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At least 721 records · Page 40Linked to original sources

PubMed2007

Base excision repair proteins are required for integrin-mediated suppression of bleomycin-induced DNA breakage in murine lung endothelial cells.

Engagement of integrin cell adhesion receptors suppresses bleomycin (BLM)-induced DNA strand breakage in endothelial cells. Previous investigation of cells from poly(ADP-ribose) polymerase (PARP)-1 knockout mice and with an inhibitor of the enzyme indicated that this facilitator of base excision repair (BER) is required for integrin-mediated suppression of DNA strand breakage. Here, small inhibitory RNA (siRNA) was used to assess the requirement for the BER proteins, DNA ligase III (Lig3) alpha, PARP-1, and X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1), and for the long-patch BER ligase, DNA ligase I (Lig1), in integrin-mediated protection from BLM-induced DNA breakage. Murine lung endothelial cells (MLECs) were transfected with siRNA, treated with anti-beta1 integrin antibody, and then BLM. 3'-OH in DNA and accumulation of phosphorylated histone H2AX (gammaH2AX), which reflects double-strand breakage, were measured. Integrin antibody inhibited the increases in 3'-OH caused by BLM in MLECs transfected with either control or Lig1 siRNA. However, after knockdown of Lig3alpha, PARP-1, or XRCC1, suppression of DNA breakage by integrin antibody was limited. BLM increased gammaH2AX levels, and integrin treatment inhibited this by 57 to 73% in MLECs transfected with control siRNA. Integrin engagement also inhibited increases in gammaH2AX in BLM-treated cells transfected with Lig1 siRNA. In contrast, Lig3alpha, PARP-1, and XRCC1 siRNAs prevented integrin-mediated inhibition of BLM-induced gammaH2AX levels. The results suggest that the BER proteins, Lig3alpha, PARP-1, and XRCC1, are required for integrin-mediated suppression of BLM-induced DNA breakage.

Animals↗

PubMed2006

Adeno-associated virus type 2 contains an integrin alpha5beta1 binding domain essential for viral cell entry.

Integrins have been implicated as coreceptors in the infectious pathways of several nonenveloped viruses. For example, adenoviruses are known to interact with alphaV integrins by virtue of a high-affinity arginine-glycine-aspartate (RGD) domain present in the penton bases of the capsids. In the case of adeno-associated virus type 2 (AAV2), which lacks this RGD motif, integrin alphaVbeta5 has been identified as a coreceptor for cellular entry. However, the molecular determinants of AAV2 capsid-integrin interactions and the potential exploitation of alternative integrins as coreceptors by AAV2 have not been established thus far. In this report, we demonstrate that integrin alpha5beta1 serves as an alternative coreceptor for AAV2 infection in human embryonic kidney 293 cells. Such interactions appear to be mediated by a highly conserved domain that contains an asparagine-glycine-arginine (NGR) motif known to bind alpha5beta1 integrin with moderate affinity. The mutation of this domain reduces transduction efficiency by an order of magnitude relative to that of wild-type AAV2 vectors in vitro and in vivo. Further characterization of mutant and wild-type AAV2 capsids through transduction assays in cell lines lacking specific integrins, cell adhesion studies, and cell surface/solid-phase binding assays confirmed the role of the NGR domain in promoting AAV2-integrin interactions. Molecular modeling studies suggest that NGR residues form a surface loop close to the threefold axis of symmetry adjacent to residues previously implicated in binding heparan sulfate, the primary receptor for AAV2. The aforementioned results suggest that the internalization of AAV2 in 293 cells might follow a "click-to-fit" mechanism that involves the cooperative binding of heparan sulfate and alpha5beta1 integrin by the AAV2 capsids.

Amino Acid Motifs↗

PubMed2003

Foot-and-mouth disease virus receptors: comparison of bovine alpha(V) integrin utilization by type A and O viruses.

