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PubMed2003

Redox regulation of surface protein thiols: identification of integrin alpha-4 as a molecular target by using redox proteomics.

Thiols affect a variety of cell functions, an effect known as redox regulation. We show here that treatment (1-2 h) of cells with 0.1-5 mM N-acetyl-L-cysteine (NAC) increases surface protein thiol expression in human peripheral blood mononuclear cells. This effect is not associated with changes in cellular glutathione (GSH) and is also observed with a non-GSH precursor thiol N-acetyl-D-cysteine or with GSH itself, which is not cell-permeable, suggesting a direct reducing action. NAC did not augment protein SH in the cytosol, indicating that they are already maximally reduced under normal, nonstressed, conditions. By using labeling with a non permeable, biotinylated SH reagent followed by two-dimensional gel electrophoresis and analysis by MS, we identified some of the proteins associated with the membrane that are reduced by NAC. These proteins include the following: integrin alpha-4, myosin heavy chain (nonmuscle type A), myosin light-chain alkali (nonmuscle isoform), and beta-actin. NAC pretreatment augmented integrin alpha-4-dependent fibronectin adhesion and aggregation of Jurkat cells without changing its expression by fluorescence-activated cell sorter, suggesting that reduction of surface disulfides can affect proteins function. We postulate that some of the activities of NAC or other thiol antioxidants may not only be due to free radical scavenging or increase of intracellular GSH and subsequent effects on transcription factors, but could modify the redox state of functional membrane proteins with exofacial SH critical for their activity.

Acetylcysteine↗
PubMed1996

Mechanisms of colon cancer binding to substratum and cells.

Binding of colon cancer to extracellular matrix (ECM) proteins and mesenchymal cells that comprise the basement membrane is important in migration and metastasis. This study defines the conditions and surface structures necessary for adhesion of HT-29 cells to ECM proteins and cell monolayers. Binding began within minutes and peaked by 1 hr, with 80-95% of HT-29 cells binding to the ECM proteins, collagen IV, laminin, fibronectin, and vitronectin and 40-75% binding to monolayers of fibroblasts, smooth muscle cells, and HT-29 cells. Treating mesenchymal cells with the fibrogenic cytokines, IL-1, IL-4, or TNF-alpha, which increase production of ECM proteins, did not alter binding of HT-29 cells to these monolayers. Attachment of HT-29 cells to cell monolayers was inhibited by cytochalasin D and sodium azide, but not cycloheximide or neuraminidase. Attachment to ECM proteins, in contrast, was unaffected by any of these metabolic inhibitors but required certain divalent cations (Mg2+ and Mn2+ but not Ca2+). Antibody to the integrin beta 1, chain (CD29) eliminated binding to collagen and laminin but not to fibronectin, fibroblasts, and HT-29 monolayers. Antibody to the vitronectin receptor inhibited binding to fibronectin. Antibodies to integrin alpha 1-alpha 6 chains had no effect on any adhesion event. Three colon cancer cell lines were tested for expression of VLA antigens: alpha 2 and alpha 3 were detected on all three, alpha 1 and alpha 6 were variably expressed, while alpha 4 and alpha 5 were absent. This study demonstrates that several mechanisms account for tumor cell attachment to substratum and cells.

Basement Membrane↗
PubMed1994

Influence of the epididymis on integrins and matrix proteins of human spermatozoa.

Spermatozoa alter their antigenity and develop the ability of binding to zona pellucida and to vitellus during the epididymal transit. The involvement of spermatozoal adhesion molecules (AM), especially beta 1-integrins in this binding process between the gametes is very likely. Therefore, the influence of epididymis on the binding capacity of AM was indirectly investigated by comparison of AM on ejaculated and on testicular human spermatozoa and spermatogenic cells, respectively. The AM-expression was detected on ejaculated spermatozoa by flow cytometry (EPICS PROFILE II, Coulter Corp., Krefeld, Germany) and on spermatogenic cells by immunohistology using monoclonal antibodies against. beta 1-integrins and matrix proteins. The alpha-chains 3, 5, 6 of the beta 1-integrins and fibronectin were found on ejaculated spermatozoa as well as on spermatogenic cells except spermatogonia. The alpha-4-chain and laminin could only be detected after the epididymal transit of spermatozoa, whereas, the beta-chain of beta 1-integrins was missing on the ejaculated spermatozoa. These findings suggest that AM are predominantly expressed on spermatogenic cells before the epididymal transit but an epididymis-mediated modulation of AM, i.e. masking, demasking or activating of cryptodeterminants is possible. On this way dysfunction of epididymis could be followed by an impairment of AM-mediated binding capacity of spermatozoa.

