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PubMed2004

Bovine respiratory syncytial virus infection influences the impact of alpha- and beta-integrin-mediated adhesion of peripheral blood neutrophils.

Neutrophil migration into the airways and pulmonary tissue is a common finding in bovine respiratory syncytial virus (BRSV) infections. Although neutrophil trans-endothelial migration in general depends on beta2-integrins, alternative integrins such as the alpha4-integrins have been implicated. In this study, rolling and firm adhesion of peripheral blood neutrophils isolated from healthy and BRSV-infected calves to tumour necrosis factor (TNF)-alpha activated pulmonary endothelium was investigated under flow conditions in vitro. For neutrophils obtained from healthy animals, inhibition of the beta2-integrin reduced firm adhesion to 63% and inhibition of alpha4-integrin to 73% compared with untreated controls. Inhibition of both integrins reduced firm adhesion to 25%. Rolling velocity, which is used as a parameter for integrin involvement in neutrophil rolling, increased 1.7-fold by blocking beta2-integrin and was significantly augmented to 2.5-fold by blocking both alpha4- and beta2-integrins. For neutrophils obtained from BRSV-infected animals, however, rolling velocities at 10 days after infection (p.i.) were not influenced by blocking adhesion of alpha4- and beta2-integrins, indicating that these integrins did not support neutrophil rolling. In addition, the inhibition of firm adhesion by blocking both alpha4- and beta2-integrins was reduced significantly 9 days post-infection, resulting in a residual 68% neutrophil binding at 9 days p.i. Non-blocked firm adherence was not reduced, indicating that binding was achieved by other mechanisms than through alpha4- and beta2-integrins. These results demonstrate an important function for alpha4- and beta2-integrins in rolling and firm adherence of bovine neutrophils, to TNF-alpha-activated endothelium and show the dynamic use of these integrins for adhesion and migration by neutrophils in the course of BRSV infection.

Animals↗

PubMed1997

Complementation of dominant suppression implicates CD98 in integrin activation.

The integrin family of adhesion receptors are involved in cell growth, migration and tumour metastasis. Integrins are heterodimeric proteins composed of an alpha and a beta subunit, each with a large extracellular, a single transmembrane, and a short cytoplasmic domain. The dynamic regulation of integrin affinity for ligands in response to cellular signals is central to integrin function. This process is energy dependent and is mediated through integrin cytoplasmic domains. However, the cellular machinery regulating integrin affinity remains poorly understood. Here we describe a genetic strategy to disentangle integrin signalling pathways. Dominant suppression occurs when overexpression of isolated integrin beta1 cytoplasmic domains blocks integrin activation. Proteins involved in integrin signalling were identified by their capacity to complement dominant suppression in an expression cloning scheme. CD98, an early T-cell activation antigen that associates with functional integrins, was found to regulate integrin activation. Furthermore, antibody-mediated crosslinking of CD98 stimulated beta1 integrin-dependent cell adhesion. These data indicate that CD98 is involved in regulating integrin affinity, and validate an unbiased genetic approach to analysing integrin signalling pathways.

Animals↗

PubMed2005

Role of integrin receptors for fibronectin, collagen and laminin in the regulation of ovarian carcinoma functions in response to a matrix microenvironment.

Integrins play an important role in cellular matrix interactions requisite for cancer cell adhesion, growth, migration and invasion. In this study, we have investigated the expression of integrin subunits alpha3, alpha6, alphav and beta1 in normal ovaries, benign ovarian tumors and ovarian carcinomas of different pathological grades. The expression of these integrins in ovarian cancer cell lines was also investigated, and their role in sustaining proliferation, adhesion, migration and invasion in cohort with the activation of signaling pathways in response to extracellular matrices (ECM) was evaluated. We demonstrate a differential expression pattern of alpha3, alpha6, alphav and beta1 integrin subunits in ovarian carcinomas compared to normal ovaries and benign ovarian tumors. Ovarian cancer cell lines (Hey, Ovcar3 and Peo.36) demonstrated significantly high expression of alpha3, alpha6, alphav and beta1 integrin subunits. A significant increase in proliferation and adhesion (P<0.05) in response to collagen 1 (Coll) and laminin (LM), ligands for integrin receptor alpha3beta1 and alpha6beta1 was observed in ovarian cancer cell lines. On the other hand, fibronectin (FN), a receptor for alphavbeta1 integrin, increased proliferation in all ovarian cancer cell lines studied but only enhanced adhesion in Hey cell line (P<0.05). Neutralizing antibodies against alpha3, alpha6, alphav and beta1 integrin subunits inhibited ECM-induced proliferation, but increased adhesion to ECM was inhibited by beta1 integrin subunit antibody. No suppression of Coll, LM and FN-induced (Hey cells only) adhesion was observed in the presence of alpha3 or alphav subunit antibodies but LM-induced adhesion was inhibited by blocking alpha6 subunit functions. LM, FN and Coll enhanced chemotactic migration in Hey cells, but direct invasion across ECM was observed only in the presence of LM and Coll. Blocking antibodies against alpha3, alpha6 and beta1 integrin subunits inhibited both chemotactic migration and invasion of Hey cells in response to respective ECM. Adhesion of ovarian cancer cells to FN, Coll and LM activated Ras, Erk and Akt pathways. Neutralizing alphav and beta1 functions did not inhibit FN-induced activation of Ras and Erk pathways but inhibited the Akt pathway. On the other hand, antibodies against alpha6 and beta1 subunits, but not alpha3 subunit, inhibited LM-induced activation of Ras but did not inhibit the downstream Akt pathway. Neutralizing beta1 subunit function however, inhibited LM-induced Erk activation. Coll-induced activation of Ras, Erk and Akt pathways was inhibited by alpha3 and beta1 integrin subunit antibodies. These results indicate that alpha3beta1, alphavbeta1 and alpha6beta1 integrin mediate proliferation, adhesion, migration and invasion of ovarian cancer cells in response to ECM and targeting these integrins to modulate integrin-ECM interactions in tumor cells may be a promising tool to reduce the dissemination of ovarian carcinoma in vivo.

