SEARCH · PubMed Health

Results for “Integrin”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 613 records · Page 34Linked to original sources

PubMed2003

Integrins are involved in synaptogenesis, cell spreading, and adhesion in the postnatal brain.

Integrins are a major family of heterodimeric surface glycoproteins that act as adhesion molecules, have a spectrum of extracellular matrix (ECM) molecules as their ligands, and regulate a variety of cellular functions. Integrins are known to be critical to embryonic brain development, and recent studies have indicated their essential role in adult brain function, although their role in postnatal brain development and function has not been examined. Here, we used the organotypic slice culture system to investigate the role of integrins in postnatal hippocampal development by exposing the tissue to either an integrin competitive antagonist, the peptide GRGDSP containing Arg-Gly-Asp (RGD) attachment site, or to function-blocking beta(1)-integrin antibodies to disrupt integrin interactions. These experiments revealed that beta(1)-integrin antibodies interfered with spreading of the culture, resulting in a rapid and marked diminution of slice area. beta(1)-integrin antibodies and RGD peptide disrupted cell adhesion, causing cell detachment and migration of glial cells from the explant. The majority of the detached cells were of macroglial origin and switched to expression of the intermediate filament proteins vimentin and nestin, suggesting a developmental regression. The organotypic organization of slice cultures was not affected, although exposure to either integrin antagonist or antibody resulted in a statistically significant reduction in the number of synapses measured in the apical dendrites of CA1 pyramidal neurons. The results demonstrate that integrins markedly affect postnatal CNS development, in both ultrastructural construction and organizational processes.

Animals↗

PubMed2000

High affinity interactions of Coxsackievirus A9 with integrin alphavbeta3 (CD51/61) require the CYDMKTTC sequence of beta3, but do not require the RGD sequence of the CAV-9 VP1 protein.

Integrins are transmembrane molecules involved in numerous cell matrix, cell-cell adhesion phenomena and also utilised as viral receptors. These interactions with integrins are mediated by brief oligopeptide recognition sequences. The Arg-Gly-Asp sequence (RGD), is recognized by many integrins, including integrin alphavbeta3 (CD51/61). Coxsackievirus A9 (CAV-9), a human pathogen that has an Arg-Gly-Asp sequence in the VP1 capsid protein, has been known to be one of the many viruses that utilise integrin alphavbeta3 as a receptor. In order to determine important binding sites of CAV-9 on integrin alphavbeta3, we performed binding studies of CAV-9 on CHO-alphavbeta3, CHO-alphavbeta1 and CHO-alphavbeta1-3-1 mutant cell line, in the presence of function blocking mAb specific for integrin alphavbeta3 and natural ligand vitronectin. Our experiments show that the CYDMKTTC sequence (187-193 residue) of integrin beta3, which has been shown to be involved in ligand specificity, is an important binding site for CAV-9. We also report that an RGD-less Coxsackievirus A9 mutant can bind efficiently on the ligand binding site of integrin alphavbeta3. Thus documenting the capability of this RNA virus to interact with integrin alphavbeta3, without the presence of an Arg-Gly-Asp sequence.

Amino Acid Sequence↗

PubMed1998

Alphav integrins mediate adhesion and migration of breast carcinoma cell lines.

Integrins with the alphav subunit are involved in cell adhesion and cellular signaling. Some alphav integrins have been associated with tumor progression and dissemination. The objective of this study was to assess the contribution of alphav integrins to the adhesive and migratory behavior of cells derived from breast carcinoma (BCA). The expression and function of alphav integrins was characterized in three BCA cell lines which exhibit different metastatic potentials. These include MCF-7 cells which metastasize inefficiently, MDA-MB-231 cells, which have a moderate metastatic potential, and MDA-MB-435 cells, which metastasize extensively. Each cell type displays a different repertoire of alphav integrins on the cell surface. The complement of alphav integrins on each cell type influences their ability to adhere and migrate. The most striking difference among these cell lines was the expression of the alphavbeta3 integrin. The highly metastatic MDA-MB-435 cells express substantial levels of this receptor, whereas MDA-MB-231 and MCF-7 cells do not. The MDA-MB-435 cells showed a greater ability to adhere and to migrate and this functional difference can largely be attributed to the expression of alphavbeta3 integrin. This characterization is a first step toward determining the role of alphav integrins in animal models of BCA metastasis, and lends support to the hypothesis that the alphavbeta3 integrin can be a contributing factor in metastatic disease.