Antigens, CD↗
PubMed2005

The integrins of the urochordate Ciona intestinalis provide novel insights into the molecular evolution of the vertebrate integrin family.

BACKGROUND: Integrins are a functionally significant family of metazoan cell surface adhesion receptors. The receptors are dimers composed of an alpha and a beta chain. Vertebrate genomes encode an expanded set of integrin alpha and beta chains in comparison with protostomes such as drosophila or the nematode worm. The publication of the genome of a basal chordate, Ciona intestinalis, provides a unique opportunity to gain further insight into how and when the expanded integrin supergene family found in vertebrates evolved. RESULTS: The Ciona genome encodes eleven alpha and five beta chain genes that are highly homologous to their vertebrate homologues. Eight of the alpha chains contain an A-domain that lacks the short alpha helical region present in the collagen-binding vertebrate alpha chains. Phylogenetic analyses indicate the eight A-domain containing alpha chains cluster to form an ascidian-specific clade that is related to but, distinct from, the vertebrate A-domain clade. Two Ciona alpha chains cluster in laminin-binding clade and the remaining chain clusters in the clade that binds the RGD tripeptide sequence. Of the five Ciona beta chains, three form an ascidian-specific clade, one clusters in the vertebrate beta1 clade and the remaining Ciona chain is the orthologue of the vertebrate beta4 chain. CONCLUSION: The Ciona repertoire of integrin genes provides new insight into the basic set of these receptors available at the beginning of vertebrate evolution. The ascidian and vertebrate alpha chain A-domain clades originated from a common precursor but radiated separately in each lineage. It would appear that the acquisition of collagen binding capabilities occurred in the chordate lineage after the divergence of ascidians.

Amino Acid Sequence↗
PubMed1992

Expression of murine beta 7, alpha 4, and beta 1 integrin genes by rodent mast cells.

The screening of a rat mast cell cDNA library with a probe selected to recognize those genes preferentially or exclusively expressed by mast cells identified a rat gene sequence, RF-17, that shared homology with the beta-integrins. This integrin was expressed in rat tissues enriched for mast cells and T cells. The rat RF-17 sequence was used to isolate the murine homologue from a spleen cDNA library. The murine gene encodes a protein of 806 amino acids that is the probable homologue to the human beta 7 chain. Transcripts specific for the murine gene are found in the thymus, spleen, and lung. To attempt to identify the gene product for this new integrin chain, we examined the murine T cell line TK-1, which expresses a novel integrin heterodimer, lymphocyte Peyer's patch high endothelial venule adhesion molecule (LPAM-1), of a known alpha 4 chain and an unknown beta P chain, for expression of murine beta 7 (RF-17). This cell line expresses high levels of RF-17 transcripts, suggesting that beta P is encoded by the beta 7 gene. Bone marrow cells induced to differentiate into mast cells via IL-3 express the beta 7 gene as well as the genes encoding the murine integrin alpha 4 and beta 1 proteins. Surface staining analysis indicates that these cells express an alpha 4-containing integrin complex throughout the differentiation process. These data suggest that the Peyer's patch homing LPAM-1 receptor expressed by a subset of T cells consists of the beta 7 gene product and the alpha 4 chain, and that this integrin chain complex is also found on the surface of maturing mast cells. The presence of beta 1 transcripts also suggests that these maturing mast cells possess the LPAM-2 integrin complex (alpha 4/beta 1) as well. The experimental strategy described in this manuscript has, thus, identified a novel murine beta-integrin chain that is expressed by rodent T cells and mast cells.

Amino Acid Sequence↗
PubMed1990

Identification of a novel integrin beta subunit expressed on cultured monocytes (macrophages). Evidence that one alpha subunit can associate with multiple beta subunits.

