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Results for “Integrin alpha2beta1”

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At least 505 records · Page 28Linked to original sources
PubMed2005

Glycoprotein Ia 807TT/873AA genotype is not associated with myocardial infarction.

OBJECTIVE: The glycoprotein Ia/IIa complex is a major platelet collagen receptor. Its surface expression is influenced by two linked single nucleotide polymorphisms (C807T and G873A) in the glycoprotein Ia (GPIa) gene. In this study we aimed to determine the frequency of GPIa C807T/G873A genotype in patients with myocardial infarction (MI) and healthy controls in Turkish population and association between these dimorphisms and risk factors of MI. METHODS: We examined GPIa (C807T/G873A) genotypes in 158 patients with MI and 145 healthy controls. Distributions of the C807T and G873A dimorphisms were investigated by genotyping DNA using multiplexed allele-specific PCR. RESULTS: There was no association between GPIa genotypes and MI. We further analysed each group for all known risk factors such as plasma lipid levels, cigarette smoking, diabetes, hypertension, gender, age, MI history and body mass index. When compared with other two genotypes for glycoprotein Ia (GT/GA and CC/GG), TT/AA showed an association with higher high-density lipoprotein (HDL) -cholesterol levels in the healthy control group, but none in the group with MI. CONCLUSION: The 807TT/873AA genotype of the GPIa gene alone or in combination with risk factors had no major effect on MI, however, it appears to be associated with higher HDL-cholesterol levels in healthy subjects.

Adult↗
PubMed2006

Matrix-specific suppression of integrin activation in shear stress signaling.

Atherosclerotic plaque develops at sites of disturbed flow. We previously showed that flow activates endothelial cell integrins, which then bind to the subendothelial extracellular matrix (ECM), and, in cells on fibronectin or fibrinogen, trigger nuclear factor-kappaB activation. Additionally, fibronectin and fibrinogen are deposited into the subendothelial ECM at atherosclerosis-prone sites at early times. We now show that flow activates ECM-specific signals that establish patterns of integrin dominance. Flow induced alpha2beta1 activation in cells on collagen, but not on fibronectin or fibrinogen. Conversely, alpha5beta1 and alphavbeta3 are activated on fibronectin and fibrinogen, but not collagen. Failure of these integrins to be activated on nonpermissive ECM is because of active suppression by the integrins that are ligated. Protein kinase A is activated specifically on collagen and suppresses flow-induced alphavbeta3 activation. Alternatively, protein kinase Calpha is activated on fibronectin and mediates alpha2beta1 suppression. Thus, integrins actively cross-inhibit through specific kinase pathways. These mechanisms may determine cellular responses to complex extracellular matrices.

Animals↗
PubMed2004

The fibril-associated collagen IX provides a novel mechanism for cell adhesion to cartilaginous matrix.

Collagen IX is the prototype fibril-associated collagen with interruptions in triple helix. In human cartilage it covers collagen fibrils, but its putative cellular receptors have been unknown. The reverse transcription-PCR analysis of human fetal tissues suggested that based on their distribution all four collagen receptor integrins, namely alpha1beta1, alpha2beta1, alpha10beta1, and alpha11beta1, are possible receptors for collagen IX. Furthermore primary chondrocytes and chondrosarcoma cells express the four integrins simultaneously. Chondrosarcoma cells, as well as Chinese hamster ovary cells transfected to express alpha1beta1, alpha2beta1, or alpha10beta1 integrin as their only collagen receptor, showed fast attachment and spreading on human recombinant collagen IX indicating that it is an effective cell adhesion protein. To further study the recognition of collagen IX we produced recombinant alphaI domains in Escherichia coli. For each of the four alphaI domains, collagen IX was among the best collagenous ligands, making collagen IX exceptional compared with all other collagen subtypes tested so far. Rotary shadowing electron microscopy images of both alpha1I- and alpha2I-collagen IX complexes unveiled only one binding site located in the COL3 domain close to the kink between it and the COL2 domain. The recognition of collagen IX by alpha2I was considered to represent a novel mechanism for two reasons. First, collagen IX has no GFOGER motif, and the identified binding region lacks any similar sequences. Second, the alpha2I domain mutations D219R and H258V, which both decreased binding to collagen I and GFOGER, had very different effects on its binding to collagen IX. D219R had no effect, and H258V prevented type IX binding. Thus, our results indicate that collagen IX has unique cell adhesion properties when compared with other collagens, and it provides a novel mechanism for cell adhesion to cartilaginous matrix.

