Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Integrin Alpha V (ITGAV)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_619


Historical Background

The term “integrin” was coined by R.O. Hynes in 1986 to describe a family of adhesion proteins which integrate the cytoskeleton with the extracellular matrix and external stimuli. These integrins are composed of alpha and beta subunits to form a complete signaling molecule. The αv subunit forms a complete integrin complex through heterodimerization with one of five β subunit binding partners: beta 1 (β1), beta 3 (β3), beta 5 (β5), beta 6 (β6), or beta 8 (β8). The first αv integrin characterized was αvβ3, which was originally termed the “vitronectin receptor,” as it bound to plasma-derived vitronectin. The αvβ3 integrin was purified from plasma in 1985 by R. Pytela and then cloned and sequenced in 1986 by S. Suzuki. The name “vitronectin receptor” was quickly proven to be a misnomer as αvβ3 displays highly promiscuous binding (Table 1). The other αv integrins were then identified over the next decade, and their binding to various extracellular ligands (Table 1), expression sites, and physiologic and pathologic functions are still being characterized.
Integrin Alpha V (ITGAV), Table 1

The alpha v integrins binding a variety of extracellular ligands

αv Integrin

Original name

CD designation

ECM ligands

Soluble ligands

Miscellaneous ligands




FN, VN, OPN, LN, denatured collagens


CD171, RGD


Platelet IIIa, VNR


FN, VN, OPN, LN, SPARC, periostin, canstatin, vWF, tenascin, BSP, COMP, tumstatin, denatured collagen type I

LAP-TGFβ, FGN, TSP, Cyr61, MMP-2, MMP-9, FGF-2, FGF-1, urokinase, plasmin, prothrombin

CD171, ADAM, fibrillin, PECAM-1, MGF-E8, ICAM-4, urokinase receptor, angiostatin, cardiotoxin, Del-1, RGD




FN, VN, OPN, SPARC, periostin, canstatin, BSP

LAP-TGFβ, TSP, Cyr61

Del-1, CCN3, MGF-E8, RGD




FN, VN, OPN, tenascin








— Represents not available. ADAM disintegrin and metalloproteinase domain-containing proteins, FGN fibrinogen, FGF fibroblast growth factor, FN fibronectin, ICAM intracellular adhesion molecule, LAP-TGFβ TGFβ latency-associated peptide, LN laminin, MGF-E8 milk fat globule-EGF factor 8 protein, MMP matrix metalloproteinase, OPN osteopontin, PECAM platelet endothelial cell adhesion molecule, RGD arginine-glycine-aspartic acid, TSP thrombospondin, VN vitronectin, VNR vitronectin receptor.

Expression Sites

Integrin αv is essential for embryonic and perinatal development, with a complete knockout being lethal. Approximately 80% of integrin αv-null mice die between embryonic day (E) 10 and E12 due to placental defects, while the remaining 20% die perinatally from massive hemorrhages or cleft palates. Using conditional knockouts, the αv integrin was proven to be important for the development of cardiomyocytes, eye basal epithelium, glial cells, sebaceous glands, pancreatic cells, the palate, and limbs (Fig. 1a). In adult tissues, the integrin αv regulates angiogenesis, wound healing, tumorigenesis, bone remodeling, vasculogenesis, inflammation, atherosclerosis, and neurogenesis (Fig. 1b) (Bouvard et al. 2001). The role of αv integrin in these tissues is based on its ability to switch between active and inactive conformations, resulting in the activation of signaling cascades.
Integrin Alpha V (ITGAV), Fig. 1

Major expression sites of integrin alpha v. (a) Integrin alpha v is expressed in the heart, eye, brain, pancreas, palate, muscles, digestive tract, and limbs during development. (b) In the adult, integrin alpha v is located on blood vessels, cornea (top left inset), odontoblasts, pancreas, skin, central nervous system; in the bone (on osteoblasts and osteoclasts) (bottom right inset); and in the blood (on the endothelium, monocytes, macrophages, T cells, and platelets) (top right inset) (Illustration by David Schumick, BS, CMI. Reprinted with the permission of the Cleveland Clinic Center for Medical Art & Photography © 2011. All Rights Reserved).