Three members of the alpha(V) integrin family of cellular receptors, alpha(V)beta(1), alpha(V)beta(3), and alpha(V)beta(6), have been identified as receptors for foot-and-mouth disease virus (FMDV) in vitro. The virus interacts with these receptors via a highly conserved arginine-glycine-aspartic acid (RGD) amino acid sequence motif located within the betaG-betaH (G-H) loop of VP1. Other alpha(V) integrins, as well as several other integrins, recognize and bind to RGD motifs on their natural ligands and also may be candidate receptors for FMDV. To analyze the roles of the alpha(V) integrins from a susceptible species as viral receptors, we molecularly cloned the bovine beta(1), beta(5), and beta(6) integrin subunits. Using these subunits, along with previously cloned bovine alpha(V) and beta(3) subunits, in a transient expression assay system, we compared the efficiencies of infection mediated by alpha(V)beta(1), alpha(V)beta(3), alpha(V)beta(5), and alpha(V)beta(6) among three strains of FMDV serotype A and two strains of serotype O. While all the viruses could infect cells expressing these integrins, they exhibited different efficiencies of integrin utilization. All the type A viruses used alpha(V)beta(3) and alpha(V)beta(6) with relatively high efficiency, while only one virus utilized alpha(V)beta(1) with moderate efficiency. In contrast, both type O viruses utilized alpha(V)beta(6) and alpha(V)beta(1) with higher efficiency than alpha(V)beta(3). Only low levels of viral replication were detected in alpha(V)beta(5)-expressing cells infected with either serotype. Experiments in which the ligand-binding domains among the beta subunits were exchanged indicated that this region of the integrin subunit appears to contribute to the differences in integrin utilizations among strains. In contrast, the G-H loops of the different viruses do not appear to be involved in this phenomenon. Thus, the ability of the virus to utilize multiple integrins in vitro may be a reflection of the use of multiple receptors during the course of infection within the susceptible host.

Amino Acid Motifs↗

PubMed2005

Rapid access of antibodies to alpha5beta1 integrin overexpressed on the luminal surface of tumor blood vessels.

Integrin alpha(5)beta(1) is overexpressed on endothelial cells of tumor vessels and is uniformly and rapidly accessible to antibodies in the bloodstream. Here, we determined whether antibodies rapidly gain access to integrin overexpressed on the abluminal (basolateral) surface of endothelial cells through vascular leakiness or whether the rapid accessibility results instead because the integrin is overexpressed on the luminal (apical) surface of endothelial cells due to loss of cell polarity. Using tumors in RIP-Tag2 transgenic mice as a model, we first compared the binding pattern of intravascular anti-alpha(5)beta(1) integrin antibody with the leakage pattern of nonspecific IgG. The distributions did not match: anti-alpha(5)beta(1) integrin antibody uniformly labeled the tumor vasculature, but IgG was located in patchy sites of leakage. We next injected an antibody to fibrinogen/fibrin, which resulted in patchy labeling of tumors that matched the leakage of IgG and the overall distribution of fibrin in tumors. Similarly, injected antibodies to the basement membrane protein fibronectin, a ligand of alpha(5)beta(1) integrin, or type IV collagen produced patchy sites of leakage instead of uniform labeling of vascular basement membrane. Differences in the kinetics of labeling, which for alpha(5)beta(1) integrin antibody was near maximal by 10 minutes but for the other antibodies gradually increased over 6 hours, indicated differences in accessibility of their respective targets. Isosurface rendering of confocal microscopic images was consistent with antibody binding to alpha(5)beta(1) integrin on the luminal surface of endothelial cells. Together, these findings indicate that the rapid accessibility of alpha(5)beta(1) integrin in RIP-Tag2 tumors results from overexpression of the integrin on the luminal surface of tumor vessels.

Adenoma, Islet Cell↗

PubMed1998

Role of beta 1 integrins in human endometrium and decidua during implantation.

