiple N-glycosylation sites, only those located on specific motifs have these roles [144,145][18][19]. Integrins also contain O-glycans associated with the adhesion and migration of tumor cells, but their functions are less investigated due to difficulties in their isolation. 

1.2. 3D structures of Integrins

 
X-ray crystallography, NMR spectroscopy, cryogenic electron microscopy, and molecular modeling methods solved the integrin structures and contributed to understanding their behavior. The first 3D structure of an integrin was the crystal structure of the integrin ectodomain for αvβ3 [146][20]. Up to now, there are more than 100 solved structures concerning various integrins’ parts, usually in complex with different ligands. The solved integrin-ligand complexes revealed the structures of binding sites and crucial interactions between inhibitor and ligand [20][2]. It is beyond the scope of this paper to discuss all X-ray structures. Readers can find relevant information in reviews on this subject [7,13,20,147,148,149][2][21][22][23][24][25]. In this section, we will discuss some solved structures of integrins, as well predicted 3D structures by homology modeling.
Integrins play an essential role in the immune system by mediating leukocyte adhesion and their transmigration from blood to tissue during leucocyte adhesion [150][26]. Therefore, it is unsurprising that integrins involved in immunological functions were studied more intensively than others. The αXβ2 integrin was the first solved structure of the ectodomain containing the αI domain [151][27]. The integrins αvβ3 and αIIbβ3 belong to the most investigated. These integrins are present on platelets and are associated with platelet functions in hemostasis and thrombosis, and they also participate in cancer progression [152][28]. The crystal structures of the complete integrin αvβ3 ectodomain plus α/β transmembrane fragment [153][29] and the intact integrin αIIbβ3 in a nanodisc lipid bilayer were solved recently [154][30]. Both integrins adopted a similar bent conformation, in which the ligand binding site is near the membrane surface.
The solved crystal structures of integrin ectodomains and I domains [7,20,21,149,155][2][21][25][31][32] revealed that integrins exist during activation in the dynamic equilibrium of at least three major conformers: bent-closed (BC), open-closed (OC), and open-extended (OE)] [7,156,157][21][33][34]. Three conformers are schematically shown in Figure 1. Interactions of integrins with extracellular and cytosolic ligands (activators) trigger a large conformational movement that changes conformational equilibrium. In the absence of a ligand, a salt bridge interaction between helices of the cytoplasmic tails of α and β subunits hold the resting integrin in a low-affinity conformation [158][35]. Interactions of some protein activators, e.g., talin, with CT of β-subunits and membrane break this salt bridge, separate the α- and β-subunits, and the integrins switch to an extended conformation [159][36] of the α and β ectodomains that retains its low ligand affinity. Then, integrins interacting with extracellular ligands change to an open-extended, high-activity conformation [160][37]. It was observed [161][38] that after activation, integrins form ~100 nm clusters of ~50 integrins assisted in an early adhesion of cells.
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Figure 1. Schematic representation of domain architecture during activation of integrins that (a) contain or (b) lack an αI domain. L = ligand.
Recently, the conformational equilibriums of three conformers of the α5β1 integrin have been investigated by kinetics measurements using three different ligands [156][33]. The determined values of the free energy ΔG for the bent-closed (BC) and the extended-closed (EC) conformer are in the range from −1.2 kcal/mol to −1.8 kcal/mol and −0.7 kcal/mol to −1.2 kcal/mol, respectively, compared to the extended-open (EO) conformer (ΔGEO = 0.0 kcal/mol). For the cyclic RGD peptide (cRGD) as the ligand, the values are ΔGBC = −1.5 kcal/mol, ΔGEC = −1.1 kcal/mol, and ΔGEO = 0.0 kcal/mol corresponding to the population of x(BC):x(OC):x(OE) = 64.3%:31.3%:4.6%. Interestingly, the authors also found that variation in the N-glycosylation site number modulates conformational equilibria. The results revealed that bent-closed and extended-closed conformations are stabilized by a lower number of N-glycosylation sites on integrin α5β1 [156][33].
The αI domain is the ligand-binding site in the integrins containing this domain. Structural studies of the αI domains (α2, αM, and αL) complexed with a ligand and without a ligand revealed three distinct conformations: closed, intermediate, and open [162,163,164,165][39][40][41][42]; it was suggested that the closed conformation that lacks a ligand is the most stable [7][21]. The αI domain possesses a Rossmann fold, and at the C-terminal end of the central β-sheet is a MIDAS binding motif that coordinates a divalent-metal binding site. The crystal structure of αLβ2 also revealed the presence of a ligand-induced allosteric site [166][43]. In contrast, integrins lacking the αI domain bind ligands in a binding site of the βI domain that is homologous to the αI domain. Readers can find a detailed discussion of the conformational changes of integrins in recent papers [7,13,20,149][2][21][22][25].

1.3. Molecular Modeling of Integrins’ Structures

Simultaneously with an effort to describe the 3D structure and conformational dynamic of integrins using experimental methods, molecular modeling methods were applied to provide additional information and aimed to fill the gaps in missing experimental data. The first homology model of an integrin was constructed in 1992 for the α-integrin EF hand-like sequence using the calmodulin sequence as a template [167][44]. A computational approach was used to design mutations that stabilized the αI domain of the αMβ2 integrin in either the open or closed conformation [168][45]. The analysis of the predicted mutants revealed that the conformational change in αI domain mediates ligand binding and that computationally proposed ligands are more active than previously suggested ligands.
Up to now, there are no crystal structures reported for the leukocyte integrin α4β1. The first step in generating a complete 3D structure of α4β1 was a homology model of β-subunits, including a bound Mg2+ ion [169][46]. The model was constructed using the I domain of integrin CD11B/CD18 containing Mg2+ ion as the template [170][47]. Then, several steps of restrained energy minimization and molecular dynamics, followed by a final minimization, were used to obtain the final homology model. The ligand-binding mechanism of the α4β1 integrin was studied by docking various molecules, including the vascular cell adhesion molecule (VCAM-1), into the active site of the model. The results shed light on the interactions of β4 with its ligands and explained the binding mechanism of α4β1 with the native ligand VCAM-1. Additionally, a qualitative explanation of the ligand binding selectivity between α4β1 and α4β7 was proposed.
The solved crystal structures of the complete unconstrained ectodomain plus short C-terminal transmembrane stretches of the &#;V and &#;3 subunits of the αvβ3 integrin [146,153][20][29] made it possible to construct a model for the ectodomain of the human αvβ5 integrin [171][48]. Homology modeling used the crystal coordinates of αvβ3 in its bound conformation as a template. The modeled receptor was refined using energy minimization and molecular dynamics simulations in explicit solvent. The resulting αvβ5 model was used to investigate a ligand binding selectivity toward αvβ3 and αvβ5 by docking various ligands into both integrins. Comparison of both structures and docking results explained the binding differences of both integrins by revealing that ligands with bulky substituents neighboring the carboxylate group are hampered by a “roof” presented on the top of the MIDAS region in αvβ5.
The homology of the platelet integrin αIIbβ3 has also been reported [172][49]. At the time of generating the homology model of the αIIb N-terminal portion of integrin αIIbβ3, the high-resolution structures of integrin αIIbβ3 were unavailable. The refined model was validated experimentally. The homology model revealed structural features responsible for the αIIbβ3 integrin function and proposed an interpretation of the role of naturally occurring mutations that produce Glanzmann thrombasthenia. However, more than 38 crystal structures related to integrin αIIbβ3 are now available that provide information on the mechanism of the αIIbβ3 integrin function [20][2]. The homology model of the extended full-length integrin αIIbβ3 was generated based on the crystal structures of the αvβ3 ectodomain [146,173][20][50] and on the β2 PSI/hybrid/I-EGF1-3 construct [174][51], including of computer models of the TM helices [175][52]. The model was complemented with N- and O-glycans, computer models of the TM helices, and NMR structures of the cytoplasmic domains [176,177,178][53][54][55]. The generated models were fit in the EM⁄ET maps, and their hydrodynamic parameters were then computed and compared with the experimental data. Later, the authors [179][56] refined this model (Figure 2a) using the new crystallographic structure of the integrin αIIbβ3 ectodomain [180][57] and the NMR structures of its transmembrane/cytoplasmic segments [181][58].