Alpha V Structure

The αv subunit N-terminus contains a β-propeller domain consisting of seven 60-amino-acid repeats which fold to create a seven-bladed β-propeller structure (Fig. 2a). Blades 4–7 of this β-propeller each contain a Ca2+, Mg2+, or Mn2+ cation in the β-hairpin loop, which may interact with the upper leg to maintain rigidity of the integrin. This ligand-binding, seven-bladed head connects to the cell membrane by a ~170-Å “leg.” The leg contains an Ig-like “thigh” domain and two large β-sandwich domains in the “calf” region. The second β-sandwich domain includes a proteolytic cleavage site. In the “knee” region of the αv subunit leg, a metal ion is bound when the integrin is ligated (Mg2+) or unligated (Ca2+). Mn2+ binds to the αv integrin knee region and stimulates activation by imitating ligand binding. This knee region is also the site of a 135° hinge which is in a sharp bend when the integrin is inactive, but is linear in the activated integrin (Fig. 2a) (Arnaout et al. 2005; Byzova et al. 1998; Plow et al. 2000; Qin et al. 2004; Takada et al. 2007). Under non-reducing conditions, the αv subunit has an apparent molecular weight of approximately 150 kDa. However, once reduced, the αv subunit splits into a heavy chain of 120 kDa and a light chain of 25 kDa (Byzova et al. 1998). The αv integrin subunit’s tail associates with the β integrin subunit cytoplasmic tail through a conserved GFFKR motif proximal to the transmembrane region (Fig. 2b) (Takada et al. 2007). The αv integrin complexes bind to a variety of extracellular ligands and cluster with growth factor receptors, tyrosine kinase receptors, and other membrane glycoproteins to mediate intracellular signaling.
Integrin Alpha V (ITGAV), Fig. 2

The structure and activation of integrin alpha v. (a) Ribbon structure of the inactive and active integrin αvβ3, where integrin alpha v is on the left. (b) Domain structure of integrin alpha v and integrin beta 3. Divalent cation binding sites are indicated by small circles on the extracellular domains. The transmembrane and intracellular regions depict binding motifs for several signaling pathways and proteins. The GFFKR domain, which interacts with the beta subunit, is highlighted. (c) Model of integrin activation showing integrin alpha v in an inactive, low-affinity state on the left, at a high-affinity state in the center, and the ligand-bound, activated state on the right. Integrin activation is marked by conformational changes and the transition of the transmembrane domains from crossed to separate (Illustration by David Schumick, BS, CMI. Reprinted with the permission of the Cleveland Clinic Center for Medical Art & Photography © 2011. All Rights Reserved).

Integrin Alpha V Activation and Signaling

Integrin Activation

Integrins on the plasma membrane exist in a low-affinity or high-affinity state (Fig. 2c). The low-affinity, resting state is maintained by interactions between the transmembrane domains and cytoplasmic tails of the αv and β subunits. The state of the αv integrin is partially controlled by divalent cations. Ca2+ association inhibits ligand binding of the αv integrins, while the presence of Mg2+ is required for ligand binding. Association of Mn2+ with the αv integrin imitates ligand binding leading to signaling. Once Mg2+ is associated, an extracellular ligand has bound, and intracellular signaling proteins are present, the integrin rapidly switches to a reversible high-affinity state with signaling between the cytoplasmic tail, the transmembrane domain, and the extracellular ligand binding pocket (Fig. 2c) (Plow et al. 2000; Qin et al. 2004). Conformational changes in the extracellular domains control integrin activation and are necessary for ligand binding. The transmembrane domains contribute to integrin activation through alterations in the interaction of their GxxG dimerization motifs. Separation of the transmembrane domains is proposed to be necessary for integrin activation and signaling (Fig. 2c). The cytoplasmic tails of the integrins have essential roles in regulating the signaling responsible for and in response to integrin activation.