Carcinoma↗

PubMed1999

Amino acid motifs required for isolated beta cytoplasmic domains to regulate 'in trans' beta1 integrin conformation and function in cell attachment.

The role of beta cytoplasmic domains in regulating beta1 integrin conformation and function in cell attachment is not fully understood. In this study, we tested the ability of transiently expressed beta cytoplasmic domains connected to an extracellular reporter domain to regulate 'in trans' the conformation of endogenous beta1 integrins, and compared these effects on cell attachment. We found that chimeric receptors containing either the beta1, beta3 or beta5 cytoplasmic domains inhibited the expression of the conformationally dependent 9EG7 and 12G10 epitopes on endogenous beta1 integrins. In contrast, chimeric receptors containing the beta4 or alpha5 cytoplasmic domain, or a control receptor lacking a cytoplasmic domain, had no effect. This inhibition occurred in a dose-dependent manner that required high levels of expression of the chimeric receptor. These results suggest that beta1 integrin conformation can be regulated by conserved cytosolic interactions involving beta cytoplasmic domains. This is further supported by our findings that mutations within amino acid motifs conserved among these beta cytoplasmic domains, specifically the NXXY, NPXY and TST-like motifs, reduced the ability of these chimeric receptors to regulate beta1 integrin conformation. Interestingly, the chimeric receptors inhibited cell attachment in a similar dose-dependent manner and required intact NXXY, NPXY, and TST-like motifs. The beta1 chimera also inhibited the binding of soluble fibronectin to endogenous beta1 integrins. Thus, the concomitant inhibition in the expression of conformation-dependent integrin epitopes, cell attachment and ligand binding by the chimeras, suggests that the expression of the 9EG7 and 12G10 epitopes correlates with integrin function. However, Mn2+, which is an extracellular activator of integrin function, increased 9EG7 expression to basal levels in the presence of the beta1 chimera, but did not rescue cell attachment to the same extent. Thus, although the beta1 integrin conformation recognized by mAb 9EG7 may be required for cell attachment, it is not sufficient, suggesting that the beta chimeras may be inhibiting both ligand binding and post-ligand binding events required for cell attachment. In addition, the inhibitory effects of the chimeric receptors on cell attachment were not reversed by the addition of the pharmacological agents that inhibit intracellular signals previously shown to inhibit integrin function. This finding, together with the requirement for high levels of the chimeric receptors and the fact that mutations in the same conserved motifs in heterodimeric beta1 integrins have been reported to regulate beta1 integrin conformation and function in cell attachment, suggest that beta cytoplasmic domains regulate these processes by interacting with cytosolic factors and that the regulatory effect of the chimeras may be due to their ability to titrate proteins from endogenous integrins.

Amino Acid Sequence↗

PubMed1998

Transcription of alpha2 integrin gene in osteosarcoma cells is enhanced by tumor promoters.