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Figure 2. Homology model of (a) extended full-length integrin αIIbβ3 [179][56]; PM0076386 entry in PMDB database, the AlphaFold homology model of (b) α4β1, (c) the α subunit of α4β1, and (d) the β subunit of α4β1 [182][59].
The recently developed deep-learning method AlphaFold [119][60] has been used to generate a homology model of the α4β1 integrin [182][59]. AlphaFold produced 25 partially optimized homology structures, including a pLDDT scoring function that evaluates the intra-domain confidence interval. Structures of all homology models were superposed using the USCF ChimeraX program. The analysis of overlapped 3D structures revealed only slight differences in non-structuralized loops. The selected homology model, based on pLDDT, was optimized, and its stability was evaluated with MD simulation using AMBER. The final 3D homology model of the α4β1 integrin is shown in Figure 2b, together with the homology structures of the α subunit (Figure 2c), and β subunit (Figure 2d).

2. Integrins as Therapeutic Targets

Integrins in Diseases

Integrins, as transmembrane glycoproteins located on the surfaces of the cells, recognize many physiological ligands [229][61]. They bind through their ectodomains with numerous ligands and, thus, are involved in cell–cell and cell–ECM interactions influencing cell migration and ECM assembly and remodeling. Among the most relevant ligands belong ICAM-1 (Intercellular Adhesion Molecule 1; also known as CD54), VCAM-1 (Vascular Cell Adhesion Molecule 1; CD106), MAdCAM-1 (Mucosal Addressin Cell Adhesion Molecule 1), E-cadherin, PECAM-1 (Platelet Endothelial Cell Adhesion Molecule 1; CD31), EPCR (Endothelial Cell Protein C Receptor), thrombomodulin, fibronectin, collagen, and irisin [230][62]. The cytoplasmic domain of integrins also interacts with many cytoskeletal proteins and signaling molecules. These interactions mediate fundamental cell processes associated with diverse physiological and pathological pathways. Though integrin–ligand interactions play a pivotal role in maintaining the health conditions of various tissues, their aberrant activation is detrimental in multiple diseases, including development, immunity, hemostasis and thrombosis, inflammation, angiogenesis, tumor growth and metastasis, multiple sclerosis, inflammatory bowel disease, nephritis, osteoporosis, sickle cell disease, and fibrosis [9,13,24,231,232][3][22][63][64][65]. Many papers exist regarding the role of aberrant integrin adhesion and signaling in the pathogenesis of many human diseases. It is beyond this paper’s scope to discuss this complex area of research in detail. Therefore, the following sections only briefly discuss the importance of integrins in various diseases, and readers may find more detailed insight in available reviews.
Inflammation. Activated integrins are involved in leukocyte extravasation from blood to inflamed tissues. This process consists of multiple sequential molecular interactions called leukocyte adhesion cascade [150,233][26][66]. Circulating leukocytes interact during tethering and rolling with selectins on the activated endothelium. These contacts are identified by chemokines, which trigger inside-out activation (by binding effectors to the cytoplasmic tail of the β subunit) of leukocyte integrins (e.g., αLβ2, αMβ2, α4β1, and α4β7) that then bind to their counter-receptors on the endothelium, including ICAMs and VCAMs. Binding these adhesion ligands stabilizes the high-affinity integrin conformation and strengthens the binding of leukocytes to the endothelium. Firmly bound leukocytes crawl along the endothelium and finally migrate through the endothelium to inflamed sites [183][67].
Integrins are crucial components of the leukocyte adhesion cascade responsible for proper leukocyte homing in inflammatory responses. Their role is documented by patients with leukocyte adhesion deficiency (LAD) syndromes who suffer from recurrent infections and bleeding disorders. It was discovered that a mutation in β2 integrins is responsible for LAD affecting the interaction with kindlins-3, and as a result, leukocytes cannot get to the inflammation site [235][68]. A complete failure of platelet aggregation to form a clot caused by mutations of the αIIbβ3 integrin is characteristic of Glanzmann’s thrombasthenia [236][69]. Abnormal bleeding that can be life-threatening is a typical symptom of patients suffering from Glanzmann’s thrombasthenia. Another genetic disease is Epidermolysis bullosa, a connective tissue disorder that causes your skin to blister and tear easily, caused by a mutation of the α6β4 integrin [237][70]. Symptoms are often severe with life-threatening complications. Integrins are crucial in preventing chronic inflammation by removing apoptotic neutrophils by macrophages in acute inflammation, an efferocytosis process [238][71].
Inflammatory bowel diseases. Leukocyte integrins play a prominent role in inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC). Uncontrolled inflammation of the gastrointestinal tract is typical for IBDs [239,240][72][73]. The migration of activated T-lymphocytes to the intestinal vasculature is mediated by interactions of α4β1, α4β7, and αEβ7 integrins with their ligands VCAM-1, MAdCAM-1, and E-cadherin. In the inflamed gut of IBDs patients, an increased number of VCAM-1 and MAdCAM-1 ligands were observed that contributed to the increase of pro-inflammatory lymphocytes, which are retained through enhanced interactions between the αEβ7 integrin and E-cadherin. Thus, aberrant interactions of α4β1, α4β7, and αEβ7 integrins with their ligands VCAM-1, MAdCAM-1, and E-cadherin play critical roles in the pathogenesis of BDIs [239][72]. Therefore, the therapy based on inhibiting these interactions may be beneficial for treating patients suffering from BDIs.
Arthritis. Inflammation of the synovium tissue is characteristic of chronic inflammatory arthritides. Rheumatoid arthritis (RA) is the best-studied disease in this group [241,242,243][74][75][76]. In RA, enhanced pro-inflammatory cell levels cause overexpression integrin receptors and their ligands [244][77]. The analysis of integrin distribution in synovial tissue of RA revealed [243][76] an increased expression of collagen-, laminin-, and fibronectin-binding integrins, especially those containing α5, αv, and β1 subunits. Additionally, an upregulation of the αLβ2 (LFA-1) integrin that enhances the migration of immune cells into the synovial tissue was observed [243][76]. Enhanced levels of these integrins causes the overproduction of matrix-degrading enzymes and fibroblasts that degrade cartilage, and thus preserve RA. All these findings suggest integrins’ crucial role in RA disease that can be restrained with integrin inhibitors.
Fibrosis. Five integrins containing the αv subunit (αvβ1, αvβ3, αvβ5, αvβ6, and αvβ8) have been identified to play a relevant role in fibrotic diseases [245][78] in several organs, including the heart, blood vessels, lung, kidney, liver, and skin [246][79]. Typical for fibrosis is ECM stiffening with loss of elasticity and excessive tissue deposition with a debilitating condition [247][80]. Under chronic injury or inflammation, integrins activate pro-fibrotic transforming growth factor β (TGFβ). Induced fibroblasts upregulate ECM production, leading to fibrosis progression. It was found that αv integrins are upregulated in fibrotic diseases, and studies using knockout mice demonstrated that deletion of αv integrins might attenuate fibrosis progression [248][81].
Atherosclerosis. Integrin signaling plays a crucial role in atherosclerosis, a chronic inflammatory disease affecting large arteries [249,250][82][83]. The binding of the αIIbβ3 integrin with fibrinogen is involved in platelet aggregation, and β2 integrins (αM4β2 and αLβ2) control macrophage binding. An overexpression of integrins and their ligands was observed in atherosclerosis [249][82]. For example, an upregulation of the α4β7 integrin and its ligands VCAM-1 and MAdCAM-1 was found in atherosclerosis, and the atherosclerotic plaque area was significantly reduced in the α4β7 deficient mice [251,252][84][85]. In addition, attenuated atherosclerosis was observed upon deletion of other integrins, such as the leukocyte αXβ2 [253][86], αvβ3 [254][87], and α5β1 [255][88]. Therefore, the inhibition of these integrins has the potential to reduce the progression of atherosclerosis.
Eye diseases. Integrins play an essential role in normal development and the development of pathological processes in the eye [26][89]. For example, the αvβ6 integrin is a key player in corneal fibrosis [256][90]; integrins α1, α3, α4, αL, β1, β3, and β4 were upregulated in the heredity eye disease Fuchs’ corneal dystrophy [257][91]. The αL integrin plays a vital role in dry eye diseases, and its inhibition significantly improves ailments [258][92]. In glaucoma, the αvβ3 integrin was upregulated in retinal ganglion cells and the glial cells of the nerve head after nerve crush in mice [259][93]. The examples mentioned above documented some eye diseases associated with the deregulation of integrins.
