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PubMed1996

Novel peptide ligands for integrin alpha 6 beta 1 selected from a phage display library.

Integrin alpha 6 beta 1 is a major adhesion receptor for the basement membrane, specifically binding to laminin-1. To identify the peptide sequences recognized by alpha 6 beta 1, we screened a 15-mer phage display library by panning with alpha 6 beta 1 purified from human placenta. DNA sequencing of 73 randomly picked phage revealed that three clones were dominantly enriched after repeated panning with alpha 6 beta 1. None of the peptide sequences displayed on these phage showed significant homology to laminin-1. A synthetic peptide modeled after the sequence displayed by one of these phage, designated P3, was found to strongly inhibit the binding of laminin-1 to alpha 6 beta 1. This inhibitory effect of the P3 peptide seems to be specific for alpha 6 beta 1, since it did not affect the binding of fibronectin to integrin alpha 5 beta 1. A synthetic peptide with a scrambled P3 amino acid sequence barely inhibited the binding of laminin-1 to alpha 6 beta 1. When coated on a substratum after conjugation with bovine serum albumin, the P3 peptide was capable of promoting cell spreading in an alpha 6 beta 1-dependent manner, although the peptide with the scrambled sequence showed activity similar to that of a control peptide. These results taken together indicate that the P3 peptide is a novel ligand for integrin alpha 6 beta 1 with potent cell spreading activity.

Amino Acid Sequence↗
PubMed2003

Interactions of proteases, protease inhibitors, and the beta1 integrin/laminin gamma3 protein complex in the regulation of ectoplasmic specialization dynamics in the rat testis.

During spermatogenesis, developing germ cells migrate progressively across the seminiferous epithelium. This event requires extensive restructuring of cell-cell actin-based adherens junctions (AJs), such as the ectoplasmic specialization (ES, a testis-specific AJ type), between Sertoli cells and elongating/elongate spermatids. It was postulated that proteases and protease inhibitors worked in a yin-yang relationship to regulate these events. If this is true, then it is anticipated that both proteases and protease inhibitors are found at the ES. Indeed, matrix metalloprotease (MMP)-2, membrane-type 1 (MT1)-MMP and their inhibitor, tissue-inhibitor of metalloproteases (TIMP)-2, were shown to localize at the apical ES. In order to identify the putative MMP substrate as well as the unknown binding ligand for alpha6beta1 integrin in the ES, immunofluorescent microscopy coupled with immunoprecipitation techniques were used to demonstrate that laminin gamma3, largely a germ cell product, was present at the apical ES and could form a bona fide complex with beta1-integrin. Furthermore, the structural interactions of MMP-2 and MT1-MMP with laminin gamma3 and beta1-integrin, but not with N-cadherin or nectin-3, have implicated the crucial role of MMP-2/MT1-MMP in the regulation of integrin/laminin-based ES dynamics. Using an in vivo model to study AJ dynamics where adult rats were treated with 1-(2,4-dichlorobenzyl)-indazole-3-carbohydrazide (AF-2364) to disrupt Sertoli-germ cell adhesive function, an induction of active MMP-2, active MT1-MMP and TIMP-2 but not active MMP-9 was detected between 0.5 and 8 h after AF-2364 treatment. This time frame coincided with the depletion of elongating/elongate spermatids from the epithelium, illustrating the synergistic relationships between MMP-2, MT1-MMP, and TIMP-2 in AJ disassembly. Perhaps the most important of all, the use of a specific MMP-2 and MMP-9 inhibitor, (2R)-2-[(4-biphenylylsulfonyl)amino]-3-phenylpropionic acid, could effectively delay the AF-2364-induced elongating/elongate spermatid loss from the epithelium, demonstrating the pivotal role of MMP-2 activation in ES disassembly. Collectively, these studies illustrate that the beta1-integrin/laminin gamma3 complex is a putative ES-structural protein complex, which is regulated, at least in part, by the activation of MMP-2 involving MT1-MMP and TIMP-2 at the apical ES. The net result of this interaction likely regulates germ cell movement in the seminiferous epithelium.

Adherens Junctions↗
PubMed1995

Integrin receptor alpha 6 beta 1 is localized at specific sites of cell-to-cell contact in rat seminiferous epithelium.