Antigens, CD↗

PubMed1995

Role of the PS integrins in Drosophila development.

The PS1 and PS2 integrins of Drosophila are heterodimers of alphaPS1betaPS and alphaPS2betaPS subunits, respectively, with very strong structural similarity to vertebrate integrins. Cell transfection experiments indicate that the PS integrins are receptors for extracellular matrix components and are functionally analogous to vertebrate integrins. Matrix ligands from Drosophila tissues have been identified for PS1 and PS2 integrins, using transformed cells and a cell-spreading assay. Mutations in all three subunit genes have been identified, and the phenotypes of mutants indicate that PS integrins are required for the proper morphogenesis of a number of embryonic tissues. Using methods to produce genetic mosaics and transformation of integrin transgenes into whole animals, integrin functions in adult morphogenesis also have been examined. In the pupal wing, integrins are critically required to maintain the connection between dorsal and ventral epithelia, and recent results suggest that in early pupal development, the integrins are acting as specific receptors, as opposed to a non-specific cell-matrix glue.

Animals↗

PubMed2002

Alterations in fibroblast alpha1beta1 integrin collagen receptor expression in keloids and hypertrophic scars.

Keloids and hypertrophic scars are significant symptomatic clinical problems characterized by excess collagen. Although extensive research has focused on fibroblasts and collagen turnover in these aberrant scars, little work has been done on the expression of integrins (cell membrane structures that link cells to extracellular matrix) within these lesions. Integrin-mediated regulation of collagen synthesis has previously been observed in explanted fibroblasts from normal and fibrotic dermis, and integrin alpha1 knockout mice maintain increased collagen synthesis consistent with a role for alpha1beta1 in providing negative feedback on collagen synthesis. These findings suggested the need to evaluate integrin roles in keloids and hypertrophic scars. In this study we examined integrin expression in keloids (n = 11), hypertrophic scars (n = 5), radiation ulcers (n = 2), and normal skin specimens (n = 8). We used a novel approach to analysis by isolating dermal fibroblasts directly from tissue (without explant culture) and determining surface integrin expression by flow cytometry. We found that keloids and hypertrophic scars have marked alterations in fibroblast integrin expression and contain several distinct populations of fibroblasts. One of these populations expresses high levels of alpha1 integrin, and the proportion of these cells is higher in keloids (63% +/- 3.6% SEM) and hypertrophic scars (45% +/- 2.7% SEM) than in normal skin tissues (28% +/- 4.7% SEM). The different populations of fibroblasts defined by integrin expression merge, however, when the cells are serially cultured, suggesting that there may be aspects of the dermal microenvironment that maintain the integrin phenotypic heterogeneity in dermal fibroblasts.

Adult↗

PubMed2005

Increased expression and function of integrins in enterocytes by endotoxin impairs epithelial restitution.

BACKGROUND & AIMS: Experimental necrotizing enterocolitis (NEC) is characterized by circulating endotoxin (lipopolysaccharide [LPS]) and impaired enterocyte migration. We hypothesized that LPS increases integrin function and cell-matrix adhesion, leading to impaired enterocyte migration in the pathogenesis of NEC. METHODS: NEC-like intestinal injury was induced in newborn rats by hypoxia/gavage feedings, and restitution was determined by assessing bromodeoxyuridine-labeled enterocytes along the crypt-villus axis. Newborn mice were injected with 5 mg/kg LPS. IEC-6 cells were treated with LPS +/- LY294002 or wortmannin, and beta 1- and alpha 3-integrins were assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunofluorescence. Beta 1-integrin function was determined by adherence of fibronectin beads to IEC-6 monolayers. Migration of IEC-6 cells into a scraped wound was measured by time-lapse microscopy. RESULTS: Newborn intestinal injury was associated with decreased intestinal restitution and increased alpha 3- and beta 1-integrin expression in the ileal mucosa, which also was observed after LPS injection. In IEC-6 cells, LPS caused an increase in the expression of alpha 3- and beta 1-integrins, a shift of beta 1-integrins from the cytoplasm to the plasma membrane and an increase in fibronectin bead adhesion during which beta 1-integrins accumulated underneath attached beads. These effects could be reversed with LY294002 or wortmannin, suggesting phosphatidylinositol-3-phosphate kinase (PI3K) dependence. The increased integrin-matrix adhesion by LPS led to an inhibition of enterocyte migration, which could be reversed by anti-beta 1-antibodies. CONCLUSIONS: Enterocyte migration is inhibited by LPS through increased expression and function of alpha 3- and beta 1-integrins. Modulation of enterocyte migration via integrins may provide novel insights into the pathogenesis of NEC, in which intestinal restitution is impaired.