Cancer. A multistep process of cancer development includes tumor initiation and sustainable chronic proliferation, local invasion and intravasation into blood, surviving circulation, adhesion to the endothelium, extravasation, initial seeding, and proliferation in the target tissue [260,261,262,263][94][95][96][97]. Many studies have indicated that integrins mediate various aspects of these steps [23[98][99][100][101][102][103][104],264,265,266,267,268,269], and below, we present only a few selected examples. Biochemical and genetic studies have documented aberrant integrin activity in cancer cells associated with an altered expression of integrins, which is dependent on the cancer type and the stage of the disease [23][98]. A high abundance of various β1, β4, and αv integrins (α3β1, α4β1, α5β1, α6β4, αvβ3, αvβ5, αvβ6, and αvβ8) is associated with metastasis and frequently correlates with poor prognoses [23,267][98][102]. However, the role of integrins is not straightforward. For example, although β1 integrins play a crucial role in cancer development and the α3β1 integrin is vital for mammary cancer [270][105], the α2β1 integrin is a metastatic suppressor in breast cancer [271][106].
Genetic studies have revealed that the β4 integrin is necessary for tumor initiation and progression in mammary and skin tumorigenesis [265][100]. Additionally, it was found [269][104] that an overexpression of the αvβ3 integrin plays a vital role in developing tumor-initiating cells in lung and pancreatic cancers. These cells are assumed to contribute to cancer relapse after the initial response to treatment. Furthermore, the αvβ3 integrin was found to mediate the resistance of tumor-initiating cells to tyrosine kinase inhibitors through the activation of NF-κB in a ligand-independent manner [272][107].
Cancer metastasis is a complex multi-step process, and from a vast number of primary tumors, only a tiny number of metastases develop. To form metastasis in nearby or distant organs, cancer cells have to accomplish all of several consecutive steps: detachment from the primary tumor, intravasation to the blood vessel, survival of circulation in blood and adhesion to the endothelium, extravasation from the blood into the target organ, and proliferation in the organ microenvironment [260,263][94][97]. Accumulating experimental evidence showed that during the circulation in the blood, cancer cells utilize a similar mechanism used by leukocytes in the inflammatory cascade [273,274][108][109]. Various adhesion molecules mediate the transendothelial migration of cancer cells, including activated integrins of cancer cells, such as α4β1 binding to endothelium ligand VCAM-1 and αLβ1 binding to LCAM-1.
However, the role of integrins is more complex, and some data suggest that laminin-binding integrins α3β1 and α6β4 might have an inhibitory effect on cancer metastasis [275][110]. The dual role of the α3β1 integrin was shown in breast cancer. The absence of integrin α3β1 reduced the survival of mice, and increased tumor growth was observed [276][111]. Similarly, the α3 subunit of the α3β1 integrin interacts with various ECM ligands, and its function depends on the cancer type. In patients with hepatocellular carcinoma (HCC), the expression of α3 negatively correlated with tumor growth and metastasis [277][112]. An opposite functioning of α9 was observed in breast cancer, where knocking out α9 significantly reduced tumor growth, angiogenesis, and metastasis [278][113].
Integrins are also involved in ECM remodeling to induce cancer cell invasion, with cancer-associated fibroblasts (CAFs) playing a vital role. It was found [279][114] that the αvβ3 integrin expressed by CAFs participates in CAFs’ assembling of fibronectin and metastasis. In addition, other integrins, such as the α5β1 integrin [280][115], αvβ6 integrin [281[116][117],282], and α9β1 integrin, promote the recruitment of CAFs. Angiogenesis supplies nutrition for tumor survival and supports tumor cell transfer into blood vessels for circulation. Three endothelial integrins, namely αvβ3, αvβ5, and α5β1 mediate tumor angiogenesis [283][118]. It has been shown that tumors use integrin-ECM interactions as one of the strategies to escape anti-tumor therapies [284][119]. To achieve this goal, tumors overexpress integrins, such as β1, and activate signaling pathways that block the effect of drugs [285,286][120][121].
Integrins as a route to invasion by viruses and bacteria. Various pathogens can exploit integrins as receptors to attach and enter the host cells; for review, see references [287,288,289,290][122][123][124][125]. Over time, viruses have evolved multiple mechanisms to colonize host cells. The binding to the host is the first step of virus entry (internalization), and among different receptors, viruses utilize integrins.
Several viruses display on the viral surface proteins containing amino acid moiety RGD, which they use for binding with RGD-binding integrins [289][124] (αvβ1, αvβ3, αvβ5, αvβ6, αvβ8, α8β1, and αIIbβ3). Among those, many adenoviruses interact with αv integrins as documented by the solved structure of the complex with the αvβ5 integrin by cryoelectron microscopy [291][126]. The binding starts virus internalization, and it was shown that inhibition of binding resulted in a significant decrease in viral infection [292][127]. Interestingly, adenovirus binding also induces the clustering of integrins that enhance infection. Similarly, several members of the Herpesviridae family, such as Kaposi’s sarcoma-associated herpes virus or human herpes virus 8, utilize the αvβ3 integrin [293][128]. The integrins αIIbβ3 and αvβ3 function as receptors for pathogenic strains of hantaviruses, while non-pathogenic strains of the Prospect Hill virus utilize the β1 integrin [294,295][129][130]. Coxsackievirus, a member of the enterovirus family, uses the αvβ6 integrin for cell entry [296][131]. Interactions of retrovirus human immunodeficiency virus 1 (HIV-1) with the α4β7, αvβ5, αvβ3, and α5β1 integrins are critical for cell entry [297,298,299][132][133][134]. Among other RGD-binding viruses, deadly Ebola virus interactions with the α5β1 integrin are essential for fibroblast infection [300][135]. Other viruses using RGD moiety for engagements with host cells include Zika virus [301][136] (αvβ5), rotavirus [302][137] (αvβ3), and foot-and-mouth disease [303][138] (αvβ6). Recently, it was suggested that SARS-CoV-2 might also use RGD-binding integrins as cell receptors through interactions with spike protein [304,305][139][140].
Not all viruses recognize RGD moiety for their interactions with integrins. An alphavirus Ross River virus associated with polyarthritis utilizes the binding of integrins α1β1 and α2β1 for cell entry and infection [306][141]. The role of the α2β1 integrin is supported by blocking infection with function-antibodies against α2β1 [306][141]. Rotavirus spike protein uses different spike amino acids moieties to enter a cell: the YFL domain binds with the α4β1 and α4β7 integrins [307][142], and the GPR moiety interacts with the αXβ2 integrin [308,309][143][144]. Human echovirus, which is associated with meningoencephalitis, utilizes for successfully infecting cell clusters of the α2β1 integrin [310][145]. Interestingly, HIV-1, in addition to binding RGD-binding integrins, also uses interactions with the α4β7 integrin for efficient cell-to-cell spreading [298][133].
Integrin receptors are also vital for many bacterial infections, and in the following, only some examples will be presented. More details can be found in reviews [288,290][123][125]. Some bacteria use an adhesion, a protein expressed on their surface, to interact with integrins on host cells to initiate cell entry. For example, Yersinia bacteria cause pain and tenderness in the abdomen, nausea, and diarrhea, and use the protein invasin to interact with five β1 integrins, namely α3β1, α4β1, α5β1, α6β1, and αvβ1, for efficient host cell entry [311][146]. Helicobacter pylori is linked to various stomach diseases, and the host clustered β1 integrins attach bacteria through a type 4 secretion system to the cell membrane [312][147]. Borrelia burgdorferi bacteria is a source of Lyme disease, and a membrane protein P66 binding to β3 integrins has been identified as the mechanism of bacteria adhesion [313][148].