Amino Acid Sequence↗
PubMed2006

The role of beta1 integrin subfamily in anchorage-dependent apoptosis of breast carcinoma cells differing in multidrug resistance.

Integrin expression was investigated in MCF-7 human breast adenocarcinoma line and in the MCF-7Dox line, which was selected from MCF-7 by a resistance to multiple antitumor drugs (MDR). We have shown that acquisition of MDR was accompanied by a drastically reduced expression of some integrins of the beta1-subfamily (alpha2beta1, alpha3beta1, alpha6beta1) and of alpha vbeta5 intergin in the adenocarcinoma cells. In contrast, expression of alpha5beta1 integrin was markedly increased in the MDR cells. Along with multiple antitumor drug resistance, MCF-7Dox cells demonstrate elevated resistance to anchorage-dependent apoptosis (anoikis) and enhanced in vitro invasive activity. To elucidate the implication of beta1-integrins in the above phenotypic modifications, the effect of beta1-integrin signaling was assayed. Stimulation of beta1-mediated signaling was accomplished by treating of the cells with antibodies to the beta1-subunit common for members of the beta1-subfamily. These data show that activation of beta1-integrin signaling markedly upregulated anoikis of the adenocarcinoma cells.

Anoikis↗
PubMed2006

Matrilins mediate weak cell attachment without promoting focal adhesion formation.

The matrilins form a family of non-collagenous adaptor proteins in the extracellular matrix. The extracellular ligand interactions of matrilins have been studied in some detail, while the potential interplay between matrilins and cells has been largely neglected. Except for matrilin-4, all matrilins mediate cell attachment, but only for matrilin-1 and -3 the binding is clearly dose dependent and seen already at moderate coating concentrations. Even so, much higher concentrations of matrilin-1 or -3 than of fibronectin are required for cell attachment to reach plateau values. Integrins contribute to the matrilin-mediated cell attachment, but the binding does not lead to formation of focal contacts and reorganisation of the actin cytoskeleton. Cells deficient in beta1 integrins are able to adhere, although weaker, and matrilins do not bind the soluble integrin alpha1beta1 and alpha2beta1 ectodomains. Cell surface proteoglycans may promote the attachment, as cells deficient in glycosaminoglycan biosynthesis adhere less well to matrilin-3. Even so, exogenous glycosaminoglycans are not able to compete for the attachment of HaCaT cells to matrilins.

Animals↗
PubMed2005

Mycophenolate mofetil modulates adhesion receptors of the beta1 integrin family on tumor cells: impact on tumor recurrence and malignancy.

BACKGROUND: Tumor development remains one of the major obstacles following organ transplantation. Immunosuppressive drugs such as cyclosporine and tacrolimus directly contribute to enhanced malignancy, whereas the influence of the novel compound mycophenolate mofetil (MMF) on tumor cell dissemination has not been explored. We therefore investigated the adhesion capacity of colon, pancreas, prostate and kidney carcinoma cell lines to endothelium, as well as their beta1 integrin expression profile before and after MMF treatment. METHODS: Tumor cell adhesion to endothelial cell monolayers was evaluated in the presence of 0.1 and 1 microM MMF and compared to unstimulated controls. beta1 integrin analysis included alpha1beta1 (CD49a), alpha2beta1 (CD49b), alpha3beta1 (CD49c), alpha4beta1 (CD49d), alpha5beta1 (CD49e), and alpha6beta1 (CD49f) receptors, and was carried out by reverse transcriptase-polymerase chain reaction, confocal microscopy and flow cytometry. RESULTS: Adhesion of the colon carcinoma cell line HT-29 was strongly reduced in the presence of 0.1 muM MMF. This effect was accompanied by down-regulation of alpha3beta1 and alpha6beta1 surface expression and of alpha3beta1 and alpha6beta1 coding mRNA. Adhesion of the prostate tumor cell line DU-145 was blocked dose-dependently by MMF. In contrast to MMF's effects on HT-29 cells, MMF dose-dependently up-regulated alpha1beta1, alpha2beta1, alpha3beta1, and alpha5beta1 on DU-145 tumor cell membranes. CONCLUSION: We conclude that MMF possesses distinct anti-tumoral properties, particularly in colon and prostate carcinoma cells. Adhesion blockage of HT-29 cells was due to the loss of alpha3beta1 and alpha6beta1 surface expression, which might contribute to a reduced invasive behaviour of this tumor entity. The enhancement of integrin beta1 subtypes observed in DU-145 cells possibly causes re-differentiation towards a low-invasive phenotype.