The present study was undertaken to investigate the expression and function of beta 1 integrins in human endometrium and decidua. Fluorescence-activated flow cytometry demonstrated the greater expression of the beta 1, alpha 1, alpha 2, and alpha 5 subunits of the beta 1 integrin family in cultured stromal cells from the midsecretory phase than in those of the early proliferative phase. The addition of estradiol (E2) and progesterone (P) to cultured stromal cells in the early proliferative phase increased the expression of beta 1 integrins in vitro. The immunohistochemical distribution of beta 1 integrins demonstrated predominantly glandular epithelial staining in the proliferative phase, and stromal and glandular staining in the midsecretory phase. Flow cytometry also demonstrated the expression of beta 1, alpha 1, alpha 2, alpha 3, alpha 5, and alpha 6 subunits of beta 1 integrin family in cultured decidual cells. Immunohistochemistry confirmed the beta 1 integrin cell surface phenotypes in cultured decidual cells observed by flow cytometry. In the subsequent experiment, the effects of antibodies against specific beta 1 integrin heterodimers on mouse embryo attachment and spreading were tested to identify the role of beta 1 integrins in early implantation. We developed assays for the attachment of mouse embryos and for trophoblastic spreading on cultured human decidual cells. The addition of antibodies directed against beta 1 and alpha integrin subunits to cultured decidual cells did not affect the rates of hatching or attachment of the blastocysts, whereas the outgrowth of embryos on the decidual cells was inhibited by their antibodies in a dose-dependent manner. Thus, beta 1 integrin in human endometrium and decidua may be important in mediating the organization of extracelllar matrix proteins derived from embryos during the early stage of implantation.

Adult↗

PubMed1993

Distribution of integrin cell adhesion receptors on normal bronchial epithelial cells and lung cancer cells in vitro and in vivo.

The interactions of bronchial epithelial cells with the basement membrane control cell morphology, differentiation, and proliferation in addition to having a major role in malignant transformation. Since these interactions are mediated by the integrin family of cell adhesion receptors, we characterized the integrin repertoire and adhesive properties of normal human bronchial epithelial cells in culture and cell lines derived from nine lung carcinomas using subunit-specific monoclonal antibodies. In addition, the integrin repertoire of three of the transformed cell lines was reexamined after the cells formed tumor nodules in immunodeficient mice. Bronchial epithelial cells in culture expressed multiple integrin subunits with the capability of binding to collagen and laminin (alpha 2, alpha 3, and alpha 6) and at least two subunits that are capable of mediating adhesion to fibronectin (alpha 3 and an alpha v-containing integrin). The alpha v beta 3 vitronectin receptor was not present. This distribution closely mimicked that seen by bronchial epithelial cells in situ. Cell lines derived from transformed pulmonary epithelial cells showed great heterogeneity with respect to integrin expression--some showing fewer, some greater, and some the same types of integrins as nontransformed epithelial cells. Only slight changes in integrin expression were seen in tumor cells propagated in immunodeficient mice. Although the adhesion characteristics of the transformed cells mirrored their adhesion receptor profile, no correlation between integrin profile and the ability to grow in SCID mice was observed. This study defines the integrin repertoire of human bronchial epithelial cells and sets the stage for future investigations exploring how the regulation and signal transduction mechanisms of these receptors might affect important pulmonary processes such as bronchial cell differentiation, wound healing, and malignant transformation.

Animals↗

PubMed1993

Expression of integrins and basement membrane components by wound keratinocytes.

Extracellular matrix proteins and their cellular receptors, integrins, play a fundamental role in keratinocyte adhesion and migration. During wound healing, keratinocytes detach, migrate until the two epithelial sheets confront, and then regenerate the basement membrane. We examined the expression of different integrins and their putative ligands in keratinocytes during human mucosal wound healing. Migrating keratinocytes continuously expressed kalinin but not the other typical components of the basement membrane zone: type IV collagen, laminin, and type VII collagen. When the epithelial sheets confronted each other, these missing basement membrane components started to appear gradually through the entire wound area. The expression of integrin beta 1 subunit was increased in keratinocytes during migration. The beta 1-associated alpha 2 and alpha 3 subunits were expressed constantly by wound keratinocytes whereas the alpha 5 subunit was present only in keratinocytes during reepithelialization. Furthermore, migrating cells started to express alpha v-integrins which were not present in the nonaffected epithelium. All keratinocytes also expressed the alpha 6 beta 4 integrin during migration. In the migrating cells, the distribution of integrins was altered. In normal mucosa, beta 1-integrins were located mainly on the lateral plasma membrane and alpha 6 beta 4 at the basal surface of basal keratinocytes in the nonaffected tissue. In wounds, integrins were found in filopodia of migrating keratinocytes, and also surrounding cells in several cell layers of the migrating sheet. The results indicate that migrating keratinocytes, in deep human wounds enlarge their integrin repertoire. The changes in integrin expression take place concomitantly with changes in the basement membrane composition, suggesting a close interplay of these two groups of molecules during wound healing.