Integrin alpha2beta1 is a heterodimeric transmembrane receptor for collagens. In osteogenic cells the expression of alpha2beta1 integrin is induced by both Kirsten sarcoma virus and chemical transformation. The association of alpha2 integrin with transformed cell phenotype was studied further by testing the effects of two tumor promoters, 12-O-tetradecanoylphorbol 13-acetate (TPA) and okadaic acid (OA), on human MG-63 osteosarcoma cells. TPA, an activator of protein kinase C, increased the cell surface expression of alpha2 integrin and the corresponding mRNA levels. Nuclear run-on assays indicated that TPA activated the transcription of alpha2 integrin gene. TPA also slightly increased the expression of alpha3 integrin but had no effect on the transcription of alpha5, alphav, or beta1 integrin subunits. OA, an inhibitor of serine/threonine phosphatases, increased alpha2 integrin gene transcription and mRNA levels, but in contrast to TPA, OA decreased alpha3 integrin expression. The increased expression of alpha2 integrin on TPA-treated MG-63 cells led to faster cell spreading on type I collagen. Our results link the enhanced transcription of alpha2 integrin gene to tumor progression and show the independent regulation of alpha2 integrin compared to other integrin genes.

Antigens, CD↗

PubMed1995

Up-regulation of a novel integrin alpha-chain (alpha mt) on human fetal myotubes.

Integrin expression and distribution was studied in cloned human fetal G6 myoblasts and myotubes. Immunoprecipitation of beta 1 integrins from surface iodinated and metabolically labeled G6 cells typically showed a five-fold induction of a beta 1 integrin associated protein upon differentiation. Under non-reducing conditions this beta 1 associated protein migrated as 145 kD. No such beta 1 associated protein was observed in the myogenic L8 rat cell line, before or after differentiation. The beta 1 integrin associated cell surface protein present in G6 myotubes remained associated with the beta 1 subunit in the presence of 1% Triton X-100 and 0.5 M NaCl. Like integrin alpha-chains, the protein dissociated from the beta 1 integrin subunit at low pH. Immunoprecipitation of G6 myotubes further indicated the presence of alpha 1, alpha 3, alpha 5, and alpha v integrins, and small amounts of alpha 4 and alpha 6 integrins. Immunodepletion with integrin alpha-chain antibodies to alpha 1, alpha 3, alpha 4, alpha 5, alpha 6, and alpha v integrin chains could not deplete the beta 1 integrin associated protein, indicating that it did not interact with any of these known integrin heterodimers. Upon treatment with reducing agents, the beta 1 integrin associated protein migrated in SDS-PAGE as a 155 kD protein. The decreased mobility in SDS-PAGE upon reduction is a feature shared with alpha 1, alpha 2, and alpha 9 integrin alpha-chains. Antibodies to alpha 1 immunoprecipitated an integrin heterodimer distinct from the 155 kD protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Differentiation↗

PubMed2000

The effect of integrin antibodies on the attachment and proliferation of human Tenon's capsule fibroblasts.

The integrins are protein heterodimers consisting of noncovalently associated alpha and beta subunits. The adhesive interactions mediated by integrins are necessary for cellular survival and proliferation. In this study we investigated the effects of three different integrin antibodies on the proliferation of human Tenon's capsule fibroblasts in tissue culture. Human Tenon's capsule fibroblasts were cultured into 96 well plates and treated with different concentrations (ranging from 10(-6) to 1 microg ml(-1)) of three different integrin antibodies: human integrin alpha-2 antibody, human integrin alpha-3 antibody and human integrin alpha-5/FnR (fibronectin receptor) antibody. Coulter counter, hexosaminidase, and 3H-thymidine assays were used to determine the inhibitory effects of these integrin antibodies on ocular fibroblasts on days 0 (attachment), 1,3 and 7 following antibody treatment. The concentration of each antibody required to produce a proliferation 50% less than the control (ID50) was calculated for each assay. With respect to attachment, all three antibodies studied displayed some inhibitory activity. All three antibodies also displayed dose-dependent antiproliferative properties, especially at the highest concentration tested after 7 days of exposure. The integrin alpha-2 antibody was the most potent of the inhibitors, followed by the integrin alpha-3 antibody, with the integrin alpha-5 antibody being the least potent antibody tested. In addition, the anti-proliferative activities of the integrin alpha-2 and integrin alpha-3 antibodies increased with increasing incubation time. In conclusion, these integrin antibodies demonstrated some inhibitory effects on the attachment and proliferation of human Tenon's capsule fibroblasts in culture. Further investigation will be required to determine whether integrin antibodies can significantly limit scar formation in vivo without significant toxicity.

Antibodies↗

PubMed1993

Integrins and their ligands.