Androstadienes↗

PubMed1995

Alpha 4 beta 1 integrin-dependent cell adhesion is regulated by a low affinity receptor pool that is conformationally responsive to ligand.

alpha 4 beta 1 integrin (VLA-4) appears to be unique among the leukocyte integrins in that it can initiate the adhesion of circulating lymphocytes without cellular activation. It is not known how lymphocytes or other cell types maintain constitutive levels of alpha 4 beta 1 integrin activity. The current report describes a monoclonal antibody, 15/7, that recognizes a high affinity or ligand-occupied conformation of beta 1 integrin. Studies with 15/7 revealed that alpha 4 beta 1 integrin-dependent adhesion of leukocytic cell lines is mediated by a population of low affinity receptors that is conformationally responsive to ligand; the 15/7 epitope could be induced by nanomolar concentrations of soluble VCAM-1 or by micromolar concentrations of a peptide derived from the type III connecting segment domain of fibronectin (as ligands for alpha 4 beta 1 integrin). The same receptors were also responsive to adhesion activating reagents, such as Mn2+, activating anti-beta 1 integrin antibodies, and phorbol myristate acetate, which induced the 15/7 epitope directly and/or decreased the concentration of ligand required for epitope induction. In addition to the responsive receptor pool, cells expressed a second population of alpha 4 beta 1 integrin that was conformationally restrained, failing to respond to ligand or to any of the activating reagents. The relative size of the responsive and inactive receptor pools, as well as the affinity of the responsive receptors, represented a stable phenotype of different cell types and played important roles in defining the cells' adhesive capacity and ligand specificity. Similar receptor populations were measured on lymphocyte subsets in whole blood. These studies provide insight into how cells maintain different constitutive levels of alpha 4 beta 1 integrin activity, and how the activity of beta 1 integrin can be modulated by activators of cell adhesion.

Amino Acid Sequence↗

PubMed2001

Sustained activation of extracellular signal-regulated kinase stimulated by hepatocyte growth factor leads to integrin alpha 2 expression that is involved in cell scattering.

We have previously shown that hepatocyte growth factor (HGF) selectively increases the expression of integrin alpha(2) in Madin-Darby canine kidney (MDCK) cells. In this study, we have further investigated the signal transduction pathways responsible for the event and its role in HGF-induced cell scattering. We found that the level of integrin alpha(2)beta(1) expression induced by HGF correlated with the extent of cell scattering and that a functional blocking antibody against integrin alpha(2) at the concentration of 25 microg/ml partially (40%) inhibited the HGF-induced cell scattering. However, in the presence of the specific phosphatidylinositol 3-kinase inhibitor LY294002 or the selective Src family kinase inhibitor PP1, although cells retained their response to HGF for increasing integrin alpha(2) expression, they failed to scatter, indicating that increased expression of integrin alpha(2) alone is not sufficient for cell scattering. Moreover, epidermal growth factor, which induced a transient (1 h) activation of extracellular signal-regulated kinase (ERK) in MDCK cells, only slightly increased integrin alpha(2) expression and failed to trigger cell scattering. Conversely, HGF induced a sustained (at least 12 h) activation of ERK in the cells. Expression of constitutively active ERK kinase (MEK) in MDCK cells led to increased expression of integrin alpha(2) even in the absence of HGF stimulation. In contrast, expression of ERK phosphatase or dominant negative MEK inhibited HGF-induced integrin alpha(2) expression. Taken together, our results suggest that the increased expression of integrin alpha(2)beta(1) by HGF is at least partially required for cell scattering and that the duration of MEK/ERK activation is likely to be a crucial determinant for cells to activate integrin alpha(2) expression and cell scattering.

Animals↗

PubMed2003

Crucial role of the specificity-determining loop of the integrin beta4 subunit in the binding of cells to laminin-5 and outside-in signal transduction.