Cell Adhesion↗
PubMed2006

Defective beta1-integrins expression in arsenical keratosis and arsenic-treated cultured human keratinocytes.

BACKGROUND: beta1-integrins, which localize to the basolateral surface of basal keratinocytes, are important in the differentiation control and proliferation of the epidermis. Many cutaneous diseases with perturbed differentiation, including arsenical keratosis, show altered patterns of integrin distribution and expression. Arsenic may induce arsenical keratosis through the differentiation and apoptosis aberration by integrins. The purpose of this study is to investigate the role of integrin and arsenic in the pathogenesis of arsenical keratosis. METHODS: Twenty-five specimens obtained from 25 patients with arsenical keratosis disease were studied. Immunohistochemistry staining to beta1, alpha2beta1, or alpha3beta1 integrins was performed in arsenical keratosis and clinically normal perilesional skin. Western blotting was used to assess the expression of integrin beta1 and focal adhesion kinase (FAK) in arsenic-treated cultured keratinocytes. RESULTS: A decreased expression of beta1, alpha2beta1, or alpha3beta1 integrins was demonstrated in arsenical keratosis and clinical normal perilesional skin in a large proportion of arsenical keratosis cases studied. The expressions of integrin beta1 and FAK were both decreased in arsenic-treated keratinocytes. CONCLUSIONS: Our results suggest that arsenic induces abnormal differentiation in arsenical keratosis via the effects of integrin expression in keratinocytes.

Aged↗
PubMed1999

Selective increase of alpha2-integrin sub-unit expression on human carcinoma cells upon EGF-receptor activation.

The effects of chronic EGF exposure on expression of the alpha2beta1 collagen and alpha5beta1 fibronectin receptor in a pair of human carcinoma cell lines (A431 and A549) with differential responses to EGF in a short-term ECM-cell adhesion assay were investigated. Treatment with EGF at 10 ng/ml for 24 hr increased on both cell lines the expression of the alpha2- but not the beta1- or alpha5-integrin sub-units, and concomitantly cellular adhesion was increased on collagen IV but not on fibronectin. Increased collagen adhesion of A549 cells could be blocked by alpha2- and beta1-integrin-sub-unit antibodies down to control levels, while it was blocked by alpha2-integrin-sub-unit antibody only by 60% and completely by the beta1-integrin-sub-unit antibody on A431 cells. EGF induced disparate shifts in cell morphologies (dome-like structures, A431, vs. spindle-like fibroblastoid, A549) with concomitant opposite changes in the expression/localization of E-cadherin in cell-cell contacts. This could be taken as an indication for cell-type-specific differential changes in the ratio of cell-ECM vs. cell-cell contacts. The EGF-induced up-regulation of the alpha2beta1 integrin was instrumental in increasing collagen adhesion of A549 but only partly in the case of A431 cells, in which cells the alpha2beta1 integrin may have additional functions besides serving as cell-ECM receptor.

Adenocarcinoma↗
PubMed2004

Integrin profile and in vivo homing of human smooth muscle progenitor cells.