Some bacteria express proteins that bind to the protein fibronectin from ECM and through fibronectin to host cell integrins in the so-called sandwich model [314][149]. For example, Staphylococcus bacteria cause mucosal or septicemic infection and express two fibronectin-binding proteins, FnbpA and B. These proteins interact with the α5β1 integrin and can be inhibited by RGD peptides [315][150]. Streptococcus bacteria use a similar mechanism responsible for acute pharyngitis in humans [316][151] and by Porhyronomas bacteria that causes periodontitis [317][152]. A common bacterium, Pseudomonas aeruginosa, causes acute or chronic lung infections and employs interactions with α5β1 and αvβ5 integrins and their ligands fibronectin and vitronectin to invade host cells [318][153]. Neisseria bacteria cause sexually transmitted gonorrhea disease (N. gonorrhoeae) and meningitis (N. meningitidis). Infections by Neisseria commence with an attachment to host cell surfaces. Then, the host cell receptors trigger signaling, activating the α5β1 and αvβ3 integrins with the following cell entry [319][154]. The above-discussed example illustrates the crucial importance of integrins’ recognition in viral and bacterial infections. In many cases, they mediate attachment, internalization, and tissue. Thus, they represent potential targets for therapeutic intervention.

References

  1. Hogervorst, F.; Kuikman, I.; von dem Borne, A.E.; Sonnenberg, A. Cloning and sequence analysis of beta-4 cDNA: An integrin subunit that contains a unique 118 kd cytoplasmic domain. EMBO J. 1990, 9, 765–770.
  2. Zheng, Y.; Leftheris, K. Insights into Protein-Ligand Interactions in Integrin Complexes: Advances in Structure Determinations. J. Med. Chem. 2020, 63, 5675–5696.
  3. Pan, L.; Zhao, Y.; Yuan, Z.; Qin, G. Research advances on structure and biological functions of integrins. Springerplus 2016, 5, 1094.
  4. Hynes, R.O. Integrins: Bidirectional, allosteric signaling machines. Cell 2002, 110, 673–687.
  5. Barczyk, M.; Carracedo, S.; Gullberg, D. Integrins. Cell Tissue Res. 2010, 339, 269–280.
  6. Cai, X.; Thinn, A.M.M.; Wang, Z.; Shan, H.; Zhu, J. The importance of N-glycosylation on beta3 integrin ligand binding and conformational regulation. Sci. Rep. 2017, 7, 4656.
  7. Gu, J.; Taniguchi, N. Regulation of integrin functions by N-glycans. Glycoconj. J. 2004, 21, 9–15.
  8. Marsico, G.; Russo, L.; Quondamatteo, F.; Pandit, A. Glycosylation and Integrin Regulation in Cancer. Trends Cancer 2018, 4, 537–552.
  9. Paszek, M.J.; DuFort, C.C.; Rossier, O.; Bainer, R.; Mouw, J.K.; Godula, K.; Hudak, J.E.; Lakins, J.N.; Wijekoon, A.C.; Cassereau, L.; et al. The cancer glycocalyx mechanically primes integrin-mediated growth and survival. Nature 2014, 511, 319–325.
  10. Thomas, R.; Menon, V.; Mani, R.; Pruszak, J. Glycan Epitope and Integrin Expression Dynamics Characterize Neural Crest Epithelial-to-Mesenchymal Transition (EMT) in Human Pluripotent Stem Cell Differentiation. Stem Cell Rev. Rep. 2022, 18, 2952–2965.
  11. Zhao, Y.; Sato, Y.; Isaji, T.; Fukuda, T.; Matsumoto, A.; Miyoshi, E.; Gu, J.; Taniguchi, N. Branched N-glycans regulate the biological functions of integrins and cadherins. FEBS J. 2008, 275, 1939–1948.
  12. Janik, M.E.; Litynska, A.; Vereecken, P. Cell migration-The role of integrin glycosylation. Biochim. Et Biophys. Acta-Gen. Subj. 2010, 1800, 545–555.
  13. Tvaroska, I. Glycosyltransferases as targets for therapeutic intervention in cancer and inflammation: Molecular modeling insights. Chem. Pap. 2022, 76, 1953–1988.
  14. Varki, A. Biological roles of glycans. Glycobiology 2017, 27, 3–49.
  15. Reily, C.; Stewart, T.J.; Renfrow, M.B.; Novak, J. Glycosylation in health and disease. Nat. Rev. Nephrol. 2019, 15, 346–366.
  16. Costa, A.F.; Campos, D.; Reis, C.A.; Gomes, C. Targeting Glycosylation: A New Road for Cancer Drug Discovery. Trends Cancer 2020, 6, 757–766.
  17. Vasconcelos-Dos-Santos, A.; Oliveira, I.A.; Lucena, M.C.; Mantuano, N.R.; Whelan, S.A.; Dias, W.B.; Todeschini, A.R. Biosynthetic Machinery Involved in Aberrant Glycosylation: Promising Targets for Developing of Drugs Against Cancer. Front Oncol. 2015, 5, 138.
  18. Isaji, T.; Sato, Y.; Zhao, Y.; Miyoshi, E.; Wada, Y.; Taniguchi, N.; Gu, J. N-glycosylation of the beta-propeller domain of the integrin alpha5 subunit is essential for alpha5beta1 heterodimerization, expression on the cell surface, and its biological function. J. Biol. Chem. 2006, 281, 33258–33267.
  19. Luo, B.H.; Springer, T.A.; Takagi, J. Stabilizing the open conformation of the integrin headpiece with a glycan wedge increases affinity for ligand. Proc. Natl. Acad. Sci. USA 2003, 100, 2403–2408.
  20. Xiong, J.P.; Stehle, T.; Diefenbach, B.; Zhang, R.; Dunker, R.; Scott, D.L.; Joachimiak, A.; Goodman, S.L.; Arnaout, M.A. Crystal structure of the extracellular segment of integrin alpha Vbeta3. Science 2001, 294, 339–345.
  21. Luo, B.H.; Carman, C.V.; Springer, T.A. Structural basis of integrin regulation and signaling. Annu. Rev. Immunol. 2007, 25, 619–647.
  22. Bachmann, M.; Kukkurainen, S.; Hytonen, V.P.; Wehrle-Haller, B. Cell Adhesion by Integrins. Physiol. Rev. 2019, 99, 1655–1699.
  23. Xiong, J.P.; Goodman, S.L.; Arnaout, M.A. Purification, analysis, and crystal structure of integrins. Methods Enzymol. 2007, 426, 307–336.
  24. Srichai, M.B.; Zent, R. Integrin Structure and Function. In Cell-Extracellular Matrix Interactions in Cancer; Pozzi, A., Ed.; Springer: New York, NY, USA, 2009; pp. 19–41.
  25. Liddington, R.C. Structural aspects of integrins. Adv. Exp. Med. Biol. 2014, 819, 111–126.
  26. Ley, K.; Laudanna, C.; Cybulsky, M.I.; Nourshargh, S. Getting to the site of inflammation: The leukocyte adhesion cascade updated. Nat. Rev. Immunol. 2007, 7, 678–689.
  27. Xie, C.; Zhu, J.; Chen, X.; Mi, L.; Nishida, N.; Springer, T.A. Structure of an integrin with an alphaI domain, complement receptor type 4. EMBO J. 2010, 29, 666–679.
  28. Huang, J.; Li, X.; Shi, X.; Zhu, M.; Wang, J.; Huang, S.; Huang, X.; Wang, H.; Li, L.; Deng, H.; et al. Platelet integrin alphaIIbbeta3: Signal transduction, regulation, and its therapeutic targeting. J. Hematol. Oncol. 2019, 12, 26.
  29. Xiong, J.P.; Mahalingham, B.; Alonso, J.L.; Borrelli, L.A.; Rui, X.; Anand, S.; Hyman, B.T.; Rysiok, T.; Muller-Pompalla, D.; Goodman, S.L.; et al. Crystal structure of the complete integrin alphaVbeta3 ectodomain plus an alpha/beta transmembrane fragment. J. Cell Biol. 2009, 186, 589–600.
  30. Choi, W.S.; Rice, W.J.; Stokes, D.L.; Coller, B.S. Three-dimensional reconstruction of intact human integrin alphaIIbbeta3: New implications for activation-dependent ligand binding. Blood 2013, 122, 4165–4171.
  31. Campbell, I.D.; Humphries, M.J. Integrin structure, activation, and interactions. Cold Spring Harb. Perspect. Biol. 2011, 3, a004994.