The vitronectin receptor (VnR) is one member of a subset of cell adhesion receptors within the integrin supergene family which shares the beta 3 subunit (IIIa). We show here that the VnR is absent from the surface of monocytes freshly isolated from blood but is expressed on these cells after a period of in vitro culture. Such cultured monocytes (macrophages) from a patient with type I Glanzmann's thrombasthenia, however, failed to express the VnR. Instead, immunoprecipitation with a monoclonal antibody directed to the VnR alpha chain (alpha v) revealed a novel integrin comprising alpha v associated noncovalently with a 100-kDa beta subunit (beta 3b), immunologically unrelated to the VnR beta subunit (beta 3a). This same novel integrin complex was also identified on 10-day-old macrophages from healthy donors, but on these cells, the beta 3b subunit was co-expressed with the classical VnR complex of alpha v beta 3a. The novel beta 3b subunit was not identified by monoclonal or polyclonal antibodies to IIIa (beta 3a) nor by a monoclonal antibody to the classical VnR complex. The beta 3b subunit could be distinguished from beta 3a by its relatively greater migration on sodium dodecyl sulfate-polyacrylamide gel electrophoresis after reduction, by its distinct isoelectric point upon two-dimensional gel electrophoresis, and by one-dimensional peptide mapping. Neither platelets nor B lymphoblasts from this patient with Glanzmann's thrombasthenia expressed any VnR on their surface, whereas control cells from a normal donor expressed the classical VnR but not the beta 3b subunit. The two beta chains, and hence also the combined receptor complexes, appeared to be differentially regulated. These findings provide the first example of an integrin alpha chain complexed with more than a single beta chain in the same cell. Furthermore, the differential regulation of expression of the different beta subunits that associate with the VnR alpha chain on cultured monocytes suggests a role for the novel receptor complex during monocyte/macrophage differentiation.

Adult↗
PubMed1996

Beta1 integrin-mediated activation of focal adhesion kinase and its association with Fyn and Zap-70 in human NK cells.

Adhesive interactions mediated by cell surface receptors have been shown to induce signal transduction pathways that regulate changes in cellular function. We have reported recently that fibronectin (FN) receptors, alpha4beta1 and alpha5beta1 integrins, on NK cells transduce transmembrane signals leading to tyrosine phosphorylation of 60-, 70-, and 120-kDa proteins. In the current study, we have identified a 120-kDa phosphoprotein as the focal adhesion kinase (p125FAK), a structurally unique nonreceptor protein tyrosine kinase that localizes to focal adhesions. Activity of p125FAK was induced by adhesion of NK cells to plastic-immobilized FN, by cross-linking of cell surface-bound FN or FN fragments, FN120 or FN40, with anti-FN mAb, or by cross-linking of alpha4beta1 or alpha5beta1 integrins with alpha-chain-specific Abs. We also observed that enhanced in vitro kinase activity was associated with immunoprecipitates of alpha4beta1 or alpha5beta1 integrins from lysates of FN-adherent NK cells as compared with BSA-treated NK cells. In addition to p125FAK activity, FN-induced kinase activity was also found to be mediated by Fyn, Lyn, and Zap-70, as assessed by in vitro phosphorylation of the immunoprecipitated kinases in the presence of [gamma-32P]ATP. Clustering of FN receptors on NK cells by agonists such as immobilized FN or alpha4- or alpha5-specific Abs also induced association of Fyn and Zap-70 with p125FAK. Our observations indicate that activation and phosphorylation of p125FAK as well as Zap-70 and certain kinases of the src family play an important role in formation of active signaling complexes in response to triggering via beta1 integrins on NK cells. These results also suggest the existence of cross-talk or points of convergence between the beta1 integrin-mediated and other receptor-signaling pathways.

Cell Adhesion↗
PubMed1990

Constitutive and induced phosphorylation of the alpha- and beta-chains of the CD11/CD18 leukocyte integrin family. Relationship to adhesion-dependent functions.