Inside-Out Signaling

Activation signals can be transduced from the cytoplasmic tail to the extracellular domain in response to intracellular activation or in response to mechanical stress, known as inside-out signaling. Conversely, the binding of integrins to soluble or fixed ligands stimulates intracellular cascades, known as outside-in signaling (Arnaout et al. 2005; Qin et al. 2004). In inside-out signaling, integrins are activated by signals from G protein–coupled receptors, by growth factor receptors, or due to mechanical stresses which activate the αv subunit. Integrin activation and intracellular signaling molecules lead to phosphorylation of the β subunit cytoplasmic tail and its interaction with cytoskeletal adaptor proteins. The cytoskeletal adaptor proteins talin and kindlin regulate integrin activation and affinity. The talin head region binds the β subunit cytoplasmic tail and results in increased ligand affinity of the αv integrin (Qin et al. 2004; Takada et al. 2007). In addition, kindlin proteins facilitate talin binding and coordinate control of integrin affinity, cell spreading, and cell adhesion (Plow et al. 2009). The adaptor proteins involved inside-out signaling are described in greater detail below.

Outside-In Signaling

Outside-in integrin signaling results in clustering of integrins and their binding partners on the plasma membrane and the transmission of signals to the cytoplasmic tail leading to cytoskeletal reorganization (Arnaout et al. 2005; Qin et al. 2004). The various proteins involved in membrane clustering and signal transduction are described in detail below. Once in the high-affinity state, integrins cluster together with other cellular receptors to transmit signals. The final activation step is increased avidity of integrins for their ligands. The inactivation of integrins has not been elucidated. Integrins must separate from their ligands and intracellular partners to terminate signaling or for cell migration. Adhesion complexes can disassemble, remodel, or slide by changes in integrin affinity and association. Competitor binding and proteolysis of binding partners and β cytoplasmic tails can also return integrins to their inactive state (Qin et al. 2004).


Integrin activation results in the clustering of integrins with growth factor receptors on the plasma membrane. This interaction facilitates signaling and leads to specificity and synergistic effects on several signaling pathways. The αv integrins modulate transforming growth factor β (TGFβ) by binding to the TGFβ latency–associated peptide (LAP-TGFβ) and by directly binding to the TGFβ receptor (TGFβR). This clustering activates TGFβRII resulting in the recruitment of TGFβRI and stimulation of the TGFβ pathway. Integrin αvβ3 is also involved in another cell-surface complex with urokinase-type plasminogen activator (uPA),  uPA receptor (uPAR), and the low-density lipoprotein receptor. The activation of  uPAR and αvβ3 results in activation of TGFβ, initiating an autocrine activation loop. Thus, these receptors are internalized and recycled after activation to stop the autocrine loop and  uPAR is inactived by the plasminogen activator inhibitor protein. Integrin αvβ3 also interacts with the vascular endothelial growth factor (VEGF) receptors (VEGFR2) on blood vessels to coordinate and amplify angiogenesis (Somanath et al. 2009). VEGF stimulates the formation of a complex between VEGFR2 and αvβ3 on endothelial cells. Further, VEGFR2 phosphorylation is diminished in the absence of αvβ3. In addition, αvβ3 directly interacts with the receptors: platelet-derived growth factor (PDGF) receptor, fibroblast growth factor receptor (FGFR3), insulin receptor substrate (IRS)-1, and Met. The IRS-1 complexes with αvβ3 integrin with Grb2 and phosphoinositide-3 kinase (PI3k). Interactions between vitronectin and hepatocyte growth factor stimulates the clustering of αvβ3 integrin with Met. Integrin αvβ3 also binds insulin-like growth factor-1 (IGF-1) directly and can also cluster and bind to the IGF-1 receptor (IGF1R) (Somanath et al. 2009). This binding triggers IGF1R phosphorylation and stimulation of the Akt and ERK1/2 pathways and enhances cell proliferation. The IGF-1, IGFR1, and αvβ3 integrin were shown to cluster in a ternary complex on the cell surface (Somanath et al. 2009). In addition to integrin αvβ3, integrin αvβ5 has been shown to cross-talk with the epidermal growth factor (EGF) receptor (EGFR). The EGFR and αv integrins cooperate to control cell-cycle progression. EGFR stimulates Raf, while integrins stimulate Ras. These two proteins can then interact to induce ERK signaling (Rüegg and Mariotti 2003).