  32. Zhu, J.; Zhu, J.; Springer, T.A. Complete integrin headpiece opening in eight steps. J. Cell Biol. 2013, 201, 1053–1068.
  33. Li, J.; Su, Y.; Xia, W.; Qin, Y.; Humphries, M.J.; Vestweber, D.; Cabanas, C.; Lu, C.; Springer, T.A. Conformational equilibria and intrinsic affinities define integrin activation. EMBO J. 2017, 36, 629–645.
  34. Springer, T.A.; Dustin, M.L. Integrin inside-out signaling and the immunological synapse. Curr. Opin. Cell Biol. 2012, 24, 107–115.
  35. Hughes, P.E.; Diaz-Gonzalez, F.; Leong, L.; Wu, C.; McDonald, J.A.; Shattil, S.J.; Ginsberg, M.H. Breaking the integrin hinge. A defined structural constraint regulates integrin signaling. J. Biol. Chem. 1996, 271, 6571–6574.
  36. Kim, C.; Ye, F.; Hu, X.; Ginsberg, M.H. Talin activates integrins by altering the topology of the beta transmembrane domain. J. Cell Biol. 2012, 197, 605–611.
  37. Shimaoka, M.; Takagi, J.; Springer, T.A. Conformational regulation of integrin structure and function. Annu. Rev. Biophys. Biomol. Struct. 2002, 31, 485–516.
  38. Changede, R.; Xu, X.; Margadant, F.; Sheetz, M.P. Nascent Integrin Adhesions Form on All Matrix Rigidities after Integrin Activation. Dev. Cell 2015, 35, 614–621.
  39. Shimaoka, M.; Xiao, T.; Liu, J.H.; Yang, Y.; Dong, Y.; Jun, C.D.; McCormack, A.; Zhang, R.; Joachimiak, A.; Takagi, J.; et al. Structures of the alpha L I domain and its complex with ICAM-1 reveal a shape-shifting pathway for integrin regulation. Cell 2003, 112, 99–111.
  40. Emsley, J.; Knight, C.G.; Farndale, R.W.; Barnes, M.J.; Liddington, R.C. Structural basis of collagen recognition by integrin alpha2beta1. Cell 2000, 101, 47–56.
  41. Sen, M.; Yuki, K.; Springer, T.A. An internal ligand-bound, metastable state of a leukocyte integrin, alphaXbeta2. J. Cell Biol. 2013, 203, 629–642.
  42. Bajic, G.; Yatime, L.; Sim, R.B.; Vorup-Jensen, T.; Andersen, G.R. Structural insight on the recognition of surface-bound opsonins by the integrin I domain of complement receptor 3. Proc. Natl. Acad. Sci. USA 2013, 110, 16426–16431.
  43. Potin, D.; Launay, M.; Monatlik, F.; Malabre, P.; Fabreguettes, M.; Fouquet, A.; Maillet, M.; Nicolai, E.; Dorgeret, L.; Chevallier, F.; et al. Discovery and development of 5-non-7-yl-methyl]-3-thiophenecarboxylic acid (BMS-587101)--a small molecule antagonist of leukocyte function associated antigen-1. J. Med. Chem. 2006, 49, 6946–6949.
  44. Tuckwell, D.S.; Brass, A.; Humphries, M.J. Homology modelling of integrin EF-hands. Evidence for widespread use of a conserved cation-binding site. Biochem. J. 1992, 285 Pt 1, 325–331.
  45. Shimaoka, M.; Shifman, J.M.; Jing, H.; Takagi, J.; Mayo, S.L.; Springer, T.A. Computational design of an integrin I domain stabilized in the open high affinity conformation. Nat. Struct. Biol. 2000, 7, 674–678.
  46. You, T.J.; Maxwell, D.S.; Kogan, T.P.; Chen, Q.; Li, J.; Kassir, J.; Holland, G.W.; Dixon, R.A. A 3D structure model of integrin alpha 4 beta 1 complex: I. Construction of a homology model of beta 1 and ligand binding analysis. Biophys. J. 2002, 82, 447–457.
  47. Lee, J.O.; Rieu, P.; Arnaout, M.A.; Liddington, R. Crystal structure of the A domain from the alpha subunit of integrin CR3 (CD11b/CD18). Cell 1995, 80, 631–638.
  48. Marinelli, L.; Gottschalk, K.E.; Meyer, A.; Novellino, E.; Kessler, H. Human integrin alphavbeta5: Homology modeling and ligand binding. J. Med. Chem. 2004, 47, 4166–4177.
  49. Filizola, M.; Hassan, S.A.; Artoni, A.; Coller, B.S.; Weinstein, H. Mechanistic insights from a refined three-dimensional model of integrin alphaIIbbeta3. J. Biol. Chem. 2004, 279, 24624–24630.
  50. Xiong, J.P.; Stehle, T.; Zhang, R.; Joachimiak, A.; Frech, M.; Goodman, S.L.; Arnaout, M.A. Crystal structure of the extracellular segment of integrin alpha Vbeta3 in complex with an Arg-Gly-Asp ligand. Science 2002, 296, 151–155.
  51. Shi, M.; Foo, S.Y.; Tan, S.M.; Mitchell, E.P.; Law, S.K.; Lescar, J. A structural hypothesis for the transition between bent and extended conformations of the leukocyte beta2 integrins. J. Biol. Chem. 2007, 282, 30198–30206.
  52. Gottschalk, K.E. A coiled-coil structure of the alphaIIbbeta3 integrin transmembrane and cytoplasmic domains in its resting state. Structure 2005, 13, 703–712.
  53. Vinogradova, O.; Vaynberg, J.; Kong, X.; Haas, T.A.; Plow, E.F.; Qin, J. Membrane-mediated structural transitions at the cytoplasmic face during integrin activation. Proc. Natl. Acad. Sci. USA 2004, 101, 4094–4099.
  54. Vinogradova, O.; Haas, T.; Plow, E.F.; Qin, J. A structural basis for integrin activation by the cytoplasmic tail of the alpha IIb-subunit. Proc. Natl. Acad. Sci. USA 2000, 97, 1450–1455.
  55. Ulmer, T.S.; Yaspan, B.; Ginsberg, M.H.; Campbell, I.D. NMR analysis of structure and dynamics of the cytosolic tails of integrin alpha IIb beta 3 in aqueous solution. Biochemistry 2001, 40, 7498–7508.
  56. Rosano, C.; Rocco, M. Solution properties of full-length integrin alpha(IIb)beta3 refined models suggest environment-dependent induction of alternative bent /extended resting states. FEBS J. 2010, 277, 3190–3202.
  57. Zhu, J.; Luo, B.H.; Xiao, T.; Zhang, C.; Nishida, N.; Springer, T.A. Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces. Mol. Cell 2008, 32, 849–861.
  58. Lau, T.L.; Kim, C.; Ginsberg, M.H.; Ulmer, T.S. The structure of the integrin alphaIIbbeta3 transmembrane complex explains integrin transmembrane signalling. EMBO J. 2009, 28, 1351–1361.
  59. Kozmon, S. Homology model of alfa4beta1 integriins. 2022; unpublished results.
  60. Jumper, J.; Evans, R.; Pritzel, A.; Green, T.; Figurnov, M.; Ronneberger, O.; Tunyasuvunakool, K.; Bates, R.; Zidek, A.; Potapenko, A.; et al. Highly accurate protein structure prediction with AlphaFold. Nature 2021, 596, 583–589.
  61. Humphries, J.D.; Byron, A.; Humphries, M.J. Integrin ligands at a glance. J. Cell Sci. 2006, 119, 3901–3903.
  62. Park, E.J.; Myint, P.K.; Ito, A.; Appiah, M.G.; Darkwah, S.; Kawamoto, E.; Shimaoka, M. Integrin-Ligand Interactions in Inflammation, Cancer, and Metabolic Disease: Insights Into the Multifaceted Roles of an Emerging Ligand Irisin. Front. Cell Dev. Biol. 2020, 8, 588066.
  63. Slack, R.J.; Macdonald, S.J.F.; Roper, J.A.; Jenkins, R.G.; Hatley, R.J.D. Emerging therapeutic opportunities for integrin inhibitors. Nat. Rev. Drug Discov. 2022, 21, 60–78.