Within each hemidesmosome, alpha6beta4 integrin plays a crucial role in hemidesmosome assembly by binding to laminin-5 in the basement membrane zone of epithelial tissue. Recent analyses have implicated "specificity-determining loops" (SDLs) in the I-like domain of beta integrin in regulating ligand binding. Here, we investigated the function of an SDL-like motif within the extracellular I-like domain of beta4 integrin. We generated point mutations within the SDL of beta4 integrin tagged with green fluorescent protein (GFP-beta4K150A and GFP-beta4Q155L). We also generated a mutation within the I-like domain of the beta4 integrin, lying outside the SDL region (GFP-beta4V284E). We transfected constructs encoding the mutated beta4 integrins and a GFP-conjugated wild type beta4 integrin (GFP-beta4WT) into 804G cells, which assemble hemidesmosomes, and human endothelial cells, which express little endogenous beta4 integrin. In transfected 804G cells, GFP-beta4WT and GFP-beta4V284E colocalize with hemidesmosome proteins, whereas hemidesmosomal components in cells expressing GFP-beta4K150A and GFP-beta4Q155L are aberrantly localized. In endothelial cells, GFP-beta4WT and mutant proteins are co-expressed at the cell surface with alpha6 integrin. When transfected endothelial cells are plated onto laminin-5 matrix, GFP-beta4WT and GFP-beta4V284E localize with laminin-5, whereas GFP-beta4K150A and GFP-beta4Q155L do not. GFP-beta4WT and GFP-beta4V284E expressed in endothelial cells associate with the adaptor protein Shc when the cells are stimulated with laminin-5. However, GFP-beta4K150A and GFP-beta4Q155L fail to associate with Shc even when laminin-5 is present, thus impacting downstream signaling. These results provide evidence that the SDL segment of the beta4 integrin subunit is required for ligand binding and is involved in outside-in signaling.

Amino Acid Motifs↗

PubMed1997

The integrin alpha6beta4 functions in carcinoma cell migration on laminin-1 by mediating the formation and stabilization of actin-containing motility structures.

Functional studies on the alpha6beta4 integrin have focused primarily on its role in the organization of hemidesmosomes, stable adhesive structures that associate with the intermediate filament cytoskeleton. In this study, we examined the function of the alpha6beta4 integrin in clone A cells, a colon carcinoma cell line that expresses alpha6beta4 but no alpha6beta1 integrin and exhibits dynamic adhesion and motility on laminin-1. Time-lapse videomicroscopy of clone A cells on laminin-1 revealed that their migration is characterized by filopodial extension and stabilization followed by lamellae that extend in the direction of stabilized filopodia. A function-blocking mAb specific for the alpha6beta4 integrin inhibited clone A migration on laminin-1. This mAb also inhibited filopodial formation and stabilization and lamella formation. Indirect immunofluorescence microscopy revealed that the alpha6beta4 integrin is localized as discrete clusters in filopodia, lamellae, and retraction fibers. Although beta1 integrins were also localized in the same structures, a spatial separation of these two integrin populations was evident. In filopodia and lamellae, a striking colocalization of the alpha6beta4 integrin and F-actin was seen. An association between alpha6beta4 and F-actin is supported by the fact that alpha6beta4 integrin and actin were released from clone A cells by treatment with the F-actin- severing protein gelsolin and that alpha6beta4 immunostaining at the marginal edges of clone A cells on laminin-1 was resistant to solubilization with Triton X-100. Cytokeratins were not observed in filopodia and lamellipodia. Moreover, alpha6beta4 was extracted from these marginal edges with a Tween-40/deoxycholate buffer that solubilizes the actin cytoskeleton but not cytokeratins. Three other carcinoma cell lines (MIP-101, CCL-228, and MDA-MB-231) exhibited alpha6beta4 colocalized with actin in filopodia and lamellae. Formation of lamellae in these cells was inhibited with an alpha6-specific antibody. Together, these results indicate that the alpha6beta4 integrin functions in carcinoma migration on laminin-1 through its ability to promote the formation and stabilization of actin-containing motility structures.

Actins↗

PubMed1998

Modulation of integrin activity is vital for morphogenesis.