Integrins are expressed on almost every cell type and are responsible for the linkage of the extracellular matrix with the cytoskeleton. In this review I have focused on the intra- and extracellular proteins that bind to integrins. Although many integrins bind to the same extracellular ligand, they mostly recognize different sites on these ligands. Some integrins interact with the same site but then there are requirements for different additional sequences to obtain high affinity. By modulating the expression and activity of integrins in the plasma membrane, cells can adapt their capacity of binding to the matrix. How integrins become activated is as yet not clear, but interaction with other proteins or lipids may be critical. Binding to ligands could also be modulated by alternative splicing of mRNAs for ligand binding sites in the extracellular domain. In Drosophila, the mRNA for the extracellular domain of the PS2 integrin is spliced near a site implicated in ligand binding. In humans, however, there are no indications that alternative splicing contributes to the regulation of function of the extracellular domain of integrins. The only splice variant of the extracellular domain of an integrin identified so far concerns are alpha subunit of the alpha IIb beta 3 complex, but the splicing occurs in a region that has not been implicated in cell adhesion. There is also no evidence as yet that integrin function can be modulated by alternative splicing of mRNA for the cytoplasmic domain of integrin subunits. However, the loss of function seen with some deletion mutants of the cytoplasmic domains of integrin subunits suggests that such a mechanism may well exist. In a different way the binding capacity of a given cell can be influenced by regulating the expression of its ligand or by alternative mRNA splicing of sequences encoding the cell binding domain in their ligands. In the case of fibronectin, the mRNA for one of the integrin binding sites is subject to alternative splicing. The mRNAs for the three chains of laminin appear not to be subject to alternative splicing but, by combining different variant chains of laminin, isoforms can be generated which may have different affinities for integrins. Binding of cells to the matrix therefore does not only depend on the expression and activity of the correct integrin but also of the correct variant of the ligand.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

PubMed2006

Loss of beta1D-integrin function in human ischemic cardiomyopathy.

Integrins play a pivotal role in cardiomyocyte survival and function, with integrin loss leading to myocyte apoptosis and heart failure. The aim of this study was to characterize whether regulation of integrins may contribute to cardiac remodeling in human ischemic cardiomyopathy (ICM). Myocardial tissues of the left ventricle were obtained from patients with ICM (n = 8) undergoing cardiac transplantation and from unused donor hearts (NF, n = 8). In addition, tissue samples from patients with dilated cardiomyopathy (DCM, n = 5) were analyzed. Expression of integrins beta(1)D and beta(3), the effector proteins focal adhesion kinase (FAK) and melusin, and FAK phosphorylation were examined by Western blotting, real-time-PCR and immunofluorescence analysis, respectively. Beta(1)D-integrin protein was decreased in ICM vs. NF by 36%. Beta(1)D-integrin mRNA levels and beta(1)D-integrin shedding were unchanged. Corresponding to beta(1)D-integrin regulation, FAK and phosphorylated FAK were decreased in ICM vs. NF by 54% and 49%, respectively. beta(3)-integrin and melusin were not altered in ICM. As a mediator of integrin effects, AKT kinase activity was examined. In parallel to beta(1)D-integrin and FAK, AKT activity was decreased in ICM by 44%. In contrast, none of the proteins were significantly altered in DCM compared to NF. Integrins and integrin signaling are regulated differentially in ICM and DCM with a decrease of beta(1)D-integrin and FAK in ICM. The loss of the beta(1)Dintegrin-FAK-complex in ICM was paralleled by a reduced AKT activity supporting in vitro data which demonstrate the pivotal role of intact integrin function in anti-apoptotic signaling and cell survival.

Blotting, Western↗

PubMed2001

Induction of beta3-integrin gene expression by sustained activation of the Ras-regulated Raf-MEK-extracellular signal-regulated kinase signaling pathway.

Alterations in the expression of integrin receptors for extracellular matrix (ECM) proteins are strongly associated with the acquisition of invasive and/or metastatic properties by human cancer cells. Despite this, comparatively little is known of the biochemical mechanisms that regulate the expression of integrin genes in cells. Here we demonstrate that the Ras-activated Raf-MEK-extracellular signal-regulated kinase (ERK) signaling pathway can specifically control the expression of individual integrin subunits in a variety of human and mouse cell lines. Pharmacological inhibition of MEK1 in a number of human melanoma and pancreatic carcinoma cell lines led to reduced cell surface expression of alpha6- and beta3-integrin. Consistent with this, conditional activation of the Raf-MEK-ERK pathway in NIH 3T3 cells led to a 5 to 20-fold induction of cell surface alpha6- and beta3-integrin expression. Induced beta3-integrin was expressed on the cell surface as a heterodimer with alphav-integrin; however, the overall level of alphav-integrin expression was not altered by Ras or Raf. Raf-induced beta3-integrin was observed in primary and established mouse fibroblast lines and in mouse and human endothelial cells. Consistent with previous reports of the ability of the Raf-MEK-ERK signaling pathway to induce beta3-integrin gene transcription in human K-562 erythroleukemia cells, Raf activation in NIH 3T3 cells led to elevated beta3-integrin mRNA. However, unlike immediate-early Raf targets such as heparin binding epidermal growth factor and Mdm2, beta3-integrin mRNA was induced by Raf in a manner that was cycloheximide sensitive. Surprisingly, activation of the Raf-MEK-ERK signaling pathway by growth factors and mitogens had little or no effect on beta3-integrin expression, suggesting that the expression of this gene requires sustained activation of this signaling pathway. In addition, despite the robust induction of cell surface alphavbeta3-integrin expression by Raf in NIH 3T3 cells, such cells display decreased spreading and adhesion, with a loss of focal adhesions and actin stress fibers. These data suggest that oncogene-induced alterations in integrin gene expression may participate in the changes in cell adhesion and migration that accompany the process of oncogenic transformation.