  64. Ley, K.; Rivera-Nieves, J.; Sandborn, W.J.; Shattil, S. Integrin-based therapeutics: Biological basis, clinical use and new drugs. Nat. Rev. Drug Discov. 2016, 15, 173–183.
  65. Mezu-Ndubuisi, O.J.; Maheshwari, A. The role of integrins in inflammation and angiogenesis. Pediatr. Res. 2021, 89, 1619–1626.
  66. Kourtzelis, I.; Mitroulis, I.; von Renesse, J.; Hajishengallis, G.; Chavakis, T. From leukocyte recruitment to resolution of inflammation: The cardinal role of integrins. J. Leukoc. Biol. 2017, 102, 677–683.
  67. Rose, D.M.; Alon, R.; Ginsberg, M.H. Integrin modulation and signaling in leukocyte adhesion and migration. Immunol. Rev. 2007, 218, 126–134.
  68. Abram, C.L.; Lowell, C.A. Leukocyte adhesion deficiency syndrome: A controversy solved. Immunol. Cell Biol. 2009, 87, 440–442.
  69. Nair, S.; Ghosh, K.; Kulkarni, B.; Shetty, S.; Mohanty, D. Glanzmann’s thrombasthenia: Updated. Platelets 2002, 13, 387–393.
  70. Bardhan, A.; Bruckner-Tuderman, L.; Chapple, I.L.C.; Fine, J.D.; Harper, N.; Has, C.; Magin, T.M.; Marinkovich, M.P.; Marshall, J.F.; McGrath, J.A.; et al. Epidermolysis bullosa. Nat. Rev. Dis. Prim. 2020, 6, 78.
  71. Greenlee-Wacker, M.C. Clearance of apoptotic neutrophils and resolution of inflammation. Immunol. Rev. 2016, 273, 357–370.
  72. Dotan, I.; Allez, M.; Danese, S.; Keir, M.; Tole, S.; McBride, J. The role of integrins in the pathogenesis of inflammatory bowel disease: Approved and investigational anti-integrin therapies. Med. Res. Rev. 2020, 40, 245–262.
  73. de Souza, H.S.; Fiocchi, C. Immunopathogenesis of IBD: Current state of the art. Nat. Rev. Gastroenterol. Hepatol. 2016, 13, 13–27.
  74. Orr, C.; Vieira-Sousa, E.; Boyle, D.L.; Buch, M.H.; Buckley, C.D.; Canete, J.D.; Catrina, A.I.; Choy, E.H.S.; Emery, P.; Fearon, U.; et al. Synovial tissue research: A state-of-the-art review. Nat. Rev. Rheumatol. 2017, 13, 463–475.
  75. Jang, S.; Kwon, E.J.; Lee, J.J. Rheumatoid Arthritis: Pathogenic Roles of Diverse Immune Cells. Int. J. Mol. Sci. 2022, 23, 905.
  76. Lowin, T.; Straub, R.H. Integrins and their ligands in rheumatoid arthritis. Arthritis Res. Ther. 2011, 13, 244.
  77. Wollheim, F.A. Predictors of joint damage in rheumatoid arthritis. APMIS 1996, 104, 81–93.
  78. Conroy, K.P.; Kitto, L.J.; Henderson, N.C. alphav integrins: Key regulators of tissue fibrosis. Cell Tissue Res. 2016, 365, 511–519.
  79. Herrera, J.; Henke, C.A.; Bitterman, P.B. Extracellular matrix as a driver of progressive fibrosis. J. Clin. Investig. 2018, 128, 45–53.
  80. Henderson, N.C.; Rieder, F.; Wynn, T.A. Fibrosis: From mechanisms to medicines. Nature 2020, 587, 555–566.
  81. Sciurba, J.C.; Gieseck, R.L.; Jiwrajka, N.; White, S.D.; Karmele, E.P.; Redes, J.; Vannella, K.M.; Henderson, N.C.; Wynn, T.A.; Hart, K.M. Fibroblast-specific integrin-alpha V differentially regulates type 17 and type 2 driven inflammation and fibrosis. J. Pathol. 2019, 248, 16–29.
  82. Finney, A.C.; Stokes, K.Y.; Pattillo, C.B.; Orr, A.W. Integrin signaling in atherosclerosis. Cell. Mol. Life Sci. 2017, 74, 2263–2282.
  83. Kong, P.; Cui, Z.Y.; Huang, X.F.; Zhang, D.D.; Guo, R.J.; Han, M. Inflammation and atherosclerosis: Signaling pathways and therapeutic intervention. Signal Transduct. Target. Ther. 2022, 7, 131.
  84. Zhi, K.; Li, M.; Zhang, X.; Gao, Z.; Bai, J.; Wu, Y.; Zhou, S.; Li, M.; Qu, L. alpha4beta7 Integrin (LPAM-1) is upregulated at atherosclerotic lesions and is involved in atherosclerosis progression. Cell. Physiol. Biochem. 2014, 33, 1876–1887.
  85. Oksala, N.; Parssinen, J.; Seppala, I.; Klopp, N.; Illig, T.; Laaksonen, R.; Levula, M.; Raitoharju, E.; Kholova, I.; Sioris, T.; et al. Kindlin 3 (FERMT3) is associated with unstable atherosclerotic plaques, anti-inflammatory type II macrophages and upregulation of beta-2 integrins in all major arterial beds. Atherosclerosis 2015, 242, 145–154.
  86. Wu, H.; Gower, R.M.; Wang, H.; Perrard, X.Y.; Ma, R.; Bullard, D.C.; Burns, A.R.; Paul, A.; Smith, C.W.; Simon, S.I.; et al. Functional role of CD11c+ monocytes in atherogenesis associated with hypercholesterolemia. Circulation 2009, 119, 2708–2717.
  87. Chen, J.; Green, J.; Yurdagul, A., Jr.; Albert, P.; McInnis, M.C.; Orr, A.W. alphavbeta3 Integrins Mediate Flow-Induced NF-kappaB Activation, Proinflammatory Gene Expression, and Early Atherogenic Inflammation. Am. J. Pathol. 2015, 185, 2575–2589.
  88. Yurdagul, A., Jr.; Green, J.; Albert, P.; McInnis, M.C.; Mazar, A.P.; Orr, A.W. alpha5beta1 integrin signaling mediates oxidized low-density lipoprotein-induced inflammation and early atherosclerosis. Arter. Thromb. Vasc. Biol. 2014, 34, 1362–1373.
  89. Mrugacz, M.; Bryl, A.; Falkowski, M.; Zorena, K. Integrins: An Important Link between Angiogenesis, Inflammation and Eye Diseases. Cells 2021, 10, 1703.
  90. Wu, W.; Hutcheon, A.E.K.; Sriram, S.; Tran, J.A.; Zieske, J.D. Initiation of fibrosis in the integrin Alphavbeta6 knockout mice. Exp. Eye Res. 2019, 180, 23–28.
  91. Weller, J.M.; Zenkel, M.; Schlotzer-Schrehardt, U.; Bachmann, B.O.; Tourtas, T.; Kruse, F.E. Extracellular matrix alterations in late-onset Fuchs’ corneal dystrophy. Investig. Ophthalmol. Vis. Sci. 2014, 55, 3700–3708.
  92. Storm, R.J.; Persson, B.D.; Skalman, L.N.; Frangsmyr, L.; Lindstrom, M.; Rankin, G.; Lundmark, R.; Domellof, F.P.; Arnberg, N. Human Adenovirus Type 37 Uses alphaVbeta1 and alpha3beta1 Integrins for Infection of Human Corneal Cells. J. Virol. 2017, 91, e02019-16.
  93. Wang, A.G.; Yen, M.Y.; Hsu, W.M.; Fann, M.J. Induction of vitronectin and integrin alphav in the retina after optic nerve injury. Mol. Vis. 2006, 12, 76–84.
  94. Labelle, M.; Hynes, R.O. The initial hours of metastasis: The importance of cooperative host-tumor cell interactions during hematogenous dissemination. Cancer Discov. 2012, 2, 1091–1099.
  95. Chambers, A.F.; Groom, A.C.; MacDonald, I.C. Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer 2002, 2, 563–572.
  96. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell 2011, 144, 646–674.