BACKGROUND: Recently, we identified circulating smooth muscle progenitor cells (SPCs) in human peripheral blood. The integrin profile of such progenitors is currently unknown and may affect their in vivo homing characteristics. In this study, we determined the integrin profile of vascular progenitors and SPC adhesion to extracellular matrix (ECM) proteins in vitro and in vivo. METHODS AND RESULTS: SPCs and endothelial progenitor cells (EPCs) were isolated from peripheral blood of healthy human subjects, and expression of surface integrins and adhesion to several vascular ECM proteins were determined. Homing of SPCs in vivo to specific ECM protein was determined by intracoronary infusion of fluorescent SPCs into porcine coronary arteries containing a fibronectin-coated mesh stent. SPCs had high expression of beta1 integrin, moderate expression of alpha1, low levels of alpha(v)beta3, and did not express alpha(v)beta5, beta2, alpha2beta1, or alpha4beta1 integrins. In contrast, EPCs had high expression of alpha2beta1, alpha(v)beta3, alpha(v)beta5, beta1, and alpha1 and minimal expression of alpha4beta1. Moreover, SPCs showed increased adherence to fibronectin and collagen type I compared with vitronectin, consistent with their integrin profile, and demonstrated a similar degree of in vivo attachment to fibronectin-coated mesh. CONCLUSIONS: These data for the first time show a spectrum of integrin expression on vascular progenitors and suggest the potential importance of integrins in mediating adherence of SPCs to specific ECM both in vitro and in vivo.

Animals↗
PubMed2001

Distribution of the collagen-binding integrin alpha10beta1 during mouse development.

We have previously identified and characterised the collagen type II-binding integrin subunit alpha10, which is a member of the beta1 family and is expressed by chondrocytes. In the present study, we examined the expression of the alpha10 integrin in various mouse tissues. Immunohistochemical analysis of alpha10 on cryosections from 3-day-old mice demonstrated that alpha10beta1 was present in the hyaline cartilage of joints, vertebral column, trachea and bronchi. In addition, alpha10 was found in the ossification groove of Ranvier, in the aortic and atrioventricular valves of the heart and in the fibrous tissue lining skeletal muscle and ligaments. Overall, the distribution was distinct from that of the collagen-binding integrins alpha1beta1 and alpha2beta1. We also found that alpha10beta1was the dominating collagen-binding integrin during cartilage development. Expression of alpha10 appeared at embryonic day 11.5 (E11.5) at the same time as chondrogenesis started as judged by collagen type II expression. At E13.5, alpha10 was present throughout the anlage as well as in the perichondrium and in mesenchyme just outside the perichondrium, where it localised with collagen type I. Four weeks after birth, alpha10 was prominent both at the articular surface and in the growth plate. In conclusion, we found that integrin alpha10beta1 was a major collagen-binding integrin during cartilage development and in mature hyaline cartilage. In addition, we found that alpha10beta1 was present in some fibrous tissues.

Animals↗
PubMed2000

Abnormal phenotype of in vitro dermal fibroblasts from patients with Pseudoxanthoma elasticum (PXE).

Pseudoxanthoma elasticum (PXE) is a genetic connective tissue disease, whose gene and pathogenesis are still unknown. Dermal fibroblasts from patients affected by PXE have been compared in vitro with fibroblasts taken from sex and age-matched normal individuals. Cells were grown and investigated in monolayer, into three-dimensional collagen gels and in suspension. Compared with normal cells, PXE fibroblasts cultured in monolayer entered more rapidly within the S phase and exhibited an increased proliferation index; on the contrary, similarly to normal fibroblasts, PXE cells did not grow in suspension. Furthermore, compared with normal fibroblasts, PXE cells exhibited lower efficiency in retracting collagen type I lattices and lower adhesion properties to collagen type I and to plasma fibronectin. This behavior was associated with higher expression of integrin subunits alpha2, alpha5, alphav, whereas beta1 subunit as well as alpha2beta1 and alpha5beta1 integrin expression was lower than in controls. Compared to controls, PXE fibroblasts had higher CAM protein expression in accordance with their high tendency to form cellular aggregates, when kept in suspension. The demonstration that PXE fibroblasts have altered cell-cell and cell-matrix interactions, associated with modified proliferation capabilities, is consistent with the hypothesis that the gene responsible for PXE might have a broad regulatory role on the cellular machinery.

Adult↗
PubMed1999

Selective gene delivery to head and neck cancer cells via an integrin targeted adenoviral vector.