Cells can vary their adhesive properties by modulating the affinity of integrin receptors. The activation and inactivation of integrins by inside-out mechanisms acting on the cytoplasmic domains of the integrin subunits has been demonstrated in platelets, lymphocytes, and keratinocytes. We show that in the embryo, normal morphogenesis requires the alpha subunit cytoplasmic domain to control integrin adhesion at the right times and places. PS2 integrin (alphaPS2betaPS) adhesion is normally restricted to the muscle termini, where it is required for attaching the muscles to the ends of other muscles and to specialized epidermal cells. Replacing the wild-type alphaPS2 with mutant forms containing cytoplasmic domain deletions results in the rescue of the majority of defects associated with the absence of the alphaPS2 subunit, however, the mutant PS2 integrins are excessively active. Muscles containing these mutant integrins make extra muscle attachments at aberrant positions on the muscle surface, disrupting the muscle pattern and causing embryonic lethality. A gain- of-function phenotype is not observed in the visceral mesoderm, showing that regulation of integrin activity is tissue-specific. These results suggest that the alphaPS2 subunit cytoplasmic domain is required for inside-out regulation of integrin affinity, as has been seen with the integrin alphaIIbbeta3.

Amino Acid Sequence↗

PubMed2002

An extracellular site on tetraspanin CD151 determines alpha 3 and alpha 6 integrin-dependent cellular morphology.

The alpha 3 beta 1 integrin shows strong, stoichiometric, direct lateral association with the tetraspanin CD151. As shown here, an extracellular CD151 site (QRD(194-196)) is required for strong (i.e., Triton X-100-resistant) alpha 3 beta 1 association and for maintenance of a key CD151 epitope (defined by monoclonal antibody TS151r) that is blocked upon alpha 3 integrin association. Strong CD151 association with integrin alpha 6 beta 1 also required the QRD(194-196) site and masked the TS151r epitope. For both alpha 3 and alpha 6 integrins, strong QRD/TS151r-dependent CD151 association occurred early in biosynthesis and involved alpha subunit precursor forms. In contrast, weaker associations of CD151 with itself, integrins, or other tetraspanins (Triton X-100-sensitive but Brij 96-resistant) were independent of the QRD/TS151r site, occurred late in biosynthesis, and involved mature integrin subunits. Presence of the CD151-QRD(194-196)-->INF mutant disrupted alpha 3 and alpha 6 integrin-dependent formation of a network of cellular cables by Cos7 or NIH3T3 cells on basement membrane Matrigel and markedly altered cell spreading. These results provide definitive evidence that strong lateral CD151-integrin association is functionally important, identify CD151 as a key player during alpha 3 and alpha 6 integrin-dependent matrix remodeling and cell spreading, and support a model of CD151 as a transmembrane linker between extracellular integrin domains and intracellular cytoskeleton/signaling molecules.

Animals↗

PubMed2004

Bone sialoprotein, matrix metalloproteinase 2, and alpha(v)beta3 integrin in osteotropic cancer cell invasion.

BACKGROUND: Bone sialoprotein (BSP) interacts separately with both matrix metalloproteinase 2 (MMP-2) and integrin alpha(v)beta3 and is overexpressed in many metastatic tumors. Its role in tumor biology, however, remains unclear. We investigated whether BSP enhances cancer cell invasiveness by forming a trimolecular complex with MMP-2 and cell-surface integrin alpha(v)beta3. METHODS: Invasiveness of breast, prostate, lung, and thyroid tumor cell lines was measured with a modified Boyden chamber assay. Binding and co-localization of BSP, MMP-2, and integrin alpha(v)beta3 were investigated with immunoprecipitation and in situ hybridization. All statistical tests were two-sided. RESULTS: Treatment with BSP increased invasiveness of many breast, prostate, lung, and thyroid cancer cells through Matrigel in a dose-dependent manner. BSP at 50 nM increased the invasiveness of SW-579 thyroid cancer cells (95.2 units, 95% confidence interval [CI] = 90.4 to 100 units) by approximately 10-fold compared with that of untreated control SW-579 cells (9.1 units, 95% CI = 5.7 to 12.5 units) (P<.001). Addition of an inactive mutated BSP, in which BSP's integrin-binding RGD tripeptide was altered, or addition of integrin alpha(v)beta3-blocking antibodies resulted in invasiveness equivalent to that of untreated cells. Inhibiting cellular MMP-2 activity with chemical inhibitors or a specific antibody also blocked BSP-enhanced invasiveness. Osteopontin and dentin matrix protein 1, proteins related to BSP that also bind integrin alpha(v)beta3 and form complexes with other MMPs (but not MMP-2), did not enhance invasiveness. Immunoprecipitation showed that a complex containing BSP, integrin alpha(v)beta3, and MMP-2 formed in vitro. Addition of BSP increased the amount of MMP-2 bound by cells in an integrin-dependent fashion. Co-expression of BSP, integrin alpha(v)beta3, and MMP-2 in papillary thyroid carcinoma cells was shown by in situ hybridization. CONCLUSION: Cancer cells appear to become more invasive when BSP forms a cell-surface trimolecular complex by linking MMP-2 to integrin alpha(v)beta3.