With the aim of investigating the presence and role of integrin receptors in cell-to-cell interactions during spermatogenesis, we have immunolocalized alpha 6A integrin chain in the rat seminiferous epithelium. In both prepubertal and adult seminiferous epithelium, the antigen was found to be restricted to definite sites of intercellular contact, following a stage-specific distribution almost invariably identical to that known for beta 1 chain. In the adult seminiferous epithelium, positivity for both antigens was found exclusively around the profiles of elongating and maturing spermatids and, in most but not all stages, at a characteristic suprabasal position. In the prepubertal rat, the antigen is localized along a very regular suprabasal line of intercellular contacts. In immunoprecipitation experiments on both seminiferous epithelium explants and Sertoli cell cultures from 3-wk-old rats, anti-alpha 6A antibody coprecipitates a polypeptide of 118 kDa, presumably corresponding to beta 1 chain. These data strongly suggest that the integrin heterodimer alpha 6A beta 1 is expressed at sites of intercellular contact in the rat seminiferous epithelium. The stage-specific and restricted pattern observed by immunofluorescence suggests that this integrin is involved in regulatory interactions between Sertoli cells and germ cells during spermatogenesis.

Animals↗
PubMed2001

An angiogenic laminin site and its antagonist bind through the alpha(v)beta3 and alpha5beta1 integrins.

Angiogenesis is important for wound healing, tumor growth, and metastasis. Endothelial cells differentiate into capillary-like structures on a laminin-1-rich matrix (Matrigel). We previously identified 20 angiogenic sites on laminin-1 (alpha1beta1gamma1) by screening 559 overlapping synthetic peptides. C16, the most potent gamma1 chain peptide, blocked laminin-1-mediated adhesion and was the only gamma1 chain peptide to block attachment to both collagen I and fibronectin. This suggested that C16 was acting via a receptor common to these substrates. We demonstrated that C16 is angiogenic in vivo. Affinity chromatography identified the integrins alpha5beta1 and alpha(v)beta3 as surface receptors. Blocking antibodies confirmed the role of these receptors in C16 adhesion. C16 does not contain an RGD sequence and, as expected, an RGD-containing peptide did not block C16 adhesion nor did C16 act via MAP kinase phosphorylation. Furthermore, we identified a C16 scrambled sequence, C16S, which antagonizes the angiogenic activity of bFGF and of C16 by binding to the same receptors. Because the laminin gamma1 chain is ubiquitous in most tissues, C16 is likely an important functional site. Since the biological activity of C16 is blocked by a scrambled peptide, C16S may serve as an anti-angiogenic therapeutic agent.

Amino Acid Sequence↗
PubMed2001

Alteration of integrins by interleukin-1alpha in human pancreatic cancer cells.

INTRODUCTION: Adhesion of tumor cells to extracellular matrix (ECM) proteins plays an important role in tumor invasion and metastasis. AIMS: To investigate the expression of integrins in human pancreatic cancer cell lines and its alteration by interleukin (IL)-1alpha to examine the mechanism of adhesion of metastatic human pancreatic cancer cells to ECM proteins. METHODOLOGY: The expression of integrin subunits and their alteration by IL-1alpha were examined by flow-cytometric analysis and cellular enzyme-linked immunosorbent assay in three metastatic human pancreatic cancer cell lines (AsPC-1, BxPC-3, and SW1990) and two nonmetastatic cancer cell lines (PaCa-2 and PANC-1). In addition, assays of cancer cell adhesion to ECM proteins were performed to investigate if increased integrin expression actually affected the adhesive interaction between cancer cells and the putative integrin ECM ligands. RESULTS: The alpha(6) subunit expressed in metastatic cancer cells was enhanced by IL-1alpha. Metastatic cancer cells also showed preferential adherence to laminin compared with nonmetastatic cancer cells, and this was enhanced by IL-1alpha. CONCLUSION: In pancreatic cancer, the enhancement of alpha(6)beta(1) integrin by IL-1alpha through IL-1 receptor type I, as well as the expression of alpha(6)beta(1) integrin, plays an important role in metastasis formation.

Antigens, CD↗
PubMed1998

Cross-species interaction of porcine and human integrins with their respective ligands: implications for xenogeneic tolerance induction.