In addition, activated integrins can associate with lipid membrane rafts and membrane glycoproteins. Membrane rafts are composed of sphingolipids tightly packed with cholesterol and are ringed by flexible phospholipid-rich regions. Integrin αvβ3 localizes to membrane rafts, where it interacts with CD47 (integrin associated protein, IAP), a membrane glycoprotein. CD47 also binds thrombospondin to control the function of αvβ3 in cell migration and spreading. The binding of these two proteins recruits the Gαi subunit and diminishes intracellular cAMP leading to stimulation of G protein signaling (Rüegg and Mariotti 2003). CD47 also activates αvβ3 directly through the Gαi. These two membrane proteins may also act synergistically to effect osteoclast function, endothelial cell attachment, and cancer metastasis. The clustering of αv integrins with membrane proteins results in synergistic effects on signaling and increased binding avidity of intracellular proteins.

Intracellular Binding Partners

Integrins bind several classes of intracellular proteins: structural, adaptor, and signaling proteins, which form focal adhesions. A majority of integrin binding to intracellular partners is through the β-subunit; however, the αv subunit directly binds caveolin, calreticulin, and Rack-1. The binding of caveolin to the αv subunit occurs within the transmembrane region. Caveolin physically links the αv integrins to signaling proteins, such as Fyn, leading to the recruitment of Shc. Shc then induces signal transduction through pathway such as MAPk to promote DNA synthesis and cell-cycle progression. In addition, αv binds directly with calreticulin through the GFFKR motif to induce signaling pathways (Fig. 2b). Calreticulin is a luminal endoplasmic reticulum calcium-binding protein, which may modulate cell adhesion and signal transduction. Receptor for activated protein kinase C (Rack-1) interacts with the αv subunit. Rack-1 also binds to several of the β subunits.

In αv integrin activation, actin-binding proteins are recruited to focal adhesions and bind the cytoplasmic tail of the β subunits. These actin-binding proteins include talin, filamin, and kindlin. Talin binding to the proximal NxxY motif of the β tail induces conformational changes of the integrin subunits resulting in activation of the αv integrin (Rüegg and Mariotti 2003). Talin also binds several of the signaling kinases that function downstream of integrins. Recruitment of talin to integrins is stimulated by the unmasking of the integrin binding site, FERM (4.1, ezrin, radixin, and moeisin) domain, in the talin head by the PKC-Rap1-RIAM pathway,  calpain, or PIP2. The PKC pathway and calpain activity may control the activation state of αvβ3 on endothelial and smooth muscle cells through their effects on talin binding. The FERM domain of talin binds tyrosine 747 in the β3 subunit tail to induce signaling (Arnaout et al. 2005). In addition, talin functions as an initial contact between integrins and the actin cytoskeleton. Talin is responsible for the association of vinculin and Arp2/3 complex to actin, resulting in the stabilization and attachment of actin filaments to the focal adhesion complexes. In addition, the interaction between talin and the αvβ3 integrins is required for mechanotransduction.

Filamins also associate with the β subunit of the αv integrins. Filamins can be found in the focal adhesions with integrins, but are mainly found along the cortical actin cytoskeleton and along stress fibers. The recruitment of filamin to focal adhesions can be stimulated by mechanical stress. Filamin also binds signaling proteins that control the actin cytoskeleton, including Rho, Rac, Cdc42, and MAPK signaling proteins (Plow et al. 2009).