Bone Neoplasms↗

PubMed1997

Increased expression of integrins on fibroblast-like synoviocytes from rheumatoid arthritis in vitro correlates with enhanced binding to extracellular matrix proteins.

OBJECTIVE: To compare in vitro expression of beta 1, beta 3, and beta 4 integrins in normal fibroblast-like synoviocytes (FBS) and in FBS from rheumatoid arthritis (RA) synovium and to investigate the adhesion of normal FBS and RA-FBS to the integrin binding extracellular matrix (ECM) proteins: collagen type IV, fibronectin, laminin, and tenascin. METHODS: Expression of integrin receptors of cultured FBS was detected by flow cytometry. Attachment of FBS to ECM proteins was quantified by adhesion assays. Inhibition studies were performed using monoclonal antibodies to the integrin subunits. RESULTS: Compared with normal FBS, RA-FBS showed increased expression of alpha 1 to alpha 6, beta 1, and beta 4 integrin subunits and enhanced binding of ECM proteins. Binding to ECM proteins was partly or completely blocked by an anti-beta 1 integrin antibody and antibodies to alpha 3, alpha 5, and alpha 6 integrin subunits. The blocking efficiency was significantly (P < 0.05) higher in RA-FBS than in normal FBS. CONCLUSIONS: The enhanced expression of the beta 1 integrin receptors on cultured RA-FBS correlated with increased attachment to ECM proteins. Adhesion of normal and RA-FBS to ECM proteins is mediated through beta 1 integrin receptors. Therefore, the tight binding of rheumatoid FBS to the matrix via beta 1 integrins might play a role in ECM remodelling in the rheumatoid process in vivo.

Arthritis, Rheumatoid↗

PubMed1995

MCP-1-stimulated monocytes preferentially utilize beta 2-integrins to migrate on laminin and fibronectin.

Recruitment of monocytes to inflammatory sites involves a series of sequential attachments and detachments to extracellular matrix proteins in response to a chemoattractant gradient. In this study we compared the migration of human peripheral blood monocytes on different extracellular matrix proteins in response to monocyte chemoattractant protein-1 (MCP-1) and N-formylmethionyl-leucyl-phenylalanine. Monocytes migrated more effectively on laminin compared with other extracellular matrix proteins. In contrast, this preference was not observed with neutrophils, suggesting that the monocytes and neutrophils may have differences in their migration on extracellular matrix proteins. To study this further, function-blocking monoclonal antibodies were used to examine mechanistically whether beta 1- and beta 2-integrins were involved in monocyte migration on fibronectin or laminin in response to MCP-1. Monocyte migration on both laminin and fibronectin was blocked 100% (P < 0.05) by intact monoclonal antibody, F(ab') fragments, and F(ab')2 fragments to beta 2-integrins. We also determined that antibodies to beta 2-integrins block monocyte migration that has already been initiated. In contrast, antibody to the beta 1-integrins inhibited monocyte migration by approximately 40% (P < 0.05). Thus monocytes that express both beta 1- and beta 2-integrins require utilization of beta 2-integrins in migration on extracellular matrix proteins. The results also suggest that beta 1-integrins facilitate monocyte migration but that monocyte migration is not absolutely dependent on the interaction of beta 1-integrins with extracellular matrix proteins. In contrast, neutrophil migration is beta 2-integrin dependent and is not facilitated by beta 1-integrins.

CD18 Antigens↗

PubMed2000

Integrin alpha(3)-subunit expression modulates alveolar epithelial cell monolayer formation.

