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PubMed1997

Cytoplasmic tails of beta 1, beta 2, and beta 7 integrins differentially regulate LFA-1 function in K562 cells.

The beta 2 integrin lymphocyte function-associated antigen 1 (LFA-1) mediates activation-dependent adhesion of lymphocytes. To investigate whether lymphocyte-specific elements are essential for LFA-1 function, we expressed LFA-1 in the erythroleukemic cell line K562, which expresses only the integrin very late antigen 5. We observed that LFA-1-expressing K562 cannot bind to intercellular adhesion molecule 1-coated surfaces when stimulated by phorbol 12-myristate 13-acetate (PMA), whereas the LFA-1-activating antibody KIM185 markedly enhanced adhesion. Because the endogenously expressed beta 1 integrin very late antigen 5 is readily activated by PMA, we investigated the role of the cytoplasmic domain of distinct beta subunits in regulating LFA-1 function. Transfection of chimeric LFA-1 receptors in K562 cells reveals that replacement of the beta 2 cytoplasmic tail with the beta 1 but not the beta 7 cytoplasmic tail completely restores PMA responsiveness of LFA-1, whereas a beta 2 cytoplasmic deletion mutant of LFA-1 is constitutively active. Both deletion of the beta 2 cytoplasmic tail or replacement by the beta 1 cytoplasmic tail alters the localization of LFA-1 into clusters, thereby regulating LFA-1 activation and LFA-1-mediated adhesion to intercellular adhesion molecule 1. These data demonstrate that distinct signaling routes activate beta 1 and beta 2 integrins through the beta-chain and hint at the involvement of lymphocyte-specific signal transduction elements in beta 2 and beta 7 integrin activation that are absent in the nonlymphocytic cell line K562.

Amino Acid Sequence↗
PubMed1994

Comparative evaluation of integrin alpha- and beta-chain expression in colorectal carcinoma cell lines and in their tumours of origin.

The integrin family consists of broadly expressed cell surface adhesion receptors, each member of which is composed of a non-covalently linked alpha/beta heterodimer. Integrin receptors are involved in the interaction with matrix proteins and may contribute to invasion and metastasis of carcinomas. To examine the biological role integrins play in colorectal carcinoma we compared the expression of integrin alpha- and beta-subunits in situ and in vitro. Eight newly established cell lines derived from immunohistochemically characterized colorectal carcinomas together with two sublines obtained after nude mouse passage and the commonly used colon carcinoma lines HT-29, SW480, SW620, and COLO 205 were investigated by immunocytochemistry and flow cytometry. The carcinomas in situ expressed alpha 1-, alpha 2-, alpha 3-, alpha 6-, alpha v- and beta 1-subunits in variable amounts while being devoid of alpha 4, alpha 5, and beta 3. The individual integrin profile of the tumour in tissue was essentially maintained in vitro. However, a neo expression of the alpha 5 chain was found, together with an induction or increase in alpha 1, alpha 2, alpha 3, alpha v and beta 1 levels. No decrease in integrin subunit expression was observed. Standard-serum and serum-free medium revealed no striking differences in alpha- and beta-chain expression in the cell lines HT-29 and COLO 205. In serum-free medium, SW480 showed a slight increase of alpha 1 and alpha 5 and a decrease of alpha 3 and alpha v while SW620 expressed more alpha 1. We conclude that the great variability of adhesion receptor expression of the integrin family in colorectal carcinomas in situ is essentially maintained in vitro, although culture conditions which are only marginally influenced by serum factors unpredictably lead to some increase in expression or even induction of several integrin subunits.

Antibodies, Monoclonal↗
PubMed2001

MHC class II beta-chain and alphaIIbbeta3 integrin are expressed on T-cell progenitors in embryonic bone marrow.