Recently, additional integrin-binding proteins, the kindlin protein family, have been identified, although their complete functions remain to be elucidated. The kindlins interact with the cytoplasmic tails of β1 and β3, which localize with αv integrin. The kindlin-binding domain is located at the C-terminus of the β subunit and is separate from the domain used by talin. Kindlin binds the distal NxxY motif (tyrosine 795) of the β subunit. Kindlin and talin cooperate to control integrin affinity, with kindlins aiding talin function (Plow et al. 2009). Interestingly, the absence of kindlin-3 results in the dysfunction of integrin signaling resulting in severe defects in platelet and leukocyte function, as well as osteopenia (Malinin et al. 2010). Kindlins do not have known catalytic domains, but interact with other adaptor and signaling proteins, such as integrin-linked kinase.

The αv integrins cross-talk with proteins involved in cell–cell junctions, such as adherens junctions. One molecule in adherens junctions is nectin, which associates with the actin cytoskeleton through afadin. Nectin creates cell–cell adhesions and stimulates c-Src-mediated activation of Rap1, Cdc42, and Rac. Nectins 1 and 2 associate with αvβ3 through their extracellular domains at cell–cell adhesion sites.

Intracellular Signaling

Integrin signal transduction requires the binding of signaling proteins including protein kinases, lipid kinases, small GTPases, and phosphatases (Fig. 3). Many of these pathways are also activated by growth factors, and through their clustering with integrin, αv may have synergistic effects. The main protein kinase that is activated by the αv integrins is focal adhesion kinase (FAK). FAK localizes to focal adhesions, where it interacts with the β subunit of the αv integrins. The phosphorylation and tyrosine kinase activity of FAK is stimulated by integrin activation and binding to the extracellular matrix. FAK can also be phosphorylated by the clustering of isolated β subunit tails. FAK binds directly to talin and can also interact with vinculin and paxillin to control cell signaling and actin cytoskeletal formation. FAK activation recruits  Src or Fyn,  PI3k subunit p85, or PLCγ. These interactions stimulate the signaling cascades of Ras/Erk,  PI3k/Akt, and Crk/Dock180/Rac (Rüegg and Mariotti 2003).
Integrin Alpha V (ITGAV), Fig. 3

Integrin alpha v activation stimulates signaling pathways controlling cytoskeletal organization, cell proliferation, and integrin modulation. The alpha v integrin is either bound to the actin cytoskeletal proteins or clusters with other integrins, growth factors, and membrane proteins to promote signaling through talin, vinculin, and caveolin resulting in the activation of the Src kinases (Shc, Fyn, Grb2), MAP kinases, FAK, PI3 kinase, Rho family, or Ras family signaling pathways (Illustration by David Schumick, BS, CMI. Reprinted with the permission of the Cleveland Clinic Center for Medical Art & Photography © 2011. All Rights Reserved).

Further, the αv integrins bind integrin-linked kinase (ILK), a serine/threonine kinase that binds directly to β1 and β3 cytoplasmic tails of the αv integrins in focal adhesions (Fig. 3). The C-terminal of ILK binds the integrin β subunit, while the N-terminal domain binds PINCH, a LIM domain protein. PINCH binding to other adaptor proteins and ILK stimulation leads to the activation of several signaling pathways and actin polymerization. Further, ILK activation recruits several binding partners which result in the interaction of ILK with growth factor receptors (Siebers et al. 2005).