BACKGROUND: Organ transplantation is limited by the number of available donors. One possible solution would be the use of pigs as organ donors. However, current immunosuppressive protocols cannot prevent rejection of these organs. If donor-specific tolerance toward porcine antigens could be induced in recipients, subsequent implantation of porcine organs would be possible without further immunosuppression. Induction of tolerance can be achieved with a bone marrow transplant if donor antigen-presenting cells successfully differentiate in the recipient thymus to induce deletion of donor-reactive host cells. Migration of porcine progenitor cells to the host marrow and thymus and differentiation into tolerance-inducing antigen-presenting cells is likely to require successful interaction of porcine adhesion molecules with human ligands. In this study, we investigated whether very late antigen (VLA)4 and VLA-6 integrins, which play important roles in homing and differentiation of hematopoietic progenitor cells, function across the pig-to-human species barrier. METHODS: Static cell-to-cell and cell-to-extracellular matrix protein adhesion assays were used to examine the cross-species interaction of porcine adhesion molecules with human ligands. RESULTS: Our studies show that porcine cells adhere to various human endothelial cell monolayers and extracellular matrix proteins and demonstrate that porcine VLA-4 and VLA-6 appear to be fully cross-reactive to the human ligands vascular cell adhesion molecule-1 and laminin, respectively. CONCLUSIONS: It is likely that porcine hematopoietic progenitor cells will be able to successfully employ pVLA-4- and pVLA-6-human ligand interactions in a pig-to-human bone marrow transplantation model in order to induce donor-specific tolerance.

Animals↗
PubMed1996

Integrin VLA-6 (alpha 6 beta 1) mediates adhesion of mouse bone marrow-derived mast cells to laminin.

The development of mast cells from bone marrow precursors and their function as the mucosal- or connective-tissue-type mast cell are critically dependent on microenvironmental factors. Extracellular matrix proteins, such as collagen, fibronectin, and laminin, may represent insoluble components of the microenvironment. Recent studies have described multiple isoforms of laminin isolated from different tissues. In the present study, adhesion of mouse bone marrow-derived mast cells (BMMC) and long-term mast cell lines to Engelbreth-Holm-Swarm (EHS) tumor laminin, rat laminin, human merosin, and human placental laminin was compared. The greatest level of adhesion was found with human laminin as the substrate. By use of a newly prepared mouse VLA-alpha 6 integrin-specific mAb (MA6) together with the previously described mAb GoH3, VLA-6 (alpha 6 beta 1) integrin was found to be expressed and utilized by BMMC and long-term mast cell lines. VLA-6 has been described as a major laminin receptor with roles in diverse cell functions including cell growth and differentiation. BMMC have been shown to express a 32/67-kDa laminin receptor. Therefore, in addition to the 32/67-kDa laminin receptor described in early studies, BMMC also express VLA-6 integrin, which may have roles in the regulation of their development.

Animals↗
PubMed1998

Modulation of laminin integrin receptors in the postnatal and adult rat lung.

Recent studies have shown that type II pneumocytes, at birth and day 3 postnatally, have a diffuse distribution and localize at alveolar 'corners' between 3 and 7 days. Since alpha 3 beta 1 and alpha 6 beta 1 are laminin-binding receptors that are well expressed by rat type II alveolar epithelial cells, we postulated that they may play a role in the localization of the cells in the alveolus. To begin the evaluation of this hypothesis, we studied the temporal and spatial expression of the alpha 3, alpha 6, and beta 1 integrin subunit protein and mRNA in whole rat lungs during postnatal development by immunofluorescence, confocal microscopy, and Northern blot analysis. The temporal expression of proteins analyzed by immunochemistry, with integrin subunit specific antibodies, increased during the 3- to 7-day postnatal period and in adult lungs. Densitometric values of the alpha 3, alpha 6, and beta 1 mRNA expression, normalized to 28S rRNA, quadrupled from day 1 to day 3 postnatally. The mRNA expression of different integrin chains was elevated 1.5- to threefold from days 5 to 7 postnatally compared to day 1 levels. The alpha 3 and alpha 6 integrin subunit mRNA decreased to newborn levels in adult lungs, whereas the beta 1 integrin mRNA in adult lungs was expressed at approximately 50% of its level in newborn lungs. We postulate that the increases in alpha 3, alpha 6, and beta 1 integrin mRNA expression during the early neonatal period may be important for the spatial distribution of type II pneumocytes.