3T3 Cells↗

PubMed1994

Characterization of integrins in cultured human renal cortical tubule epithelial cells.

We have characterized the integrins present on cultured tubule epithelial cells from human renal cortexes, enriched for proximal cells, using fluorescence microscopy, immunoprecipitation, and cell adhesion assays. By immunofluorescence, the alpha 3-integrin subunit stained most intensely and was present on all cells predominantly at cell-cell contacts. The alpha 6-subunit was present on all cells in a pattern consistent with extracellular matrix contacts. The alpha 5-subunit was present on most cells in a cell-matrix contact pattern; alpha V-subunit was weakly positive and occasionally seen in cell-matrix contacts. The alpha 2-subunit was present on clusters of distal tubule cells, predominantly at cell-cell contacts. Immunoprecipitation revealed the predominant integrin to be alpha 3 beta 1 with some alpha 2 beta 1, presumably contributed by distal cells. The alpha 5 beta 1-, alpha 6 beta 1-, alpha 6 beta 4-, and alpha V beta 3-integrins, as well as trace amounts of alpha 1 beta 1-integrins, were also present. The alpha 4 beta 1-integrin was not detected. Initial attachment to fibronectin was mediated by alpha V beta 3- and alpha 5 beta 1-integrins; initial attachment to laminin was mediated by the alpha 6 beta 1- and alpha 3 beta 1- integrins and, in some preparations, by an unidentified integrin; and initial attachment to collagen type IV was mediated by alpha V beta 3-integrin and an unidentified beta 1-integrin. After extensively immunodepleting membrane extracts with anti-alpha 1, -alpha 2, -alpha 3, -alpha 4, -alpha 5, -alpha 6, and -alpha V antibodies, an anti-beta 1 antibody still precipitated an integrin. Its electrophoretic mobility differs from the laminin-binding alpha 7 beta 1-integrin. Thus we have identified many of the integrins on cortical tubule cells and their role in mediating initial attachment to extracellular matrix. However, the cell adhesion assays and immunoprecipitations suggest the presence of an unidentified beta 1-integrin that may mediate renal tubule cell attachment to laminin and collagen.

Cell Adhesion↗

PubMed2006

Beta3 integrin and Src facilitate transforming growth factor-beta mediated induction of epithelial-mesenchymal transition in mammary epithelial cells.

INTRODUCTION: Transforming growth factor (TGF)-beta suppresses breast cancer formation by preventing cell cycle progression in mammary epithelial cells (MECs). During the course of mammary tumorigenesis, genetic and epigenetic changes negate the cytostatic actions of TGF-beta, thus enabling TGF-beta to promote the acquisition and development of metastatic phenotypes. The molecular mechanisms underlying this conversion of TGF-beta function remain poorly understood but may involve signaling inputs from integrins. METHODS: beta3 Integrin expression or function in MECs was manipulated by retroviral transduction of active or inactive beta3 integrins, or by transient transfection of small interfering RNA (siRNA) against beta3 integrin. Altered proliferation, invasion, and epithelial-mesenchymal transition (EMT) stimulated by TGF-beta in control and beta3 integrin manipulated MECs was determined. Src involvement in beta3 integrin mediated alterations in TGF-beta signaling was assessed by performing Src protein kinase assays, and by interdicting Src function pharmacologically and genetically. RESULTS: TGF-beta stimulation induced alphavbeta3 integrin expression in a manner that coincided with EMT in MECs. Introduction of siRNA against beta3 integrin blocked its induction by TGF-beta and prevented TGF-beta stimulation of EMT in MECs. beta3 integrin interacted physically with the TGF-beta receptor (TbetaR) type II, thereby enhancing TGF-beta stimulation of mitogen-activated protein kinases (MAPKs), and of Smad2/3-mediated gene transcription in MECs. Formation of beta3 integrin:TbetaR-II complexes blocked TGF-beta mediated growth arrest and increased TGF-beta mediated invasion and EMT. Dual beta3 integrin:TbetaR-II activation induced tyrosine phosphorylation of TbetaR-II, a phosphotransferase reaction mediated by Src in vitro. Inhibiting Src activity in MECs prevented the ability of beta3 integrin to induce TbetaR-II tyrosine phosphorylation, MAPK activation, and EMT stimulated by TGF-beta. Lastly, wild-type and D119A beta3 integrin expression enhanced and abolished, respectively, TGF-beta stimulation of invasion in human breast cancer cells. CONCLUSION: We show that beta3 integrin alters TGF-beta signaling in MECs via Src-mediated TbetaR-II tyrosine phosphorylation, which significantly enhanced the ability of TGF-beta to induce EMT and invasion. Our findings suggest that beta3 integrin interdiction strategies may represent an innovative approach to re-establishing TGF-beta mediated tumor suppression in progressing human breast cancers.