Antibodies, Monoclonal↗

PubMed1996

Distribution of beta1 integrin during development of chick tarsometatarsal skin in vivo and in vitro.

To determine the role of beta1 integrin in chick tarsometatarsal skin development, we examined the localization of the beta1 integrin immunohistochemically in vivo and in vitro by light and electron microscopy. Beta1 integrin was present over the entire cell surface of undifferentiated epidermis at early stages (Days 5, 9, 13). Marked changes in the localization of beta1 integrin occurred during epidermal keratinization and stratification, i.e., expression of beta1 integrin decreased in the superficial and intermediate cell layers from Day 13 to Day 17. After 17 days in vivo, when keratinization of the epidermis was completed, the distribution of beta1 integrin was confined to the basal layer of the epidermis in a pericellular distribution. During all stages examined, fibroblasts in the dermis were also stained. Immunoelectron microscopic study revealed that beta1 integrin was located on the plasma membrane of keratinocytes and dermal fibroblasts. The change in beta1 integrin localization that occurred in vivo could be reproduced in cultures of developing skin in which keratinization (differentiation) or mucous metaplasia (transdifferentiation) had been induced in vitro by hydrocortisone or retinol treatment, respectively. A monoclonal antibody against beta1 integrin caused striking changes in the epidermal keratinization process and in the basement membrane structure in vitro, i.e., inhibition of keratinization and detachment of the basement membrane from the basal surface of the epidermis. These results indicate that beta1 integrin plays an important role in cell-cell and cell-extracellular matrix interactions, which are important for epidermal development of the tarsometatarsal skin.

Animals↗

PubMed1996

Changes in endothelial cell and smooth muscle cell integrin expression during closure of the ductus arteriosus: an immunohistochemical comparison of the fetal, preterm newborn, and full-term newborn rhesus monkey ductus.

Anatomical closure of the ductus arteriosus requires normally quiescent luminal endothelial cells and medial smooth muscle cells to migrate into the subendothelial space forming intimal mounds that eventually coalesce and occlude the vessel's lumen. The migration of endothelial cells and smooth muscle cells requires the presence of integrin receptors that interact with the surrounding matrix. We used immunohistochemical staining to examine the repertoires of integrins expressed by endothelial cells and smooth muscle cells during postnatal closure of the ductus arteriosus in full-term and preterm rhesus monkeys. In the fetal ductus, luminal endothelial cells have a limited repertoire of integrins. During postnatal ductus closure, luminal endothelial cells, of both term and preterm monkeys, change their phenotype and express the full repertoire of integrins found on growing capillary endothelial cells (alpha 1 beta 1, alpha 2 beta 1, alpha 3 beta 1, alpha 6 beta 1, alpha v beta 1, alpha 6 beta 4, and alpha v beta 5). Similarly, during ductus closure, smooth muscle cells of both term and preterm monkeys expand their integrin repertoire to include the alpha 5 beta 1 and alpha v beta 3 integrins; these two integrins have been shown to be essential for smooth muscle cell migration in vitro. These changes in integrin profile occur at the same time the endothelial and smooth muscle cells invade their neighboring compartments. In contrast, preterm monkeys with a persistently patent ductus lumen fail to develop these changes in integrin expression and fail to develop neointimal mounds. No evidence of intimal thickening occurs in the absence of changes in integrin expression. Therefore, endothelial cells and smooth muscle cells change phenotypes to produce the intimal thickening required for ductus closure.

Aging↗

PubMed2004

Expression of {beta}1 integrin receptors during rat pancreas development--sites and dynamics.