The stimulation of ILK, FAK, and the αv integrin β subunits results in the activation of a variety of intracellular signaling pathway including  PI3k/Akt, Ras/ MAP kinase,  Src family kinases, and the Rho GTPases: Rac, Rho, and Cdc42 (Fig. 3) (Rüegg and Mariotti 2003; Somanath et al. 2009). The  PI3k/Akt pathway regulates gene transcription, cell proliferation, migration, and survival. The Ras-MAPK signaling pathway may mediate the effects of integrins on cell proliferation, survival, and migration. Integrin stimulation of the MAPK pathways can regulate  p53, p21WAF1/CIP,  Bcl-2, and Bax, thus controlling cell-cycle progression and cell survival in response to αv activation (Rüegg and Mariotti 2003). The  Src family kinases play important roles in integrin and growth factor interaction and signaling. The signaling pathways of the  Src kinases further cross-talk with the other integrin responsive pathways (Somanath et al. 2009). The Rho GTPase family, Rho, Rac, and Cdc42, is responsible for actin polymerization, the formation of focal adhesions, cell proliferation, and regulation of gene expression. Thus, through the regulation of various signaling pathways, the αv integrins control cell survival, migration, and function within tissues (Rüegg and Mariotti 2003).

Integrin Alpha V in Angiogenesis and Wound Healing

Conditional knockout mice have demonstrated that integrin αv is not necessary for vascular development; however, it is important in adult vascular remodeling (Fig. 4a). On the resting endothelium, αvβ3 is minimally expressed, while it is upregulated during development and on vascular cells in tumors and ischemic tissues. Expression of αvβ3 on endothelial cells can also be induced by cytokines and growth factor exposure or by shear stress. Prothrombin is responsible for αvβ3 adhesion of endothelial and smooth muscle cells, thus controlling hemostasis (Byzova et al. 1998). Knockin mice (DiYF) with αvβ3 phosphorylation ablated demonstrate impaired angiogenesis. Endothelial cells from these DiYF mice display defective cell adhesion, spreading, migration, and capillary tube formation (Mahabeleshwar et al. 2006). In addition, αvβ5 integrins are located on quiescent endothelial cells. Integrin αvβ5 binds Del-1, a pro-angiogenic factor, leading to the activation of a pro-angiogenic expression program. This angiogenic program includes inducing αvβ3 and  uPAR expression. Partially, through its effects on angiogenesis, the αv integrin regulates wound healing.
Integrin Alpha V (ITGAV), Fig. 4

Integrin alpha v supports angiogenesis and tumorigenesis. (a) The αvβ5 integrin is expressed on resting endothelium, while the αvβ3 integrin is only expressed on remodeling endothelium and smooth muscle cells. Integrin αvβ3 is also expressed on platelets, macrophages, and fibroblasts involved in angiogenesis. (b) Integrins αvβ3, αvβ5, and αvβ6 are involved in tumorigenesis. Integrins αvβ3, αvβ5, and αvβ6 are expressed on primary tumor cells. In addition, integrins αvβ3 and αvβ5 are expressed on migrating tumor cells during metastasis. Integrin αvβ3 is also integral to adhesion at metastatic sites. Further, αvβ3 is located on bone marrow–derived cells (BMDC) which are recruited to tumors to support tumor growth (Illustration by David Schumick, BS, CMI. Reprinted with the permission of the Cleveland Clinic Center for Medical Art & Photography © 2011. All Rights Reserved).

Integrin αvβ3 expression is increased during wound healing, including on platelets, endothelial cells, macrophages, and fibroblasts responsible for repairing the dermis. Interestingly, mice deficient in αvβ3 demonstrate enhanced wound healing, which appears to be due to increased fibroblast recruitment and elevated TGFβ signaling. In addition, αvβ5 and αvβ6 have increased expression during wound closure of the epidermis. Integrin αvβ6 is not expressed in healthy epithelia, but is upregulated during wound healing. In epithelial cells, integrin αvβ6 bind the LAP-TGFβ promoting the interaction of TGFβ with its receptors by inducing a conformational change. Thus, expression of αvβ6, through its effects on TGFβ, controls inflammation and the response to local injury (Nemeth et al. 2007). The control that the αv integrins exert over angiogenesis and wound healing is recapitulated in tumorigenesis.