The RR5 monoclonal antibody (mAb) was obtained after immunization of mice with hemopoietic cells from chicken embryos. The cDNA encoding the protein recognized by RR5 was cloned using COS-7 cells transfected with an embryonic bone marrow (BM) cDNA library. The epitope recognized by the RR5 mAb was located on the non-polymorphic MHC class II beta-chain molecule. In the embryonic BM, RR5 labeled 50% of the c-kit expressing cells. Previous experiments have shown that the T-cell progenitors are present in the MHC class II(+)/c-kit(+) BM population along with myeloid progenitors and that T-cell and myeloid progenitors also express the integrin alphaIIbbeta3. In this study, using intrathymic cell transfer experiments in chicks, we have tested the T-cell differentiation potential of MHC class II/alphaIIbbeta3 double positive cells. It proved to be similar to that of the c-kit/MHC class II positive cells. However, injection of triple positive cells resulted in a selection of cells with an increased T-cell potential. Most of the MHC class II positive cells which do not express c-kit are prone to apoptosis, indicating that these progenitors might need a survival signal via c-kit. Interestingly, the MHC class II positive progenitors lose this expression after intrathymic transfer. Taken together our data suggest that the presence of the MHC class II beta-chain molecule on the surface of BM progenitor cells could be implicated in differentiation toward myeloid and lymphoid lineages.

Amino Acid Sequence↗
PubMed1996

Integrins beta 5, beta 3 and alpha v are apically distributed in endometrial epithelium.

Several adhesion molecules have been shown to occur at the surface of endometrial cells. One of these is the integrin alpha v subunit which associates with various beta chains including beta 5. We demonstrate the presence of integrin beta 5 polypeptide in human endometrial epithelial cells throughout the menstrual cycle using immunocytochemistry with monospecific antibodies, and at the mRNA level by thermal amplification from endometrial cDNA. Integrin beta 5 is also found in a population of bone marrow-derived cells. A notable feature of the distribution of the beta 5 subunit in the glandular and luminal epithelium is its apical localization, which may suggest an involvement in implantation. However, no evidence was found for regulated expression of epithelial beta 5. In mouse, the beta 5 subunit is found at both the apical and basal surface of epithelial cells and expression is essentially oestrous cycle-independent. Comparisons are made in both species with the distribution of the alpha v and beta 3 subunits which also localize to the apical epithelium.

Animals↗
PubMed1991

Individual embryonic fibroblasts express multiple beta chains in association with the alpha v integrin subunit. Loss of beta 3 expression with cell confluence.

The alpha chain of the vitronectin receptor, alpha v, has been found in association with the integrin subunits beta 1, beta 3, or beta 5 on different cell types. We show here that cultured embryonic fibroblasts simultaneously display alpha v beta 3, alpha v beta 1, and alpha v in association with two other beta subunits, one of which is probably beta 5. Polymerase chain reaction analysis of single cells isolated by micromanipulation identified mRNA for alpha v, beta 1, beta 3, and beta 5 in six of eight clones. Immunoprecipitation of iodinated cell surface proteins with a monoclonal antibody to alpha v indicated that the relative proportions of the different beta chains in association with alpha v varied, particularly between two different cell lines. The cytokines platelet-derived growth factor, transforming growth factor beta 1, and tumor necrosis factor alpha did not appear to alter this ratio although tumor necrosis factor alpha increased the surface expression of the alpha v-associated integrins; but overnight culture in basic fibroblast growth factor caused a lower expression of alpha v beta 1 and alpha v beta 5 with no reduction in alpha v beta 3 expression. When the cell cultures were grown to complete confluence, surface expression of beta 3 was abolished, and the expression of an unknown beta chain (beta u) became more prominent. This effect was not overcome by culturing confluent cells with basic fibroblast growth factor. Affinity column chromatography showed that alpha v beta 5 bound to vitronectin but alpha v beta 1 did not, whereas alpha v beta 1 but not alpha v beta 5 bound to fibronectin. These results suggest that, on individual cells, the beta subunits found in association with alpha v may vary according to the proliferative capacity of the cell and that the promiscuous beta 3 subunit is progressively replaced by beta subunits of individual ligand specificity.

Base Sequence↗
PubMed1996

Circulating leukocyte integrin expression in Wegener's granulomatosis.