Aging↗
PubMed1996

The role of the cytoplasmic domain of alpha 6 integrin in the assembly and function of alpha 6 beta 1 and alpha 6 beta 4.

We have studied the role of the cytoplasmic domain of alpha 6 in the assembly and function of the alpha 6 beta 4 integrin, and compared it with the role of alpha 6 in the assembly and function of alpha 6 beta 1, by transfection of cDNAs encoding cytoplasmic mutants of alpha 6 into K562 cells with or without full-length beta 4 cDNA. Des-(1022-1050)-alpha 6, which contains a deletion C-terminal to the GFFKR motif, was expressed in association with beta 1, but associated preferentially with beta 4, whereas the wild-type alpha 6 subunit associated efficiently with beta 1 and beta 4. Des-(1016-1050)-alpha 6, which lacked also the GFFKR sequence, was only expressed at the cell surface when beta 4 was available. Transient expression in COS-7 cells showed that des-(1016-1050)-alpha 6 was retained in the endoplasmic reticulum as a monomer, which suggests that truncation of the cytoplasmic domain reduces the affinity of alpha 6 for beta 1, particularly when the GFFKR sequence is absent. Although the GFFKR motif is not essential for association of alpha 6 with beta 4, it increases the stability of the alpha 6 beta 4 integrin. The cytoplasmic domain of alpha 6 is essential for inside-out and outside-in signaling via the alpha 6 beta 1 receptor, but not for adhesion via alpha 6 beta 4. We show that alpha 6 beta 4 is a constitutively active receptor. Thus, unlike adhesion by most other integrins, adhesion by alpha 6 beta 4 does not seem to depend on any active cellular process. Binding of alpha 6 beta 4 to ligand was only slightly affected by truncation of the alpha 6 cytoplasmic domain N-terminal to the GFFKR sequence and became partially dependent on metabolic energy. These data indicate that truncations of the cytoplasmic domain of the alpha 6 subunit affect the assembly and function of alpha 6 beta 1 more strongly than those of alpha 6 beta 4. This difference may be due to the greater affinity of alpha 6 for beta 4 than for beta 1, which makes alpha 6 beta 4 less susceptible to the effect of truncations.

Amino Acid Sequence↗
PubMed1994

Bio-histochemical aspects of integrins (alpha 2 beta 1, alpha 6 beta 1) in invasive mammary carcinomas: an immunohistochemical study.

Immunohistochemical expression of integrins was examined in 39 human invasive mammary carcinomas, of which 34.2% and 43.6% expressed integrins alpha 2 beta 1 and alpha 6 beta 1, respectively. Immuno-electron microscopy clearly demonstrated that the integrins were in the cell membrane of the carcinoma cells. Similar expression of integrin alpha 2 beta 1 or alpha 6 beta 1 in both the intraductal component and invasive portion of the same tumor was seen in 76.9% and 85.7% of cases, respectively. This suggested that invasive carcinoma cells retained their integrin expression after invasion through the basement membrane. Reciprocal expression of integrins alpha 2 beta 1 and alpha 6 beta 1 was seen in 20 cases. Expression of alpha 2 beta 1 was seen significantly less frequently in scirrhous carcinoma than in the more differentiated papillotubular or solid tubular carcinoma (Chi-squared test, P < 0.05). Intraductal components of carcinoma were present more frequently in cases expressing integrin alpha 2 beta 1 than in those that were negative. This suggests the potential usefulness of integrins as clinical parameters in the surgical treatment of mammary carcinoma, since recent trials of conservative treatment for mammary carcinoma have focused on the intraductal spread of the tumor cells.

Antigens, CD↗
PubMed1997

Integrin adhesion molecules in the endometrial glandular epithelium in patients with endometriosis or adenomyosis.