Integrin Alpha V in Cancer and Metastasis

Integrins αvβ3, αvβ5, and αvβ6 regulate tumor formation and progression in a variety of cancers (Fig. 4b) (Nemeth et al. 2007). Integrin αvβ3 mediates the tumor growth, migration, and metastasis of several cancers including breast and prostate. The adhesion of these cancers to bone is αvβ3 dependent and is integral to the development of bone metastases. Further, a variety of cancer-derived cell lines, including those from bone marrow aspirates, express αvβ3 (De et al. 2005). In addition, αvβ3 integrin expression increases the recruitment of bone marrow–derived cells (BMDCs) to angiogenic sites within tumors and wounds. Integrin αvβ3 activation on the BMDC mediates their adhesion and migration through the endothelial layer (Fig. 4b) (Feng et al. 2008). This BMDC recruitment is mediated by platelets and is required for continued tumor growth. Further, αvβ3 integrin expression is integral to prostate cancer metastasis, where it is required for tumor growth and for tumor-induced bone formation. The activation state of the αvβ3 integrin controls the recognition of bone matrix proteins by prostate cancer cells, thus controlling metastasis (Mahabeleshwar et al. 2006; McCabe et al. 2007). In prostate cancer cells, αvβ3 also mediates cell adhesion and migration on vitronectin and osteopontin. Further, in response to EGF activation, αvβ3 stimulates the  PI3k/Akt pathway in prostate cancer cells. EGF activation signaling also cross-talks with the αvβ5 integrin–induced pathways. Stimulation of carcinoma cells by EGF induces cell migration mediated by the αvβ5 integrin. EGFR induces  Src activity and can mediate the αvβ5 integrin control of metastasis.  Src activity also mediates the αvβ3-controlled metastatic progression of pancreatic cells. Integrin αvβ5 has also been implicated in prostate cancer metastasis to bone. Expression of VEGF and its receptor VEGFR2 on prostate cancer cells results in activation of αvβ3 and αvβ5. These integrins then stimulate the migration of prostate cancer cells toward SPARC protein in bone. The activation of αvβ5 induces augmented VEGF expression creating a positive-feedback loop stimulating further prostate cancer migration (Fig. 4b) (De et al. 2003). Further, integrin αvβ5 is involved in carcinoma cell invasion and metastasis. IGF-1 can cooperate with the αvβ5 integrin to induce pulmonary metastases. Additionally, expression of αvβ6 is increased in carcinomas of the colon, ovary, lung, breast, pancreas, stomach, salivary gland, and also skin and oral squamous cell carcinomas. The αvβ6 integrin promotes carcinoma progression by stimulating invasion, inhibiting apoptosis, regulating matrix metalloproteinase (MMP)-2 and −9 expressions, and activating TGF-β. Lastly, αv is highly expressed in ovarian carcinomas, while β1 is detected in both the tumor and stroma (Nemeth et al. 2007). Thus, the αv integrin expression and function are important targets in cancer research. Correspondingly, several therapeutic agents targeting the alpha v integrin are in clinical development (Table 2).
Integrin Alpha V (ITGAV), Table 2

Integrin alpha v therapeutic agents in clinical development




αv Target

Pathological target

LM609 (Vitaxin, MEDI 522, Abegrin)




Melanoma, prostate carcinoma





Solid tumors

Cilengitide (EMD 121974)

Small cyclic RGD peptide



Pancreatic adenocarcinoma, melanoma, lymphoma




αvβ3 (also α5β1)

Solid tumors


Small molecule agonist

Bristol-Myers Squibba


Tumor neovascularization


Small molecule agonist

Bristol-Myers Squibba


Tumor neovascularization

Abciximab (ReoPro)

Chimeric antibody


αvβ3 (also αIIβ3)

Coronary intervention, psoriasis, stroke

aThese agents were developed by DuPont Pharmaceuticals, which has since been acquired by Bristol-Myers Squibb