Animals↗

PubMedDate not supplied

Increased expression of integrin beta1 is a poor prognostic factor in small-cell lung cancer.

The purpose of this study was to investigate the possible association between the expression of integrin beta1 and response to chemotherapy and survival in patients with small cell lung cancer (SCLC). One-hundred and four patients with SCLC, who had received an initial course of chemotherapy between February 1989 and July 1999, were entered into the study. There were 91 males and 13 females, with a median age of 65 years (range 40-85 years). The clinical stage of the tumors was recorded as limited disease in 43 patients and extensive disease in 61. Each patient received a full-dose of combination chemotherapy. Transbroncheal biopsy specimens of tumors obtained before chemotherapy were subjected to immunostaining for integrin beta1. Twenty-nine patients could not be evaluated for integrin beta1 immunostaining, because the tissue samples had been crushed during the biopsy procedure. Fifty-three patients had tumors with < or = 25% integrin beta1-positive cells and 22 patients had tumor with > 25% integrin beta1-positive cells. Among 75 patients whose biopsy specimens were evaluable for integrin beta1, the overall response rate to chemotherapy was 87%. When the relationship between integrin beta1 expression and tumor response to chemotherapy was considered, 17 out of 22 patients with high expression of integrin beta1 and 48 out of 53 patients with low expression of integrin beta1 showed tumor response, although the resistance rate in patients with high expression of integrin beta1 was over twice that of patients with low expression of integrin beta1 (23% vs. 9%, respectively). By comparison, the overall survival of patients with high expression of integrin beta1 (n = 22) was significantly worse than that of individuals whose tumors had low expression of integrin beta1 (n = 53; log-rank test, p=0.043; Wilcoxon test, p=0.049). The association between survival and prognostic factors was examined by multivariate regression analysis; clinical stage and integrin beta1 were found to be independent factors (p = 0.018 andp = 0.041, respectively). In conclusion, the high expression of integrin beta1 in tumor cells is a poorprognostic factor in patients with SCLC.

Adult↗

PubMedDate not supplied

Different phenotypes in human prostate cancer: alpha6 or alpha3 integrin in cell-extracellular adhesion sites.

The distribution of alpha6/alpha3 integrin in adhesion complexes at the basal membrane in human normal and cancer prostate glands was analyzed in 135 biopsies from 61 patients. The levels of the polarized alpha6/alpha3 integrin expression at the basal membrane of prostate tumor glands were determined by quantitative immunohistochemistry. The alpha6/alpha3 integrin expression was compared with Gleason sum score, pathological stage, and preoperative serum prostate-specific antigen (PSA). The associations were assessed by statistical methods. Eighty percent of the tumors expressed the alpha6 or alpha3 integrin and 20% was integrin-negative. Gleason sum score, but not serum PSA, was associated with the integrin expression. Low Gleason sum score correlated with increased integrin expression, high Gleason sum score with low and negative integrin expression. Three prostate tumor phenotypes were distinguished based on differential integrin expression. Type I coexpressed both alpha6 and alpha3 subunits, type II exclusively expressed alpha6 integrin, and type III expressed alpha3 integrin only. Fifteen cases were further examined for the codistribution of vinculin, paxillin, and CD 151 on frozen serial sections using confocal laser scanning microscopy. The alpha6/alpha3 integrins, CD151, paxillin, and vinculin were present within normal glands. In prostate carcinoma, alpha6 integrin was colocalized with CD 151, but not with vinculin or paxillin. In tumor phenotype I, the alpha6 subunit did not colocalize with the alpha subunit indicating the existence of two different adhesion complexes. Human prostate tumors display on their cell surface the alpha6beta1 and/or alpha3beta1 integrins. Three tumor phenotypes associated with two different adhesion complexes were identified, suggesting a reorganization of cell adhesion structures in prostate cancer.