  97. Obenauf, A.C.; Massague, J. Surviving at a Distance: Organ-Specific Metastasis. Trends Cancer 2015, 1, 76–91.
  98. Hamidi, H.; Ivaska, J. Every step of the way: Integrins in cancer progression and metastasis. Nat. Rev. Cancer 2018, 18, 533–548.
  99. Desgrosellier, J.S.; Cheresh, D.A. Integrins in cancer: Biological implications and therapeutic opportunities. Nat. Rev. Cancer 2010, 10, 9–22.
  100. Cooper, J.; Giancotti, F.G. Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance. Cancer Cell 2019, 35, 347–367.
  101. Seguin, L.; Desgrosellier, J.S.; Weis, S.M.; Cheresh, D.A. integrins and cancer: Regulators of cancer stemness, metastasis, and drug resistance. Trends Cell Biol. 2015, 25, 234–240.
  102. Nieberler, M.; Reuning, U.; Reichart, F.; Notni, J.; Wester, H.J.; Schwaiger, M.; Weinmuller, M.; Rader, A.; Steiger, K.; Kessler, H. Exploring the Role of RGD-Recognizing Integrins in Cancer. Cancers 2017, 9, 116.
  103. Hamidi, H.; Pietila, M.; Ivaska, J. The complexity of integrins in cancer and new scopes for therapeutic targeting. Br. J. Cancer 2016, 115, 1017–1023.
  104. Seguin, L.; Kato, S.; Franovic, A.; Camargo, M.F.; Lesperance, J.; Elliott, K.C.; Yebra, M.; Mielgo, A.; Lowy, A.M.; Husain, H.; et al. An integrin beta(3)-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. Nat. Cell Biol. 2014, 16, 457–468.
  105. White, D.E.; Kurpios, N.A.; Zuo, D.; Hassell, J.A.; Blaess, S.; Mueller, U.; Muller, W.J. Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. Cancer Cell 2004, 6, 159–170.
  106. Ramirez, N.E.; Zhang, Z.; Madamanchi, A.; Boyd, K.L.; O’Rear, L.D.; Nashabi, A.; Li, Z.; Dupont, W.D.; Zijlstra, A.; Zutter, M.M. The alpha(2)beta(1) integrin is a metastasis suppressor in mouse models and human cancer. J. Clin. Investig. 2011, 121, 226–237.
  107. Kannan, N.; Nguyen, L.V.; Eaves, C.J. Integrin beta3 links therapy resistance and cancer stem cell properties. Nat. Cell Biol. 2014, 16, 397–399.
  108. Laubli, H.; Borsig, L. Selectins promote tumor metastasis. Semin. Cancer Biol. 2010, 20, 169–177.
  109. Wirtz, D.; Konstantopoulos, K.; Searson, P.C. The physics of cancer: The role of physical interactions and mechanical forces in metastasis. Nat. Rev. Cancer 2011, 11, 512–522.
  110. Ramovs, V.; Te Molder, L.; Sonnenberg, A. The opposing roles of laminin-binding integrins in cancer. Matrix Biol. 2017, 57–58, 213–243.
  111. Ramovs, V.; Secades, P.; Song, J.Y.; Thijssen, B.; Kreft, M.; Sonnenberg, A. Absence of integrin alpha3beta1 promotes the progression of HER2-driven breast cancer in vivo. Breast Cancer Res. 2019, 21, 63.
  112. Zhang, Y.L.; Xing, X.; Cai, L.B.; Zhu, L.; Yang, X.M.; Wang, Y.H.; Yang, Q.; Nie, H.Z.; Zhang, Z.G.; Li, J.; et al. Integrin alpha9 Suppresses Hepatocellular Carcinoma Metastasis by Rho GTPase Signaling. J. Immunol. Res. 2018, 2018, 4602570.
  113. Wang, Z.; Li, Y.; Xiao, Y.; Lin, H.P.; Yang, P.; Humphries, B.; Gao, T.; Yang, C. Integrin alpha9 depletion promotes beta-catenin degradation to suppress triple-negative breast cancer tumor growth and metastasis. Int. J. Cancer 2019, 145, 2767–2780.
  114. Attieh, Y.; Clark, A.G.; Grass, C.; Richon, S.; Pocard, M.; Mariani, P.; Elkhatib, N.; Betz, T.; Gurchenkov, B.; Vignjevic, D.M. Cancer-associated fibroblasts lead tumor invasion through integrin-beta3-dependent fibronectin assembly. J. Cell Biol. 2017, 216, 3509–3520.
  115. Erdogan, B.; Ao, M.; White, L.M.; Means, A.L.; Brewer, B.M.; Yang, L.; Washington, M.K.; Shi, C.; Franco, O.E.; Weaver, A.M.; et al. Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin. J. Cell Biol. 2017, 216, 3799–3816.
  116. Peng, C.; Zou, X.; Xia, W.; Gao, H.; Li, Z.; Liu, N.; Xu, Z.; Gao, C.; He, Z.; Niu, W.; et al. Integrin alphavbeta6 plays a bi-directional regulation role between colon cancer cells and cancer-associated fibroblasts. Biosci. Rep. 2018, 38, BSR20180243.
  117. Ota, D.; Kanayama, M.; Matsui, Y.; Ito, K.; Maeda, N.; Kutomi, G.; Hirata, K.; Torigoe, T.; Sato, N.; Takaoka, A.; et al. Tumor-alpha9beta1 integrin-mediated signaling induces breast cancer growth and lymphatic metastasis via the recruitment of cancer-associated fibroblasts. J. Mol. Med. 2014, 92, 1271–1281.
  118. Foubert, P.; Varner, J.A. Integrins in tumor angiogenesis and lymphangiogenesis. Methods Mol. Biol. 2012, 757, 471–486.
  119. Eke, I.; Cordes, N. Focal adhesion signaling and therapy resistance in cancer. Semin. Cancer Biol. 2015, 31, 65–75.
  120. Kim, Y.J.; Jung, K.; Baek, D.S.; Hong, S.S.; Kim, Y.S. Co-targeting of EGF receptor and neuropilin-1 overcomes cetuximab resistance in pancreatic ductal adenocarcinoma with integrin beta1-driven Src-Akt bypass signaling. Oncogene 2017, 36, 2543–2552.
  121. Yang, D.; Tang, Y.; Fu, H.; Xu, J.; Hu, Z.; Zhang, Y.; Cai, Q. Integrin beta1 promotes gemcitabine resistance in pancreatic cancer through Cdc42 activation of PI3K p110beta signaling. Biochem. Biophys. Res. Commun. 2018, 505, 215–221.
  122. Stewart, P.L.; Nemerow, G.R. Cell integrins: Commonly used receptors for diverse viral pathogens. Trends Microbiol. 2007, 15, 500–507.
  123. Scibelli, A.; Roperto, S.; Manna, L.; Pavone, L.M.; Tafuri, S.; Della Morte, R.; Staiano, N. Engagement of integrins as a cellular route of invasion by bacterial pathogens. Vet. J. 2007, 173, 482–491.
  124. Hussein, H.A.; Walker, L.R.; Abdel-Raouf, U.M.; Desouky, S.A.; Montasser, A.K.; Akula, S.M. Beyond RGD: Virus interactions with integrins. Arch. Virol. 2015, 160, 2669–2681.
  125. Hauck, C.R.; Borisova, M.; Muenzner, P. Exploitation of integrin function by pathogenic microbes. Curr. Opin. Cell Biol. 2012, 24, 637–644.
  126. Chiu, C.Y.; Mathias, P.; Nemerow, G.R.; Stewart, P.L. Structure of adenovirus complexed with its internalization receptor, alphavbeta5 integrin. J. Virol. 1999, 73, 6759–6768.
  127. Philpott, N.J.; Nociari, M.; Elkon, K.B.; Falck-Pedersen, E. Adenovirus-induced maturation of dendritic cells through a PI3 kinase-mediated TNF-alpha induction pathway. Proc. Natl. Acad. Sci. USA 2004, 101, 6200–6205.
  128. Akula, S.M.; Pramod, N.P.; Wang, F.Z.; Chandran, B. Integrin alpha3beta1 (CD 49c/29) is a cellular receptor for Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) entry into the target cells. Cell 2002, 108, 407–419.