We investigated expression of the alpha(3)-integrin subunit by rat alveolar epithelial cells (AECs) grown in primary culture as well as the effects of monoclonal antibodies with blocking activity against the alpha(3)-integrin subunit on AEC monolayer formation. alpha(3)-Integrin subunit mRNA and protein were detectable in AECs on day 1 and increased with time in culture. alpha(3)- and beta(1)-integrin subunits coprecipitated in immunoprecipitation experiments with alpha(3)- and beta(1)-subunit-specific antibodies, consistent with their association as the alpha(3)beta(1)-integrin receptor at the cell membrane. Treatment with blocking anti-alpha(3) monoclonal antibody from day 0 delayed development of transepithelial resistance, reduced transepithelial resistance through day 5 compared with that in untreated AECs, and resulted in large subconfluent patches in monolayers viewed by scanning electron microscopy on day 3. These data indicate that alpha(3)- and beta(1)-integrin subunits are expressed in AEC monolayers where they form the heterodimeric alpha(3)beta(1)-integrin receptor at the cell membrane. Blockade of the alpha(3)-integrin subunit inhibits formation of confluent AEC monolayers. We conclude that the alpha(3)-integrin subunit modulates formation of AEC monolayers by virtue of the key role of the alpha(3)beta(1)-integrin receptor in AEC adhesion.

Animals↗

PubMed2005

A direct test of potential roles for beta3 and beta5 integrins in growth and metastasis of murine mammary carcinomas.

alphavbeta3 or alphavbeta5 integrins are widely expressed on blood and endothelial cells. Inhibition of the functions of these integrins has been reported to suppress neovascularization and tumor growth, suggesting that they may be critical modulators of angiogenesis. However, mice lacking these integrins exhibit extensive angiogenesis. Tumors arising from s.c. injections of tumor cells into mice lacking one or both integrins show enhanced tumor growth compared with growth in control mice due to both increased angiogenesis and to altered innate immune response. Other data suggest additional roles for these integrins, on either platelets or the tumor cells themselves, in enhancing tumor progression and metastasis. Here, we investigate the involvement of beta3 and beta5 integrins in the development and progression of mammary carcinomas. We intercrossed mouse mammary tumor virus (MMTV)-c-neu transgenic mice with beta3 or beta5 or beta3beta5 integrin-deficient mice and observed that multiple, large mammary tumors developed in 100% of mice on all genetic backgrounds. A statistically significant earlier onset of tumor growth was observed in the MMTV-c-neu/beta3beta5 integrin-null females compared with control mice. No major differences were observed in tumor size or number, vessel number or vessel structure and lung metastases were observed with similar frequency and size in all strains. MMTV-c-neu/beta3beta5 integrin-null mice had higher numbers of mammary acini, which may account for the earlier onset of tumors in this strain. These data indicate that alphavbeta3 or alphavbeta5 integrins are not essential for tumor growth and progression, although they might play some role in mammary gland development.

Animals↗

PubMed2006

Regulation of postangiogenic neovessel survival by beta1 and beta3 integrins in collagen and fibrin matrices.

We used the aortic ring model of angiogenesis to investigate the role of beta(1) and beta(3) integrins in postangiogenic vascular survival in collagen and fibrin matrices. Confocal microscopy studies showed that both beta(1) and beta(3) integrins were expressed in endothelial cells and pericytes of sprouting neovessels. Antibody blocking experiments demonstrated that beta(1) integrins but not beta(3) integrins were required for angiogenic sprouting in collagen. Conversely, in fibrin, blockade of both integrins was needed to inhibit angiogenesis whereas treatment with either antibody alone was ineffective. Antibody-mediated blockade of beta(1) but not beta(3) integrins accelerated vascular regression in collagen. In contrast, both anti-beta(1) and -beta(3) integrin antibodies were required to promote neovessel breakdown in fibrin. These results demonstrate that angiogenic sprouting and postangiogenic neovessel survival in collagen are critically dependent on beta(1) integrins. They also indicate that these processes involve a redundant repertoire of beta(1) and beta(3) integrins when angiogenesis occurs in fibrin. Thus, pharmacologic targeting of integrin receptors aimed at blocking neovessel formation and survival must be tailored to the specific extracellular matrix environment in which angiogenesis takes place.

Animals↗