Leukocyte adhesion and infiltration are important in the pathogenesis of Wegener's granulomatosis (WG). We tested the hypothesis that the expression of the beta 1-chain integrin VLA-4 (CD49d/CD29) and the beta 2-chain integrins LFA-1 (CD11a/CD18), Mac-1 (CD11a/CD18), and gp150,95 (CD11c/CD18) is increased on leukocytes in patients with active WG. Fifteen patients with active WG as defined by positive antineutrophil cytoplasmic autoantibody (cANCA) titers and biopsy, 30 patients with WG in remission as defined by negative cANCA titers and/or immunosuppressive therapy, 25 normal control subjects, and 12 patients with other inflammatory renal and systemic diseases were studied. Surface expression of LFA-1, Mac-1, p150, 95, and VLA-4 on neutrophils, lymphocytes, and monocytes was measured by fluorescent antibody cell sorting with monoclonal antibodies against CD11a, CD11b, CD11c, CD18, CD49d, and CD29 respectively. Immunocytochemistry and confocal microscopy were also utilized. beta 1 (CD29) and beta 2 (CD18) integrin subunit expression on neutrophils, monocytes, and lymphocytes from patients with acute WG was significantly increased compared with healthy persons and compared with patients with treated vasculitis. Furthermore, the alpha-integrin subunit CD11b expression was increased on granulocytes and monocytes, but not on lymphocytes. Finally, the alpha-integrin subunit CD11a expression was increased on monocytes. Immunocytochemistry showed that the increased immunoreactivity on neutrophils was evenly distributed on the plasma membrane and in the cytosol. Immunosuppression resulted in decreased expression of the beta 1 and beta 2-integrin subunits. It was concluded that the integrin adhesion molecules, particularly Mac-1 (CD11b/CD18), are upregulated on leukocytes in active WG. This finding suggests a role for integrin expression in the pathogenesis of WG and a possible clue for treatment.

Follow-Up Studies↗
PubMed1993

Adhesion molecule expression on B-cell chronic lymphocytic leukemia cells: malignant cell phenotypes define distinct disease subsets.

Expression of surface adhesion molecules of the Ig superfamily (CD54 and CD58), of the integrin family (beta 1, beta 2, and beta 3 chains), of the selectin family (L-selectin), and of the lymphocyte homing receptor (CD44) was analyzed on B-cell chronic lymphocytic leukemia (B-CLL) cells from 74 patients. The aim of the study was the definition of phenotypically distinct disease subsets and the correlation of adhesion molecule phenotypes with clinical parameters. Expression of CD58 on B-CLL cells defined more advanced disease stages. In comparison with beta chain-positive cases, patients whose cells did not express beta 1, beta 2, and beta 3 integrin chains fell into the most favorable prognostic group, with lower lymphocytosis and the absence of splenomegaly, diffuse bone marrow infiltration, and therapy requirement. A novel finding was the expression of beta 3 chains on cells from a minority (12 of 74) of B-CLL cases. beta 3 chains were always coexpressed with beta 1 and beta 2 chains. Two-color immunofluorescence analyses of adhesion molecules such as alpha x beta 2 integrin (LeuM5) and L-selectin (Leu8) showed that these markers were detectable on variable proportions of leukemic cells, thus confirming the intraclonal phenotypic heterogeneity of B-CLL. Differences in the intensity of CD44 expression were also shown among the various B-CLL clones. Finally, no major variations were shown by comparison of adhesion molecule phenotypes of leukemic cells simultaneously obtained from blood and bone marrow, and of CD5+ versus CD5- clones.

Adult↗
PubMed1989

Structure of the gene for cartilage matrix protein, a modular protein of the extracellular matrix. Exon/intron organization, unusual splice sites, and relation to alpha chains of beta 2 integrins, von Willebrand factor, complement factors B and C2, and epidermal growth factor.

The entire gene for chicken cartilage matrix protein (CMP) has been isolated and characterized by restriction mapping, electron microscopy, nuclease S1 mapping, and sequence analysis. The gene, which is present in a single copy in the chicken genome, is 18 kilobase pairs long and comprises eight exons and seven introns. It has two transcription initiation sites, 8 base pairs from each other. A sequence very homologous to the consensus nuclear factor III binding-site sequence, a CAT- and a TATA-like sequence are found in the promoter region and ATTAAA is used as a polyadenylation signal. The nucleotide sequence defines a primary translation product of 493 amino acids which consists of a 23-amino acid signal peptide and two large repeated domains connected by an epidermal growth factor module. Amino acid sequences homologous to those of the repeated domains are present in the type A repeats of von Willebrand factor, complement factors B and C2, and in the alpha chains of the integrins Mac-1, p150,95, and LFA-1. The exon-intron structure indicates that the CMP gene may have arisen by exon duplication and exon shuffling during evolution. The GT-AG splice rule cannot be applied for the excision of the last intron of the CMP pre-mRNA. The donor splice site of intron G is basically different from the consensus sequence indicating that a novel type of splicing mechanism might exist in cartilage.