The integrin receptors link to extracellular matrix proteins and exert a dynamic role in development by providing the physical basis for cell adhesion and controlling cell growth. In the present study, we examined changes in the expression of beta1 integrins and its associated alpha-subunits to islet cell development in the rat pancreas. A significant increase in protein expression of integrin alpha3, alpha6, and beta1 was observed from fetal to postnatal life. High mRNA levels of these integrin subunits was detected at embryonic d 18 and dropped significantly after birth with relatively low expression throughout postnatal life. Integrins alpha3, alpha5, alpha6, and beta1 were expressed in a cell-specific manner in the pancreas with high integrin immunoreactivity in duct and islet regions during fetal life, and a progressive increase later into postnatal life. The coexpression with islet and putative islet precursor markers during fetal and postnatal development suggest a role for these integrin subunits in differentiation and maturation of islets. Functional studies in vitro showed that anti-beta1 antibody treatment inhibited islet cell adhesion to extracellular matrices and disrupted islet architecture. Blockade of beta1 integrin receptor and knockdown beta1 mRNA resulted in a decrease in the expression of insulin mRNA and increased islet cell death. These results suggest that progression in islet cell development is accompanied by and dependent upon cell adhesion via beta1 integrin and its respective alpha-subunits and suggest that the beta1 family of integrins may play a critical role in islet cell architecture, development, integrity, and function.

Animals↗

PubMed2003

T-cell integrins: more than just sticking points.

T cells use integrins in essentially all of their functions. They use integrins to migrate in and out of lymph nodes and, following infection, to migrate into other tissues. At the beginning of an immune response, integrins also participate in the immunological synapse formed between T cells and antigen-presenting cells. Because the ligands for integrins are widely expressed, integrin activity on T cells must be tightly controlled. Integrins become active following signalling through other membrane receptors, which cause both affinity alteration and an increase in integrin clustering. Lipid raft localization may increase integrin activity. Signalling pathways involving ADAP, Vav-1 and SKAP-55, as well as Rap1 and RAPL, cause clustering of leukocyte function-associated antigen-1 (LFA-1; integrin alphaLbeta2). T-cell integrins can also signal, and the pathways dedicated to the migratory activity of T cells have been the most investigated so far. Active LFA-1 causes T-cell attachment and lamellipodial movement induced by myosin light chain kinase at the leading edge, whereas RhoA and ROCK cause T-cell detachment at the trailing edge. Another important signalling pathway acts through CasL/Crk, which might regulate the activity of the GTPases Rac and Rap1 that have important roles in T-cell migration.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Multiple factors contribute to integrin-talin interactions in vivo.

The cytoplasmic protein talin is an essential part of the integrin-cytoskeleton link. We characterized the interaction between integrin and two conserved regions of talin, the N-terminal ;head' domain and the C-terminus, which includes the I/LWEQ domain, within the living organism. Green-fluorescent-protein-tagged head and C-terminal domains were recruited to integrin adhesion sites. Both required integrins for recruitment, but the C-terminal domain also required endogenous talin, showing it was not recruited directly by integrins. We used chimeric transmembrane proteins containing the cytoplasmic domain of the integrin beta subunit to examine the integrin-talin head interaction. Monomeric chimeric proteins did not recruit talin head, whereas dimeric chimeras efficiently recruited it and caused a strong inhibition of integrin-mediated adhesion. These chimeras recruited surprisingly few integrin-associated proteins, indicating that recruitment of talin did not initiate a cascade of recruitment. Mutagenesis of the integrin cytoplasmic domain, within the chimera, showed the dominant-negative inhibition was not due to talin sequestration alone and that additional interactions are required.

Amino Acid Motifs↗

PubMed1995

Alteration of collagen-dependent adhesion, motility, and morphogenesis by the expression of antisense alpha 2 integrin mRNA in mammary cells.

Although integrins are known to mediate adhesive binding of cells to the extracellular matrix, their role in mediating cellular growth, morphology, and differentiation is less clear. To determine more directly the role of the alpha 2 beta 1 integrin, a collagen and laminin receptor, in mediating the collagen-dependent differentiation of mammary cells, we reduced expression of the integrin by the well differentiated human breast carcinoma cell line, T47D, by stably expressing alpha 2 integrin antisense mRNA. Flow cytometry demonstrated that the antisense-expressing clones had levels of alpha 2 beta 1 integrin on their surfaces that were decreased by 30-70%. Adhesion of antisense-expressing clones to both collagens I and IV was decreased relative to controls in a manner that correlated with the level of cell surface alpha 2 beta 1 integrin expression. Adhesion to fibronectin and laminin were not affected. Motility across collagen-coated filters in haptotaxis assays was increased for only those clones that exhibited intermediate levels of adhesion to collagen, suggesting that an intermediate density of cell-surface alpha 2 beta 1 integrin optimally supports cell motility. When cultured in three-dimensional collagen gels, T47D cells organized in a manner suggestive of a glandular epithelium. In contrast, antisense-expressing clones with decreased alpha 2 beta 1 integrin were not able to organize in three-dimensional collagen gels. The growth rate of T47D cells was reduced when the cells were cultured in three-dimensional collagen gels. Unlike adhesion, motility, and morphogenesis, growth rates were unaffected by reduction of alpha 2 beta 1 integrin expression. Our results suggest that adhesive interactions mediated by a critical level of surface alpha 2 beta 1 integrin expression are key determinants of the collagen-dependent morphogenetic capacity of mammary epithelial cells.