OBJECTIVE: To assess the role of beta 1-integrin and E-cadherin molecules in the eutopic glandular epithelium in patients with endometriosis or adenomyosis. STUDY DESIGN: Twenty-four patients with endometriosis, and 22 patients with adenomyosis diagnosed histologically were selected as subjects. The controls consisted of 29 fertile women. Eutopic endometria were obtained by curettage or immediately after the operation. The samples were immunohistochemically examined for the expression of very late activation antigen-2 (VLA-2), VLA-3, VLA-4, VLA-5, VLA-6, and E-cadherin. RESULTS: The expression of each VLA molecule and E-cadherin except VLA-4, VLA-5, and VLA-6 was significantly increased throughout the menstrual cycle in endometria in both the endometriosis and adenomyosis groups. In contrast, the expression of VLA-4 in the adenomyosis group was significantly reduced in the secretory phase. CONCLUSION: Altered expression of beta 1-integrins and E-cadherin was observed throughout the menstrual cycle in patients with endometriosis and adenomyosis, suggesting the defective microenvironment of the endometrium.

Adult↗
PubMed2006

Characterization of fibronectin assembly by platelets adherent to adsorbed laminin-111.

BACKGROUND: Various types of laminin (LN) are ubiquitous components of basement membrane and exposed to blood upon localized damage of vascular endothelial cells. Fibronectin is a plasma protein that is insolubilized into fibrils in a regulated fashion by, for example, lysophosphatidic acid (LPA)-stimulated fibroblasts or platelets spread on supportive adhesive ligands. OBJECTIVE: To study assembly of plasma fibronectin by LPA-activated platelets adherent to LN-111 via alpha6beta1 integrin. RESULTS: Platelets adherent to LN-111-bound plasma fibronectin or its N-terminal 70 kD fragment in fibrillar arrays at the periphery of spread platelets under static but not shear conditions. Formation of fibronectin arrays under static conditions was inhibited by co-incubation with the N-terminal 70 kD fragment or with a 49-amino acid peptide that binds to the N-terminal region of fibronectin. Approximately 7000 fibronectin dimers bound per adherent platelet with a K(d) of 50 nm. Bound 70 kD fragment was readily solubilized with deoxycholate (DOC), whereas bound fibronectin became progressively insoluble. Bound 70 kD fragment became resistant to DOC extraction after treatment with a cell-impermeable, reducible crosslinker. Crosslinked 70 kD fragment was found in a high molecular weight complex. As with fibroblasts, signaling molecules modulating actin cytoskeletal organization controlled expression of binding sites for the N-terminal 70 kD region of fibronectin on adherent platelets. CONCLUSIONS: These results indicate that platelets adherent to LN-111 via alpha(6)beta(1) support subsequent assembly of fibronectin, but possibly only under conditions of intermittent or stagnant blood flow.

Adsorption↗
PubMed2000

Integrin expression in oral hairy leukoplakia and normal tongue epithelium.

OBJECTIVE: To describe the expression of integrins in the epithelium of oral hairy leukoplakia (HL) and compare to that of normal lateral tongue epithelium. MATERIALS AND METHODS: Immunohistochemistry to identify integrins (alpha 2, alpha 3, alpha 5, alpha 6, alpha v, beta 1) was performed, using a standard biotin-streptavidin-peroxidase technique on five clinically and histologically confirmed frozen biopsy specimens of HL and five normal lateral tongue control tissues. RESULTS: Expression of integrins alpha 2, alpha 3, alpha 6, alpha v, beta 1 was seen both in HL epithelium and in normal control tissue. alpha 5 expression was not seen in HL or in control tissue epithelium. alpha 2 and alpha 3 were expressed mainly in the basal and suprabasal layers; alpha 6 expression was most intense on the basal surface of the basal cells, alpha v was expressed in the basal and suprabasal layers with more expression seen in the higher differentiated cell layers than the other integrins. beta 1 expression was seen in the basal and suprabasal layers only. No apparent difference between HL and normal oral mucosa was noted in the staining pattern of the various integrins. CONCLUSION: Integrins alpha 2, alpha 3, alpha 6, alpha v, beta 1 are expressed in HL and the expression pattern is not different from that of normal oral mucosa. alpha 5 is not expressed in HL or in normal oral epithelium.

Antigens, CD↗
PubMed2000

Requirement of CD9 on the egg plasma membrane for fertilization.

CD9 is an integral membrane protein associated with integrins and other membrane proteins. Mice lacking CD9 were produced by homologous recombination. Both male and female CD9-/- mice were born healthy and grew normally. However, the litter size from CD9-/- females was less than 2% of that of the wild type. In vitro fertilization experiments indicated that the cause of this infertility was due to the failure of sperm-egg fusion. When sperm were injected into oocytes with assisted microfertilization techniques, however, the fertilized eggs developed to term. These results indicate that CD9 has a crucial role in sperm-egg fusion.