Alleles↗

PubMed1999

(Alpha)3(beta)1 integrin regulates epithelial cytoskeletal organization.

Epithelial cell morphology and cytoskeletal organization are determined by interactions, with both adjacent cells and the extracellular matrix, which are mediated by integrins and cadherins. Little is known, however, of the relative contributions of integrins and cadherins to maintaining the sub-cortical cytoskeleton characteristic of epithelial cells. Since most studies that utilize integrin-blocking antibodies result in a loss of both cell-cell adhesion and sub-cortical cytoskeletal organization, it has been difficult to distinguish whether integrins and cadherins both mediate cytoskeletal assembly in epithelial cells. Therefore, cells derived from kidney collecting ducts of (alpha)3(beta)1 integrin-deficient mice were used to examine the role of integrins in epithelial cell morphology and cytoskeletal organization. In primary cell culture, (alpha)3(beta)1 integrin-deficient kidney collecting duct cells maintain cadherin-mediated cell-cell adhesions but fail to form the sub-cortical cytoskeleton that is characteristic of epithelial cells, and instead assemble actin stress fibers. Moreover, the cell-cell junctions in mutant cells were irregular, rather than being uniformly oriented perpendicular to the culture substrate. These results demonstrated that integrins have an primary and essential function in establishing and maintaining the sub-cortical cytoskeleton that is characteristic of epithelial cells. To further study the role of (alpha)3(beta)1 integrin in establishing and maintaining cytoskeletal organization in tubular epithelial cells, we derived immortalized cell lines from wild-type and (alpha)3(beta)1 integrin-deficient kidney collecting ducts that duplicated the cytoskeletal and cadherin organization observed in primary cells. E-cadherin and (alpha)- and (beta)-catenin were complexed together in equal amounts in membranes of wild-type and (alpha)3(beta)1 integrin-deficient cells. However, association of the cadherin:catenin complex with (alpha)-actinin was greatly decreased in mutant cells, indicating that integrin-mediated assembly of the sub-cortical cytoskeleton is essential for subsequent association of the cytoskeleton with the cadherin:catenin complex. These results present direct evidence for integrin:cadherin cross-regulation in which cadherin function is dependent on the presence of an integrin.

Animals↗

PubMed2000

Interaction between the cytodomains of the alpha 3 and beta 1 integrin subunits regulates remodelling of adhesion complexes on laminin.

The first step of laminin 1-induced signal transduction is initiated by the formation of alpha 6 beta 1 integrin-specific adhesion complexes. In contrast, on other laminin isoforms the adhesion complexes are alpha 3 beta 1 integrin-specific due to a transdominant regulation of the alpha 6 beta 1 integrin by the alpha 3 beta 1 integrin. To determine the mechanism of this regulation, peptides representing the cytoplasmic domain of the alpha 3 or alpha 6 integrin subunits were microinjected together with recombinant enhanced green fluorescence protein into live fibroblasts. Microinjection of the alpha 3 integrin peptide to laminin 1-adherent cells displaying alpha 6 beta 1 integrin-specific adhesion complexes resulted in the disengagement of the alpha 6 beta 1 integrin, while microinjection of green fluorescence protein alone or in combination with the alpha 6 integrin cytodomain had no effect. Further surface plasmon resonance studies revealed that the cytodomain of the beta 1 integrin subunit interacts with low affinity with the cytoplasmic tail of the alpha 3 integrin subunit, but not with that of several other alpha subunits including alpha 6. These results imply that the cytoplasmic tails of the integrin alpha subunits play a critical role in the regulation of integrin-induced signal transduction. In particular, the intracellular tail of the alpha 3 integrin subunit controls the formation of adhesion complexes in cells adhering to laminins.

Amino Acid Sequence↗

PubMed2003

[The effect of mechanical stimulation on the expression of alpha 2, beta 1, beta 3 integrins and the proliferation, synthetic function in rat osteoblasts].