Integrin Alpha V in the Bone

The αv integrins are expressed on several skeletal cells: osteoblasts, osteoclasts, and odontoblasts, during various stages of development. Expression of αvβ1 has been described at a low level on osteoclasts (Nakamura et al. 2007), while integrin αvβ3 is expressed on both osteoclasts and osteoblasts (Siebers et al. 2005; Takada et al. 2007). In the skeleton, the αvβ3 controls osteoclast migration and resorption ring formation through its effects on actin cytoskeletal organization (Bouvard et al. 2001; Nakamura et al. 2007). Osteoclasts with mutated αvβ3 integrins do not from a ruffled membrane and are unable to resorb bone, resulting in hypocalcemia (Bouvard et al. 2001). Conversely, osteoblasts overexpressing αvβ3 integrin proliferate more quickly, uptake less calcium, and have impaired mineral deposition. In addition, increased αvβ3 expression in osteoblasts correlated with increased ERK and AP-1 activity and decreased JNK activity. Interestingly, blocking αvβ3 interaction with the extracellular matrix also results in decreased mineralization. This expression of the αv integrins on bone cells regulates their attachment to the extracellular matrix and orthopedic implants.

The αv integrins are expressed on osteoblasts and osteoclasts, which are often in contact with synthetic substrates covering orthopedic implants. The success or failure of these implants is contingent upon osseointegration. The composition and topography of the implant surface can influence integrin expression and cell behavior and thus dictate the failure rate. Osteoblasts express αv integrins when exposed to titanium alloy, polystyrene (PS), or cobalt-chrome-molybdenum. In addition, implants are often coated with a variety of substrates derived from extracellular matrix proteins. Integrin αv is upregulated on osteoblasts attaching to implants coated with laminin, but not fibronectin or collagen type I (Siebers et al. 2005), while integrin αv is expressed by osteoclasts attaching to PS, collagen-coated PS, laminin-coated PS, titanium, and cobalt-chrome. In addition, the αv and β1 subunits are expressed by osteosacromas when attaching to Thermanox, uncoated titanium, hydroxyapatite, and hydroxyapatite-coated titanium. Further, Arg-Gly-Asp (RGD) peptides derived from extracellular matrix proteins have been used to coat implants improving osseointegration. Osteoblast binding to RGD peptides is dependent on the αv integrin, and synthetic RGD motifs can induce cell attachment mimicking that found on parental molecules (Lebaron and Athanasiou 2000). Different RGD peptides stimulate attachment of different integrins and can thus be used to control the attachment of specific cell types. Cyclic RGD-coated ceramic implants or hydrogel disks promote bone regeneration via osteoblast attachment to the RGD peptide through the αvβ3 and αvβ5 integrins (Hersel et al. 2003). The coating of titanium with RGD peptides induces osteoblast attachment, stimulates differentiation, and inhibits apoptosis. In addition, RGD motifs have been used to promote nerve regeneration, spinal cord repair, and corneal tissue repair in vivo (Hersel et al. 2003). Thus, RGD-based and other biomimetic coatings stimulate the adhesion of αv-expressing cells, enhancing tissue responses to implants and stimulating tissue regeneration.


The widely expressed αv integrin subunit heterodimerizes with several β-subunits to create an integrin complex capable of recognizing a plethora of extracellular ligands. These activated integrin complexes can then cluster with different growth factor receptors, including IGF, PDGF, IRS, EGF, VEGF, TGFβ, uPA, and  FGF, to stimulate several families of signaling cascades:  PI3k/Akt, MAPK, Rho GTPase family, and  Src family kinases. Thus, αv integrin activation is integral to cell survival, proliferation, and function under physiological and pathological conditions. Integrin αv activation contributes to angiogenesis, wound healing, tumorigenesis, and bone remodeling. Targeting the αv integrin provides an important therapeutic approach for cancer research, regenerative medicine, and tissue engineering.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Molecular CardiologyJoseph J. Jacobs Center for Thrombosis and Vascular Biology, Lerner Research Institute, The Cleveland ClinicClevelandUSA