Animals↗
PubMed1992

Laminin on Toxoplasma gondii mediates parasite binding to the beta 1 integrin receptor alpha 6 beta 1 on human foreskin fibroblasts and Chinese hamster ovary cells.

We investigated the role of parasite-bound laminin and the host cell beta 1 integrin receptors for this extracellular matrix protein in Toxoplasma gondii binding to fibroblasts. Laminin but not fibronectin was detected on extracellular tachyzoites by immunofluorescence and immunoblotting. Binding of parasites to CHO cells was inhibited by polyclonal antibodies to laminin and by a monoclonal antibody directed against the globular carboxyl-terminal portion of the long arm of laminin (at or near the suggested ligand-binding sites for alpha 3 beta 1 and alpha 6 beta 1), but not by a monoclonal antibody directed against the lateral short arms of laminin near the cross region of the molecule. Antibodies to the alpha 6 but not the alpha 2, alpha 3, or alpha 5 chains of the beta 1 family of integrins blocked parasite attachment to human foreskin fibroblasts and CHO cells. Attachment of T. gondii to cells via laminin on the parasite surface and laminin receptors on the mammalian cell is consistent with the capacity of the parasite to invade almost all nucleated cells.

Animals↗
PubMed2000

Aberrant development of thymocytes in mice lacking laminin-2.

In previous in vitro studies, we proposed a role for the extracellular matrix component, laminin-2, and its integrin receptor, VLA-6, in thymocyte development. The characterization of two dystrophic mouse strains with different defects in laminin-2 allowed us to examine this proposal in vivo. Mice deficient in laminin-2, dy/dy, show a significant reduction in thymus size and number of thymocytes compared to normal littermates. These mice also exhibited apparent alterations of thymic architecture. Examination of the CD4/CD8 populations in dy/dy thymi showed large relative increases in the DN (CD4- CD8-) and SP (CD4+ CD8-, CD4- CD8+) populations and a significant decrease in the DP (CD4+ CD8+) population. Further examination of the DN population for CD44 and CD25 expression showed a remarkable decrease in the more mature pre-T cell populations. Analysis of apoptosis in situ, and by flow cytometry, in dy/dy thymi revealed a significant increase in apoptotic DN thymocytes in the capsule and subcapsular regions. Interestingly, thymocyte development appeared to proceed normally in dystrophic mice expressing a mutant form of laminin-2, dy2J, as well as, in fetal and neonatal dy/dy mice. We propose that laminin-2 plays an active role in thymocyte development by delivering cell survival and differentiation signals at specific stages of development in young adult mice.

Animals↗
PubMed1998

Characteristic matrix and tubular basement membrane abnormalities in the CBA/Ca-kdkd mouse model of hereditary tubulointerstitial disease.

CBA/CaH-kdkd mice develop hereditary tubulointerstitial disease with mononuclear cell infiltration and cyst formation, possibly representing a model of human nephronophthisis. The purpose of the present investigation was to examine the components of the fibrotic changes which typically develop in the kidneys of these mice. By conventional histology, kdkd mice displayed progressive interstitial fibroblast and matrix accumulation. Immunohistological analysis of kdkd kidneys showed marked deposition of fibronectin in the tubulointerstitial space and revealed prominent irregularities for laminin and collagen type IV in the tubular basement membrane (TBM), including thickening, widening and folding. Electron microscopy confirmed the TBM abnormalities and showed marked undulation and thickening in areas of proximal tubular (PT) degeneration. Immunofluorescence staining analysis for the fibronectin receptors VLA-4 and VLA-5 showed no expression on injured proximal tubules, whereas the expression of the laminin receptor VLA-6 was increased and irregular on altered PT. Analysis of RNA derived from kdkd kidneys revealed marked upregulation of steady-state mRNA levels for the fibrogenic growth factor TGF-beta. We conclude that TBM alterations, matrix accumulation and changes in integrin expression together with enhanced TGF-beta production are typical features of kdkd tubulointerstitial disease and suggest that characteristic TBM or matrix alterations could contribute to the pathogenesis of the disease in these mice.

Animals↗