We sought to determine whether the activation event which renders the CD11/CD18 leukocyte integrin/Leu-CAM glycoproteins capable of promoting cell to cell adhesion was associated with the induced posttranslational modification of phosphorylation. In neutrophils, two species of alpha-chains, a predominant CD11b 165-kDa subunit and a minor 150-kDa CD11c subunit were found to be constitutively phosphorylated. However, the 95-kDa CD18 common beta-chain was not phosphorylated in resting cells but became strongly phosphorylated in cells incubated with PMA. The beta-chain was phosphorylated in a dose-related manner within 1 min of the addition of PMA, reached maximal intensity between 4 to 10 min, and remained fully phosphorylated at 30 min. The similarities of the kinetics of homotypic aggregation induced by PMA to the time course of phosphorylation suggest that phosporylation may be relevant to at least this type of Leu-CAM-dependent adhesion. In contrast, in the presence of FMLP which induces aggregation with different kinetics than PMA, no phosphorylation of the common beta-chain was observed over a time interval of from 30 s to 10 min further emphasizing the apparent differences in the two modes of activation to an adhesive state. The phosphorylated species on neutrophils were readily detected by immunoprecipitation with each CD18 mAb and most but not all CD11b mAb which otherwise precipitated 125I-labeled CD11b species suggesting that the CD11b alpha-chain labelled with 32P may differ slightly from the 125I-labeled species in terms of its recognition by certain CD11b mAb. In mononuclear cells, similar constitutive phosphorylation of the CD11a and CD11c alpha-chains was observed that remained unchanged in the presence of either FMLP or PMA. As was demonstrated in neutrophils, phosphorylation of the CD18 beta-chains of mononuclear cells was not constitutive but was induced in the presence of PMA and not FMLP. Taken together these data suggest the existence of specific recognition sites on beta-chains for a regulatory kinase-phosphatase system.

Amino Acid Sequence↗
PubMedDate not supplied

In vitro fertilization: increased VLA (very late antigen) integrins and fibronectin after acrosome reaction.

The pattern of detectable adhesion molecules (AM) on human ejaculated spermatozoa used for in vitro fertilization (IVF) of human oocytes was evaluated. The percentage of spermatozoa with the alpha chains 3, 4, 5, and 6 of the integrins (also called very late antigens, VLA alpha 3, 4, 5, 6), the alpha V and the beta 3 chains, as well as the matrix proteins laminin and fibronectin, were determined by flow cytometry using monoclonal antibodies against integrins and matrix proteins before and after the acrosome reaction. This reaction was induced by the low-temperature method according to P. Sanchez, E. Töpfer-Petersen, R. J. Aitken, and W. B. Schill (1991, Andrologia 23:197-203) and monitored by the binding of FITC-conjugated Pisum sativum agglutinin. Twenty-three of 34 investigated semen samples fertilized at least one oocyte (fertile group) and 11 samples did not induce a pronucleus formation or cleavage of an oocyte (infertile group). Significant differences in the classical semen parameters between both semen sample groups could be shown only for the percentage of progressively motile spermatozoa (p = .046, U test). The spermatozoa of the fertile group showed a significantly higher expression of VLA alpha 3 (p = .045) and fibronectin (p = .048). Additionally, after the loss of the acrosome a significantly higher expression of alpha 4, alpha 5, and alpha 6 chains of integrins (p < .05) was detected in the fertile semen group. In contrast, the inducibility of the acrosome reaction differed only to a nonsignificant extent (p = .094). These data suggest that spermatozoa showing a higher expression of the alpha chains of the integrins after the acrosome reaction have a better fertilization rate in vitro.

Acrosome↗
PubMed1990

Fibronectin matrix deposition and fibronectin receptor expression in healing and normal skin.

During cutaneous tissue organization, numerous critical interactions occur between cells and the extracellular matrix (ECM). Cell-matrix interactions depend on the presence of ECM receptors. Many ECM receptors, known as integrins, are heterodimeric glycoproteins consisting of one alpha and one beta chain. Integrins containing beta 1 or beta 3 chains are ECM receptors, whereas those containing beta 2 chains are leukocyte cell-cell receptors. We have used porcine cutaneous wounds as a paradigm for tissue organization and probed healing wounds and adjacent normal skin with polyclonal antibodies to fibronectin and fibronectin (alpha 5 beta 1) receptor. During re-epithelialization, the epidermis transits over a provisional matrix containing fibronectin. Migrating epidermal cells expressed fibronectin receptors in a bright linear peripheral pattern. At 10 days, when reepithelialization was complete and the basement membrane was re-established, the fibronectin matrix was markedly reduced and fibronectin-receptor expression was limited to the basolateral aspect of basal cells, as observed in normal epidermis. Beneath the migrating epidermis in 5-d wounds, granulation tissue had filled 80% of the wound space. Day-5 wound fibroblasts did not express fibronectin nor other beta 1 integrin receptors, were randomly oriented, and contained no actin bundles. Fibronectin fibrils were assembled on the surfaces of day-5 wound fibroblasts but formed few linkages between cells. Day-7 wound fibroblasts expressed fibronectin receptors, contained peripheral cytoplasmic actin bundles consistent with a contractile fibroblast phenotype, and were coaligned across the wound in parallel array with interconnecting fibronectin fibrils. The wounds contracted between 7 and 10 days. Thus the migrating epidermis consistently expressed fibronectin receptors. Fibronectin receptors were expressed by fibroblasts just prior to wound contraction.