In vivo cancer gene therapy approaches for squamous cell carcinoma of the head and neck (SCCHN) based on adenoviral vector-mediated gene delivery have been limited by the suboptimal efficacy of gene transfer to tumor cells. We hypothesized that this issue was due to deficiency of the primary adenoviral receptor, the coxsackie-adenovirus receptor (CAR), on the tumor targets. Studies of CAR levels on SCCHN cell lines confirmed that their relative refractoriness to the adenoviral vector was based on this deficiency. To circumvent this deficiency, we applied an adenoviral vector targeted to a tumor cell marker characteristic of SCCHN. In this regard, integrins of the alpha2beta1 and alpha3beta1 class are frequently overexpressed in SCCHN. Furthermore, these integrins recognize the RGD peptide motif. On this basis, we applied an adenoviral vector genetically modified to contain such a peptide within the HI loop of the fiber protein as a means to alter viral tropism. Studies confirmed that the CAR-independent gene delivery achieved via this strategy allowed enhanced gene transfer efficiencies to SCCHN tumor cells. Importantly, this strategy could achieve preferential augmentation of gene transfer in tumor cells compared with normal cells. The ability to achieve enhanced and specific gene transfer to tumor cells via adenoviral vectors has important implications for gene therapy strategies for SCCHN and for other neoplasms in general.

Adenoviridae↗
PubMed1999

Beta1 integrin antisense oligodeoxynucleotides: utility in controlling osteoclast function.

The involvement of beta1 integrins in osteoclast function has been investigated by utilising an antisense oligodeoxynucleotide (ODN) approach. 18-mer antisense and control phosphorothioate ODNs were made to a conserved internal region of beta1 integrin sequence (nucleotide positions 1634-1651 of the human beta1 fibronectin receptor). These were tested on rabbit osteoclasts for anti-adhesive and resorptive effects mediated by alphaVbeta3 and alpha2beta1, the major integrins of osteoclasts. Antisense, but not control, beta1 ODNs inhibited osteoclast adhesion to collagen-coated glass (by up to 70%), but not to glass coated with vitronectin, fibronectin or fibrinogen. Adhesion to dentine and subsequent resorption were also inhibited (up to 60%) in a sequence-specific manner. The mechanism of action was verified using both a melanoma cell line, DX3, which expresses multiple integrins at high level including alphaVbeta3 and alpha2beta1, and in a rabbit osteoclast marrow culture (BMC) system. Exposure of DX3 cells to antisense ODN for up to 48 hours reduced adhesion to FCS- and collagen-coated glass, and concomitantly inhibited beta1 protein expression assessed by FACS and Western blot analysis; expression of other integrin subunits, alphaV and beta3, was unaffected. Similarly, the beta1 protein levels in the BMC were reduced by > 75% without any effect on actin expression. These data reveal the utility of antisense ODNs in exploring osteoclast biology and further define the functional role of osteoclastic beta1 integrin(s).

Animals↗
PubMed2003

Platelets in hemostasis and thrombosis: role of integrins and their ligands.

Platelet adhesion and aggregation at the site of vascular injury are two key events in hemostasis and thrombosis. The contribution of several platelet receptors and their ligands has been highlighted in these processes. In platelet adhesion, particularly at high shear stress, GP1b-von Willebrand factor (vWF) interaction may initiate this event, which is followed by firm platelet adhesion mediated by members of the integrin family, such as beta1 (alpha2beta1, alpha5beta1) and beta3 (alphaIIbbeta3) integrins. In platelet aggregation, although GP1b-vWF, P selectin-sulfatides, and other molecules, may play some roles, the process is mainly mediated by beta3 (alphaIIbbeta3) integrin and its ligands, such as fibrinogen and vWF. Recent studies with perfusion chambers and intravital microscopy have revised the dogma established with the static (low shear stress) conditions. It is intriguing that platelet adhesion and aggregation do still occur in mice lacking both vWF and fibrinogen, suggesting that other unexpected molecule(s) may also be important in hemostasis and thrombosis.

Animals↗
PubMedDate not supplied

Vascular integrins in tumor angiogenesis: mediators and therapeutic targets.