Animals↗

PubMed1995

The alpha 2 beta 1 integrin regulates collagen-mediated MDCK epithelial membrane remodeling and tubule formation.

Previous studies have demonstrated that incubation of MDCK cell epithelial cysts in collagen gel induced a reversal in cell surface polarity that was regulated by beta 1 integrins. Further experiments were done to identify the specific collagen binding integrin involved by applying collagen gel overlays to the apical membrane of subconfluent MDCK monolayers. Cell surface levels of the apical membrane glycoprotein gp135 were monitored by ELISA to quantitate the extent of collagen-mediated membrane remodeling. After an 8 hour incubation with collagen, there was a 35% reduction in gp135 while the cell surface levels of the alpha 2, alpha 3 and beta 1 integrin subunits were not affected. Immunofluorescence microscopy confirmed the loss of gp135 from selected regions of the apical cell surface while the alpha 2 and beta 1 integrin subunits were distributed in small clusters over the entire apical membrane in both control and collagen-treated monolayers. Collagen-mediated loss of gp135 was inhibited by monoclonal antibodies which recognize either the alpha 2 or beta 1 integrin subunits but not by a monoclonal antibody against the alpha 6 beta 1 integrin. These results demonstrated that remodeling of the apical membrane had occurred, allowing the selective retention of beta 1 integrins but not gp135. They were supported by the observation that collagen-mediated loss of apical membrane microvilli was inhibited by the monoclonal antibody against the alpha 2 integrin subunit. Incubation of confluent monolayers with collagen gel induced the formation of polarized epithelial tubules within 16 hours. Epithelial tubule biogenesis was completely inhibited by monoclonal antibodies against either the alpha 2 or beta 1 integrin subunits, providing strong evidence that the alpha 2 beta 1 integrin is essential for collagen-mediated epithelial membrane remodeling and tubule formation.

Animals↗

PubMed2000

Laminin and alpha7beta1 integrin regulate agrin-induced clustering of acetylcholine receptors.

The clustering of acetylcholine receptors (AChRs) in the post-synaptic membrane of skeletal muscle is an early developmental event in the formation of the neuromuscular junction. Several studies show that laminin, as well as neural agrin, can induce AChR clustering in C2C12 myofibers. We recently showed that specific isoforms of the alpha7beta1 integrin (a receptor normally found at neuromuscular junctions) colocalize and physically interact with AChR clusters in a laminin-dependent fashion. In contrast, induction with agrin alone fails to promote localization of the integrin with AChR clusters. Together both agrin and laminin enhance the interaction of the integrin with AChRs and their aggregation into clusters. To further understand this mechanism we investigated cluster formation and the association of the alpha7beta1 integrin and AChR over time following induction with laminin and/or agrin. Our results show that the alpha7beta1 integrin associates with AChRs early during the formation of the post-synaptic membrane and that laminin modulates this recruitment. Laminin induces a rapid stable association of the integrin and AChRs and this association is independent of clustering. In addition to laminin-1, merosin (laminin-2/4) is present both before and after formation of neuromuscular junctions and also promotes AChR clustering and colocalization with the integrin as well as synergism with agrin. Using site directed mutagenesis we demonstrate that a tyrosine residue in the cytoplasmic domain of both (&agr;)7A and (&agr;)7B chains regulates the localization of the integrin with AChR clusters. We also provide evidence that laminin, through its association with the alpha7beta1 integrin, reduces by 20-fold the concentration of agrin required to promote AChR clustering and accelerates the formation of clusters. Thus laminin, agrin and the alpha7beta1 integrin act in a concerted manner early in the development of the post-synaptic membrane, with laminin priming newly formed myofibers to rapidly and vigorously respond to low concentrations of neural agrin produced by innervating motor neurons.