Animals↗
PubMed1996

Induction of mouse beta integrin expression following transfection with human alpha 4 chain.

We report here an analysis of the expression and function of the alpha chain of human VLA-4 in stable mouse L cell transfectants and the requirement for the beta chain in these processes. L cells were transfected with human alpha 4 cDNA or alpha 4 and human beta 1 cDNA. Unexpectedly, human alpha 4 cDNA, when transfected alone, could induce de novo surface expression of host beta 7 and increased expression of host beta 1. Induction of mouse beta 7 and beta 1 surface expression was not due to de novo gene activation, but instead represented alpha 4/beta intracellular subunit association and transport to the cell surface. Transfection with human beta 1 prevented surface expression of mouse beta integrins. Whereas human alpha 4 and human beta 1 subunits associated very tightly in anti-alpha 4 immunoprecipitates, human alpha 4 and mouse beta subunits were only partially associated. Furthermore, binding of human/mouse chimeric receptors to recombinant VCAM, a major ligand for alpha 4 beta 7 and alpha 4 beta 1, was very poor, whereas human alpha 4/human beta 1 receptors bound strongly to VCAM. One alpha 4 transfectant, which exhibited a tight human alpha 4/mouse beta 1 association, could be induced, but only after PMA activation, to bind strongly to VCAM. These results indicate that alpha 4 subunits have specific affinity for beta 7 and beta 1 integrins and require beta subunits for surface expression as well as high affinity ligand binding activity. Our results indicate that a tight association between the alpha 4 and beta subunit appears to be critical for ligand binding, consistent with a direct as well as regulatory role for the beta subunit in ligand binding. Furthermore, these studies demonstrate that expression of foreign recombinant proteins can alter host cell protein expression resulting in de novo surface protein expression.

Animals↗
PubMed1998

Cation binding to the integrin CD11b I domain and activation model assessment.

BACKGROUND: The integrin family of cell-surface receptors mediate cell adhesion through interactions with the extracellular matrix or other cell-surface receptors. The alpha chain of some integrin heterodimers includes an inserted 'I domain' of about 200 amino acids which binds divalent metal ions and is essential for integrin function. Lee et al. proposed that the I domain of the integrin CD11b adopts a unique 'active' conformation when bound to its counter receptor. In addition, they proposed that the lack of adhesion in the presence of Ca2+ ion reflected the stabilization of an 'inactive' I-domain conformation. We set out to independently determine the structure of the CD11 b I domain and to evaluate the structural effects of divalent ion binding to this protein. RESULTS: We have determined the X-ray structure of a new crystal form of the CD11 b I domain in the absence of added metal ions by multiple isomorphous replacement (MIR). Metal ions were easily introduced into this crystal form allowing the straight-forward assessment of the structural effects of divalent cation binding at the metal ion dependent adhesion site (MIDAS). The equilibrium binding constants for these ions were determined by titration calorimetry. The overall protein conformation and metal-ion coordination of the I domain is the same as that observed for all previously reported CD11 a I-domain structures and a CD11 b I-domain complex with Mn2+. These structures define a majority conformation. CONCLUSIONS: Addition of the cations Mg2+, Mn2+ and Cd2+ to the metal-free I domain does not induce conformational changes in the crystalline environment. Moreover, we find that Ca2+ binds poorly to the I domain which serves to explain its failure to support adhesion. We show that the active conformation proposed by Lee et al, is likely to be a construct artifact and we propose that the currently available data do not support a dramatic structural transition for the I domain during counter-receptor binding.

Amino Acid Sequence↗
PubMed1990

Interaction of integrins alpha v beta 3 and glycoprotein IIb-IIIa with fibrinogen. Differential peptide recognition accounts for distinct binding sites.