The purpose of this paper is to investigate the probable molecular mechanism in mechano-transduction of the regulation of integrins and the effects of cyclic biaxial mechanical strain on proliferation and synthetic function in the osteoblasts isolated from 3-month-old female Sprague-Dawley (SD) rats. The osteoblasts were cultured in F-12 medium contained with 10% fetal bovine serum(FBS) and grown to subconfluency in Flexercell type I dishes in a humidified incubator with 5% CO2 and 95% air at 37 degrees C. Mechanical strains were applied to the cells for periods of 30 min, 2, 4 and 8 hours every day, lasting 2 days. The amplitude of mechanical strain applied to the cells were 400, 1,000 and 4,000 mu strain respectively, at a frequency of one hertz(1 Hz). Unstrained cells were used as control. The expression of integrins alpha 2, beta 1, beta 3 on the membrane of osteoblasts and proliferation activity of osteoblasts were studied with Flow Cytometry(FCM). The content of osteocalcin, carboxyterminal propeptide of type-I procollage(PICP), total protein secreted by osteoblastes were detected with the isotope labelling method. The results showed that there are actual expressions of integrins alpha 2, beta 1, beta 3 on the membrane of osteoblasts without mechanical strain and that the expression of integrins beta 1 is highest. The mechanical strain increased the expression of integrins alpha 2, beta 1, beta 3 on the membrane of osteoblasts, but the strain-related up-regulation of expression of integrins alpha 2, beta 1, beta 3 are different in various amplitude and different duration of mechanical stains. The up-regulation of expression of integrins beta 3 is most sensitive to mechanical strain. The up-regulation of expression of integrins alpha 2, beta 1, beta 3 is higher at 4,000 mu strain than at 400, 1,000 mu strain. The mechanical strain can elevate the proliferation activity and the synthetic function of osteoblast at 400, 1,000 mu strain. However, the mechanical strain increased significant the proliferation in the osteoblasts and suppressed obviously the synthetic function in the osteoblasts. In the present study, the reaction of the osteoblasts in 3 month-old rat to the mechanical stimulation suggested that 1) expressions of integrins alpha 2, beta 1, beta 3 were increased in a amplitude of strain-dependent manner; 2) the changes of expression of integrins alpha 2, beta 1, beta 3 relate close to the changes of the proliferation and synthetic function of the osteoblasts. Low amplitude of strain can increase the proliferation and the synthetic function of the osteoblasts along with up-regulation of expression of integrins alpha 2, beta 1, beta 3; while higher amplitude of strain elevated significantly the proliferation of osteoblasts and suppressed obviously the synthetic function of the osteoblasts along with up-regulation of expression of integrins alpha 2, beta 1, beta 3. The amplitude of 4,000 mu strain is an optimal amplitude as stimulus for up-regulation of expression of integrins alpha 2, beta 1, beta 3 on the membrane of osteoblasts and increase the proliferation activity, but decrease the synthetic function of osteoblasts in the present study. Accordingly it indicates that integrins have a important role in regulation of signal transduction pathway in osteoblasts as a result of mechanical strain.

Animals↗

PubMed1995

Increase in suprabasilar integrin adhesion molecule expression in human epidermal neoplasms accompanies increased proliferation occurring with immortalization and tumor progression.

In a previous prospective study of 80 patients with squamous cell carcinoma of the upper aerodigestive tract, a progressive increase in expression of the integrin cell adhesion molecule alpha 6 beta 4 in suprabasilar cell layers of the tumor parenchyma was associated with an increase in early recurrence after therapy. In this study, we determined the relationship of the altered expression pattern of the integrin to changes occurring during benign, invasive, or metastatic stages of tumor development. Suprabasilar expression of integrin alpha 6 beta 4 appeared with neoplastic transformation in benign squamous papillomas, but homogeneous expression occurred more frequently in the parenchyma of primary and metastatic squamous cell carcinomas. The variation in the extent of suprabasilar integrin expression among the tumors corresponded to the variation in the population undergoing proliferation as determined by two independent markers of proliferation. Integrin expression was quantified in primary, HPV 16 DNA-immortalized, and v-ki-ras oncogene-transformed keratinocytes, and the pattern of expression was compared with cell cycle progression. Primary keratinocyte lines showed a bimodal distribution of integrin expression, with one population showing decreased integrin expression, cell size, and a block of cell cycle progression consistent with differentiation, whereas another population exhibited high integrin expression and full progression through the cell cycle, consistent with proliferation. HPV-immortalized and v-ki-ras-transformed cell lines undergoing continuous proliferation exhibited uniformly strong integrin expression, which was similar in intensity to that observed in the proliferating population of normal keratinocytes. Similar increases in expression of two additional integrins, alpha 2 beta 1 and alpha 3 beta 1, occurred along with integrin alpha 6 beta 4 in tissue specimens and cell lines derived from neoplasms. Thus, epidermal neoplasms display an increase in a population of cells exhibiting constitutive expression of a repertoire of integrins, which is similar to that found transiently in the acute phase of epidermal wound healing, a physiological response in which hyperproliferation, retention of multiple layers of proliferating cells, and migration occur. The association of a progressive increase in suprabasilar expression of these integrins with early tumor recurrence and advanced neoplasia suggests that constitutive expression and function of the same repertoire of integrins may be advantageous, rather than sufficient, for tumor progression.

Antigens, Surface↗