Agrin↗

PubMed2003

Diverse roles of integrins in human T lymphocyte biology.

T lymphocytes are the primary cells responsible for maintaining the immune system. There are many intricate mechanisms involved in the regulation of T cells and the integrin family of adhesive surface proteins plays a pivotal role in the control of T lymphocyte activation and functions. Integrins are heterodimeric transmembrane proteins that are not merely adhesion molecules but also function in T cell coactivation by providing a scaffold for signaling and cytoskeletal proteins that are adept at transmitting signals from the inside of the cell to the outside ("inside-out signaling") or from the outside of the cell to the inside ("outside-in signaling"). The signaling property of integrins allows for rapid responses to changes in the microenviroment of the lymphocyte. Therefore, whether the T cell needs to adhere or detach, integrins can quickly accommodate either state of the cell. Once cells are guided to sites of infection, inflammation, or antigen presentation, integrins can also participate in the initiation, maintenance, or termination of the response. This review will focus on the aspects of integrin-mediated T cell coactivation, affinity and avidity control of integrins, signaling molecules involved with integrins, association of integrins in lipid microdomains, and negative regulation of integrins.

Bacterial Proteins↗

PubMed2006

Anti-angiogenic cancer therapy based on integrin alphavbeta3 antagonism.

Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is a fundamental process during cancer progression. Anti-angiogenic strategies have been pursued for cancer treatment and prevention of cancer recurrence and metastasis. Integrins are a family of cell adhesion molecules consisting of two non-covalently bound transmembrane subunits (alpha and beta). Much research has demonstrated that integrin signaling plays a key role in tumor angiogenesis and metastasis. Integrin alphavbeta3 is highly expressed on activated endothelial cells and tumor cells but is not present in resting endothelial cells and most normal organ systems, which makes it a suitable target for anti-angiogenic cancer therapy. In this review we will focus on cancer therapy targeting integrin alphavbeta3 while other integrins (such as alpha5beta1, alphaIIbbeta3, alphavbeta5, alpha6beta4) will only be briefly mentioned when relevant. MEDI-522 (a humanized anti-human integrin alphavbeta3 monoclonal antibody) and Cilengitide (cyclic peptidic integrin alphavbeta3/alphavbeta5 antagonist) are currently in clinical trials for anti-angiogenic cancer therapy. Small interfering RNA (siRNA) that specifically silences integrin alphav and/or beta3 was reported to cause tumor shrinkage in preclinical xenograft models. Combination of anti-integrin alphavbeta3 therapy and other therapeutic approaches (such as chemotherapy, radiotherapy and gene therapy) has also been applied for cancer treatment. Mounting evidence suggests that there is potentially synergistic effect of combined therapeutic approaches over single modality alone. Lastly, integrin targeted delivery (drugs, genes, and radioisotopes) and imaging (optical, MRI, ultrasound, SPECT, and PET) is discussed in detail.

Angiogenesis Inhibitors↗

PubMed1998

Integrin-mediated platelet adhesion.

Adhesion of platelets to the damaged subendothelium is a prerequisite reaction for the initiation of hemostasis in vivo. Platelet membranes contain high concentrations of integrins and other glycoproteins (GPs) that are involved in the platelet adhesion to the extracellular matrix. In the present review, we focus on two platelet integrins, integrin alphaIIb beta3 (GPIIb/IIIa) and integrin alpha2 beta1 (GPIa/IIa) because these integrins are major components of the platelet membrane proteins and are known to contribute to platelet adhesion to fibrin(ogen) and collagen surfaces, respectively. These integrins bind soluble ligands (fibrinogen or collagen) after platelets are activated but only have low affinity towards these ligands when platelets are in the resting state. We describe the binding properties of these integrins and discuss the mechanism for the activation of these integrins. Platelets can adhere to fibrin(ogen) or collagen immobilized on a surface. When platelets adhere to a collagen- or fibrin-coated surface, they become activated and form aggregates; this is especially prominent under flow conditions. We discuss the contribution of these integrins and non-integrin proteins, GPIb and GPVI, to the platelet adhesion on to the collagen surface, especially under flow conditions, a system that most closely approximates platelet adhesion in vivo.

Animals↗