Glycoprotein (GP) IIb-IIIa is the major fibrinogen receptor on platelets and participates in platelet aggregation at the site of a wound. Integrin alpha v beta 3, which contains an identical beta-subunit, is expressed on endothelial cells and also serves as a fibrinogen receptor. Here, we demonstrate by several criteria that purified GPIIb-IIIa and integrin alpha v beta 3 bind to distinct sites on fibrinogen. First, a plasmin-generated fragment of fibrinogen lacking the RGD sequence at residues 572-574 retained the ability to bind GPIIb-IIIa, but failed to bind integrin alpha v beta 3. Second, a monoclonal antibody which exclusively recognizes the RGD sequence at fibrinogen A alpha chain residues 572-574 abolished interaction between integrin alpha v beta 3 and fibrinogen, but had only a minimal effect on fibrinogen binding to GPIIb-IIIa. Finally, we show that the difference in recognition of sites on fibrinogen by these two integrins is probably a consequence of their remarkably different ligand binding properties. Peptides corresponding to fibrinogen gamma chain residues 400-411 effectively blocked RGD sequence and fibrinogen binding by GPIIb-IIIa, but had no effect on the ability of integrin alpha v beta 3 to bind these ligands. We also show that integrin alpha v beta 3 has a higher affinity than GPIIb-IIIa for a synthetic hexapeptide containing the RGD sequence. In fact, this RGD-containing peptide was 150-fold more effective at blocking fibrinogen binding to integrin alpha v beta 3 than to GPIIb-IIIa. Collectively, our results demonstrate that integrins alpha v beta 3 and GPIIb-IIIa display qualitative and quantitative differences in their ligand binding properties, as is evident by their ability to interact with synthetic peptides. The ultimate result of these differences is the recognition of distinct sites on fibrinogen by the two integrins. These observations may have relevance in the processes of hemostasis and wound healing.

Amino Acid Sequence↗
PubMed2000

Engagement of CD11b and CD11c beta2 integrin by antibodies or soluble CD23 induces IL-1beta production on primary human monocytes through mitogen-activated protein kinase-dependent pathways.

beta2 integrins are involved in the recruitment of leukocytes to inflammatory sites and in cellular activation. We demonstrate that ligation of CD11b (Mac-1, CR3) or CD11c (p150, CR4) alpha chains of beta2 integrins by mAbs or soluble chimeric CD23 (sCD23) on human freshly isolated monocytes rapidly stimulates high levels of interleukin-1beta production. This induction takes place at the transcriptional level and is regulated by members of the mitogen-activated protein kinase (MAPK) family. Indeed, stimulation of monocytes through engagement of CD11b or CD11c results in the phosphorylation and activation of ERK1, ERK2, and p38/SAPK2 MAP kinases. U0126, a potent inhibitor of the upstream activator of ERK1/2, ie, MEK1/2, suppresses IL-1beta messenger RNA (mRNA) expression in a dose-dependent fashion, showing the implication of this pathway in the transcriptional control of IL-1beta production. On the other hand, inhibition of p38 by SB203580 indicates that this MAPK is involved in the control of IL-1beta production at both transcriptional and translational levels. Together these data demonstrate that ligation of CD11b and CD11c beta2 integrins by mAbs or sCD23 fusion proteins triggers the activation of 2 distinct MAPK signaling pathways that cooperate in controlling IL-1beta synthesis at different levels. (Blood. 2000;95:3868-3877)

Antibodies, Monoclonal↗
PubMed2000

Expression of integrin subunits correlates with differentiation of epithelial cell lineages in developing human gastric mucosa.

Laminins may play important roles in gastric gland development due to the differential localization of their alpha chains in human fetal fundic (oxyntic) mucosa. To extend this hypothesis, the current investigation was undertaken to compare the anatomical and cellular distribution of epithelial integrin subunits with those of laminin alpha chains in the human stomach at different ages (8-22 weeks of gestation) using indirect immunofluorescence. In the body, fundus and antrum regions, the beta1 and alpha6 subunits were associated with the entire epithelium at all developmental stages in the same way as laminin chains (alpha1/alpha5) detected with 4C7 monoclonal antibody. By contrast, the alpha3 and beta4 subunits of alpha3beta1 and alpha6beta4 integrins together with the laminin alpha3-chain were concentrated in the surface and foveolus compartments composed of differentiating mucous cells. Most importantly, the alpha2 integrin subunit was expressed in a rather complex pattern: (1) it was located at the base and at cell-cell boundaries of surface/foveolar epithelium, (2) was specifically repressed in differentiating parietal cells, and (3) its expression increased in maturing glands, where it became concentrated at the basal pole of epithelial cells simultaneously exhibiting a strong reactivity for laminin-2 (alpha2-chain). Taken altogether, our observations provide new evidence for the implication of different laminins and their receptors in the development of all human gastric epithelial lineages, surface mucous cells or glandular cells. The coordinated expression of alpha2 and alpha3 integrin subunits as well as the cellular re-distribution of alpha2beta1 integrin likely represent key events for the differentiation of glandular secretory cell types, especially maturing chief cells responsible for the synthesis/secretion of gastric digestive enzymes in fundic-type glands.