The notion that tumor angiogenesis may have therapeutic implications in the control of tumor growth was introduced by Dr. Judah Folkman in 1971. The approval of Avastin in 2004 as the first antiangiogenic systemic drug to treat cancer patients came as a validation of this visionary concept and opened new perspectives to the treatment of cancer. In addition, this success boosted the field to the quest for new therapeutic targets and antiangiogenic drugs. Preclinical and clinical evidence indicate that vascular integrins may be valid therapeutic targets. In preclinical studies, pharmacological inhibition of integrin function efficiently suppressed angiogenesis and inhibited tumor progression. alphaVbeta3 and alphaVbeta5 were the first vascular integrins targeted to suppress tumor angiogenesis. Subsequent experiments revealed that at least four additional integrins (i.e., alpha1beta1, alpha2beta1, alpha5beta1, and alpha6beta4) might be potential therapeutic targets. In clinical studies low-molecular-weight integrin inhibitors and anti-integrin function-blocking antibodies demonstrated low toxicity and good tolerability and are now being tested in combination with radiotherapy and chemotherapy for anticancer activity in patients. In this article the authors review the role of integrins in angiogenesis, present recent development in the use of alphaVbeta3 and alpha5beta1 integrin antagonists as potential therapeutics in cancer, and discuss future perspectives.

Animals↗
PubMed1997

The coupling of alpha6beta4 integrin to Ras-MAP kinase pathways mediated by Shc controls keratinocyte proliferation.

The signaling pathways linking integrins to nuclear events are incompletely understood. We have examined intracellular signaling by the alpha6beta4 integrin, a laminin receptor expressed in basal keratinocytes and other cells. Ligation of alpha6beta4 in primary human keratinocytes caused tyrosine phosphorylation of Shc, recruitment of Grb2, activation of Ras and stimulation of the MAP kinases Erk and Jnk. In contrast, ligation of the laminin- and collagen-binding integrins alpha3beta1 and alpha2beta1 did not cause these events. While the stimulation of Erk by alpha6beta4 was suppressed by dominant-negative Shc, Ras and RhoA, the activation of Jnk was inhibited by dominant-negative Ras and Rac1 and by the phosphoinositide 3-kinase inhibitor Wortmannin. Adhesion mediated by alpha6beta4 induced transcription from the Fos serum response element and promoted cell cycle progression in response to mitogens. In contrast, alpha3beta1- and alpha2beta1-dependent adhesion did not induce these events. These findings suggest that the coupling of alpha6beta4 integrin to the control of cell cycle progression mediated by Shc regulates the proliferation of basal keratinocytes and possibly other cells which are in contact with the basement membrane in vivo.

3T3 Cells↗
PubMed1999

Integrin function in breast carcinoma progression.

The differentiation and function of mammary epithelial cells is dependent upon the combined action of growth factor/hormone receptors and integrin receptors, which act in concert to control the signals required for normal cell function. It is now becoming clear that integrin receptors also contribute to carcinoma cell behavior and that alterations in expression and function during transformation have a large impact on breast carcinoma progression. The focus of this review is to discuss integrin-dependent functions that can be manipulated as targets for the therapeutic intervention of breast cancer. A combination of correlative and mechanistic studies have contributed to the identification of specific integrin receptors, namely alpha2beta1, alpha6beta1, and alpha6beta4, implicated in breast carcinoma progression. Although this field is still emerging and much remains to be learned, potential integrin-dependent signaling targets have been identified.

Animals↗
PubMed2005

Integrins adhesion molecules and some of their ligands in laryngeal cancer.

In this review data regarding the regular expression and distribution of integrins adhesion molecules as well as some of their ligands in cases of squamous cell carcinoma of the larynx (LSCC) are discussed. Cancer of the larynx is one of the most common malignancies of the head and neck. Upon neoplastic transformation several alterations of the integrins adhesion molecules and extracellular matrix (ECM) components are observed, i.e. the loss of the normal architecture especially depolarization of some integrins, like alpha6beta4, alpha3beta1, alpha2beta1 as well as the presence of alpha6beta1 integrin in neoplastic epithelium. Furthermore, the upregulation of alpha5beta1 integrin is a negative prognostic factor. In cases of laryngeal cancer, disorganization of the basal membrane components (laminins 1 and 5, type IV collagen, tenascin, fibronectin isoforms) which represent integrins ligands, is found. This is due to partial or complete destruction of the basal membrane, thus, permitting extravasation and migration of cancer cells. These phenomena are observed in a greater degree in tumors showing poor prognosis. It seems that damage of these adhesion complexes is important in the neoplastic process. So, further studies are necessary to establish the importance of these markers to early larynx cancer diagnosis and reach the decision on appropriate therapeutic strategies in the management of those patients.

Animals↗