  129. Gavrilovskaya, I.N.; Brown, E.J.; Ginsberg, M.H.; Mackow, E.R. Cellular entry of hantaviruses which cause hemorrhagic fever with renal syndrome is mediated by beta3 integrins. J. Virol. 1999, 73, 3951–3959.
  130. Geimonen, E.; Neff, S.; Raymond, T.; Kocer, S.S.; Gavrilovskaya, I.N.; Mackow, E.R. Pathogenic and nonpathogenic hantaviruses differentially regulate endothelial cell responses. Proc. Natl. Acad. Sci. USA 2002, 99, 13837–13842.
  131. Shakeel, S.; Seitsonen, J.J.; Kajander, T.; Laurinmaki, P.; Hyypia, T.; Susi, P.; Butcher, S.J. Structural and functional analysis of coxsackievirus A9 integrin alphavbeta6 binding and uncoating. J. Virol. 2013, 87, 3943–3951.
  132. Barillari, G.; Sgadari, C.; Fiorelli, V.; Samaniego, F.; Colombini, S.; Manzari, V.; Modesti, A.; Nair, B.C.; Cafaro, A.; Sturzl, M.; et al. The Tat protein of human immunodeficiency virus type-1 promotes vascular cell growth and locomotion by engaging the alpha5beta1 and alphavbeta3 integrins and by mobilizing sequestered basic fibroblast growth factor. Blood 1999, 94, 663–672.
  133. Arthos, J.; Cicala, C.; Martinelli, E.; Macleod, K.; Van Ryk, D.; Wei, D.; Xiao, Z.; Veenstra, T.D.; Conrad, T.P.; Lempicki, R.A.; et al. HIV-1 envelope protein binds to and signals through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells. Nat. Immunol. 2008, 9, 301–309.
  134. Barillari, G.; Gendelman, R.; Gallo, R.C.; Ensoli, B. The Tat protein of human immunodeficiency virus type 1, a growth factor for AIDS Kaposi sarcoma and cytokine-activated vascular cells, induces adhesion of the same cell types by using integrin receptors recognizing the RGD amino acid sequence. Proc. Natl. Acad. Sci. USA 1993, 90, 7941–7945.
  135. Schornberg, K.L.; Shoemaker, C.J.; Dube, D.; Abshire, M.Y.; Delos, S.E.; Bouton, A.H.; White, J.M. Alpha5beta1-integrin controls ebolavirus entry by regulating endosomal cathepsins. Proc. Natl. Acad. Sci. USA 2009, 106, 8003–8008.
  136. Wang, S.; Zhang, Q.; Tiwari, S.K.; Lichinchi, G.; Yau, E.H.; Hui, H.; Li, W.; Furnari, F.; Rana, T.M. Integrin alphavbeta5 Internalizes Zika Virus during Neural Stem Cells Infection and Provides a Promising Target for Antiviral Therapy. Cell. Rep. 2020, 30, 969–983.
  137. Guerrero, C.A.; Mendez, E.; Zarate, S.; Isa, P.; Lopez, S.; Arias, C.F. Integrin alpha(v)beta(3) mediates rotavirus cell entry. Proc. Natl. Acad. Sci. USA 2000, 97, 14644–14649.
  138. Kotecha, A.; Wang, Q.; Dong, X.; Ilca, S.L.; Ondiviela, M.; Zihe, R.; Seago, J.; Charleston, B.; Fry, E.E.; Abrescia, N.G.A.; et al. Rules of engagement between alphavbeta6 integrin and foot-and-mouth disease virus. Nat. Commun. 2017, 8, 15408.
  139. Sigrist, C.J.; Bridge, A.; Le Mercier, P. A potential role for integrins in host cell entry by SARS-CoV-2. Antiviral. Res. 2020, 177, 104759.
  140. Carvacho, I.; Piesche, M. RGD-binding integrins and TGF-beta in SARS-CoV-2 infections-novel targets to treat COVID-19 patients? Clin. Transl. Immunol. 2021, 10, e1240.
  141. La Linn, M.; Eble, J.A.; Lubken, C.; Slade, R.W.; Heino, J.; Davies, J.; Suhrbier, A. An arthritogenic alphavirus uses the alpha1beta1 integrin collagen receptor. Virology 2005, 336, 229–239.
  142. Graham, K.L.; Fleming, F.E.; Halasz, P.; Hewish, M.J.; Nagesha, H.S.; Holmes, I.H.; Takada, Y.; Coulson, B.S. Rotaviruses interact with alpha4beta7 and alpha4beta1 integrins by binding the same integrin domains as natural ligands. J. Gen. Virol. 2005, 86, 3397–3408.
  143. Graham, K.L.; Halasz, P.; Tan, Y.; Hewish, M.J.; Takada, Y.; Mackow, E.R.; Robinson, M.K.; Coulson, B.S. Integrin-using rotaviruses bind alpha2beta1 integrin alpha2 I domain via VP4 DGE sequence and recognize alphaXbeta2 and alphaVbeta3 by using VP7 during cell entry. J. Virol. 2003, 77, 9969–9978.
  144. Graham, K.L.; Zeng, W.; Takada, Y.; Jackson, D.C.; Coulson, B.S. Effects on rotavirus cell binding and infection of monomeric and polymeric peptides containing alpha2beta1 and alphaxbeta2 integrin ligand sequences. J. Virol. 2004, 78, 11786–11797.
  145. Bergelson, J.M.; Shepley, M.P.; Chan, B.M.; Hemler, M.E.; Finberg, R.W. Identification of the integrin VLA-2 as a receptor for echovirus 1. Science 1992, 255, 1718–1720.
  146. Hamzaoui, N.; Kerneis, S.; Caliot, E.; Pringault, E. Expression and distribution of beta1 integrins in in vitro-induced M cells: Implications for Yersinia adhesion to Peyer’s patch epithelium. Cell. Microbiol. 2004, 6, 817–828.
  147. Kwok, T.; Zabler, D.; Urman, S.; Rohde, M.; Hartig, R.; Wessler, S.; Misselwitz, R.; Berger, J.; Sewald, N.; Konig, W.; et al. Helicobacter exploits integrin for type IV secretion and kinase activation. Nature 2007, 449, 862–866.
  148. Coburn, J.; Cugini, C. Targeted mutation of the outer membrane protein P66 disrupts attachment of the Lyme disease agent, Borrelia burgdorferi, to integrin alphavbeta3. Proc. Natl. Acad. Sci. USA 2003, 100, 7301–7306.
  149. Joh, D.; Wann, E.R.; Kreikemeyer, B.; Speziale, P.; Hook, M. Role of fibronectin-binding MSCRAMMs in bacterial adherence and entry into mammalian cells. Matrix Biol. 1999, 18, 211–223.
  150. Fowler, T.; Wann, E.R.; Joh, D.; Johansson, S.; Foster, T.J.; Hook, M. Cellular invasion by Staphylococcus aureus involves a fibronectin bridge between the bacterial fibronectin-binding MSCRAMMs and host cell beta1 integrins. Eur. J. Cell Biol. 2000, 79, 672–679.
  151. Cue, D.; Southern, S.O.; Southern, P.J.; Prabhakar, J.; Lorelli, W.; Smallheer, J.M.; Mousa, S.A.; Cleary, P.P. A nonpeptide integrin antagonist can inhibit epithelial cell ingestion of Streptococcus pyogenes by blocking formation of integrin alpha 5beta 1-fibronectin-M1 protein complexes. Proc. Natl. Acad. Sci. USA 2000, 97, 2858–2863.
  152. Yilmaz, O.; Watanabe, K.; Lamont, R.J. Involvement of integrins in fimbriae-mediated binding and invasion by Porphyromonas gingivalis. Cell. Microbiol. 2002, 4, 305–314.
  153. Leroy-Dudal, J.; Gagniere, H.; Cossard, E.; Carreiras, F.; Di Martino, P. Role of alphavbeta5 integrins and vitronectin in Pseudomonas aeruginosa PAK interaction with A549 respiratory cells. Microbes Infect. 2004, 6, 875–881.
  154. Dehio, M.; Gomez-Duarte, O.G.; Dehio, C.; Meyer, T.F. Vitronectin-dependent invasion of epithelial cells by Neisseria gonorrhoeae involves alpha(v) integrin receptors. FEBS Lett. 1998, 424, 84–88.
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