Antigens, CD↗
PubMed1998

Selective expression of beta 7 integrin on lymphocytes undergoing apoptosis in lymphoid tissues.

It has been previously shown that the beta 7 chain of integrin forms heterodimers with the alpha 4 or alpha E chain, which plays essential roles in lymphocyte homing to mucosal lymphoid tissues. The aim of this study was to re-evaluate the possible role of the beta 7 integrin other than lymphocyte homing. We prepared spleen and lymph node lymphocytes from biopsied specimens from macaque monkeys and examined for the reactivity with a monoclonal antibody specific for the beta 7 chain. As a result, a minor population of the lymphocytes with a smaller size, which were in the early stage of apoptosis, was found to express a higher level of the beta 7 integrin than a majority of the lymphocytes with a normal size. Interestingly, the apoptotic lymphocytes expressed neither alpha 4 nor alpha E chains, suggesting that the beta 7 chain on these cells may be associated with an undefined alpha chain. These findings indicate that in the lymphoid tissues the shrunken lymphocytes undergoing apoptosis selectively express a unique beta 7 integrin.

Animals↗
PubMed1995

Integrin alpha 6 is a differentiation antigen of human granulosa cells.

We previously reported a new murine monoclonal antibody (mAb), OG-1, raised against human granulosa cells (GC) and showed that the OG-1 antigen is a cell surface differentiation-related molecule expressed on GC of follicles and on large luteal cells in the early to midluteal phase. In this study, we further characterized the OG-1 antigen. An immunohistochemical study showed that the OG-1 antigen was also expressed on endometrial glandular and stromal cells and on first trimester and term placental trophoblasts. The antigen purified from endometrium, chorionic villi, or placenta by immunoaffinity chromatography using the mAb OG-1 consisted of a 120-kilodalton (kDa) protein. Partial amino acid sequencing of the 120-kDa protein purified from placenta revealed that the 16 amino acids from the N-terminus were identical to those of the heavy chain of human integrin alpha 6, the molecular mass of which is reportedly 118-126 kDa. We examined the tissue distribution of integrins alpha 6, beta 1, and beta 4, because integrin alpha 6 forms heterodimers with integrins beta 1 or beta 4. Indirect immunofluorescence staining of various follicles and corpora lutea using two known antiintegrin alpha 6 monoclonal antibodies (450-30A1 and GoH3) showed that integrin alpha 6 was expressed on granulosa and large luteal cells in a profile similar to that of the OG-1 antigen. Integrin beta 1 was expressed on granulosa and large luteal cells, but integrin beta 4 was undetectable. Integrin beta 1 was also expressed on thecal and stromal cells. In term placentas, the OG-1 antigen and integrins alpha 6 and beta 4 were expressed on trophoblasts, whereas integrin beta 1 was expressed on villous capillary endothelia. These results indicate that the mAb OG-1 recognizes integrin alpha 6, and that integrin alpha 6 is a differentiation-related antigen of human GC, suggesting the involvement of integrins in human folliculogenesis and luteal formation.

Adult↗
PubMed1993

[Pattern of expression of integrins in alveolar epithelia of fetal and adult lungs and interstitial lung diseases].

We studied the expression of integrin alpha and beta chains on alveolar epithelia in normal and fibrotic lung tissue by immunohistochemistry. Alveolar epithelia and their precursor cells in fetal lung tissue consistently expressed alpha 1, alpha 2, alpha v and beta 1 chains. Neoexpression of alpha 4, alpha 6 and beta 4 chains was detected on alveolar epithelia of fibrotic lung tissue. Adhesion blocking assays with isolated type II pneumocytes were performed to investigate the substrate specificity of the alpha chains. alpha 1, alpha 2 and alpha 3 demonstrated a specificity for collagen, alpha 4, alpha 5 and alpha 6 for fibronectin, alpha 3 and alpha 6 for laminin and finally alpha 5 and alpha v for vitronectin.

Adult↗