Amino Acid Sequence↗
PubMed1991

Skeletal myoblasts utilize a novel beta 1-series integrin and not alpha 6 beta 1 for binding to the E8 and T8 fragments of laminin.

The E8 fragment of laminin stimulates myoblast attachment and locomotion. Myoblast attachment to laminin/E8 was blocked by anti-integrin antibodies against beta 1-chains but not by antibodies against alpha 6-chains. By contrast, other cell lines (e.g. B16, HT1080, P19, F9, Pys2, 3T3, and 3T6) were blocked both by anti-beta 1 and anti-alpha 6. All cells tested also bound to approximately 125-kDa C-terminal fragments of E8 (T8 and T8'). Immunoprecipitation of surface-iodinated myoblasts revealed beta 1-, alpha 3-, and alpha 5-integrin chains and a novel chain that co-precipitated with anti-beta 1 antibodies running at approximately 95 kDa (reduced). I125-alpha 6 beta 1 was immunoprecipitated from cells whose attachment to E8 was blocked by anti-alpha 6 antibodies. By contrast, little alpha 6 beta 1 could be immunoprecipitated from myoblasts. beta 1-Integrin and the novel alpha-chain (alpha'), Mr approximately 120,000/approximately 95.000 (nonreduced/reduced), from myoblast lysates were retained during affinity chromatography on Engelbreth-Holm-Swarm-laminin affinity columns. beta 1, alpha 1, and the novel alpha' were retained from Rugli cell lysates on Engelbreth-Holm-Swarm-laminin columns. alpha 3 was not bound. When E8 was used as affinity matrix, only beta 1 and alpha' were retained. The N-terminal sequence of Rugli alpha' was homologous to alpha-chains of beta 1-series integrins and was most similar to alpha 6 (9 identical residues out of 14). However, there were distinctive differences; in particular, 2 residues were deleted in comparison with alpha 6.

Amino Acid Sequence↗
PubMed1993

Beta 3 integrin derived peptide 217-230 inhibits fibrinogen binding and platelet aggregation: significance of RGD sequences and fibrinogen A alpha-chain.

beta 3 Integrin derived peptides 217-230 (DAPEGGFDAIMQAT) and 217-231 (Y) (DAPEGGFDAIMQATVY) at 100 microM inhibited 125I-fibrinogen binding to ADP-stimulated platelets and platelet aggregation. Peptide 217-231 (Y) (100 microM) significantly inhibited the binding of 125I-albolabrin (a disintegrin with a single RGD sequence) to ADP- and thrombin-activated platelets while it had only a slight effect on albolabrin binding to resting platelets. The 125I-beta 3 217-231 (Y) cross-linked selectively to the fibrinogen A alpha-chain. The interaction of the RGD sequence in the A alpha-chain of fibrinogen with beta 3 217-231 sequence appears to play a significant role in the events leading to platelet aggregation.

Adenosine Diphosphate↗
PubMed1993

Anchorage and lymphocyte function: extracellular matrix substrata control morphogenesis and interleukin production but have minor effects on DNA synthesis.

Contact with collagen and fibronectin substrata triggers disruption of aggregates of activated lymphocytes, pseudopodia formation and migration of these lymphocytes onto the substrata. Monoclonal antibodies to the alpha 4 and alpha 5 chains of beta 1-integrins inhibit cell substrate adhesion and aggregate disruption on fibronectin substrata. A rat monoclonal antibody to the beta 1-integrin chain inhibits lymphocyte adhesion to collagen. Two-dimensional (2D) and three-dimensional (3D) collagen substrata have virtually the same capacity to abrogate lymphocyte aggregation. Fibronectin substrata trigger the initial phase(s) of aggregate disruption as effectively as collagen but the later part of the disruption process is relatively incomplete. Serum-coated plastic does not cause aggregate disruption. These results indicate that disruption of lymphocyte aggregates is a specific event induced via cell surface receptors for extracellular matrix (ECM) components. A major difference between lymphocytes on 2D and 3D extracellular matrix substrata seems to be that the cells detach from the former whereas on the latter infiltration dominates over detachment. Collagen and fibronectin substrata are non-mitogenic for lymphocytes but they can modulate lymphocyte activation induced by allogeneic cells and Con A. Thus, 3D collagen substrata augment and prolong such induced DNA synthesis, although they slightly delay entry into the S-phase and decrease IL-2 production. Collagen substrata, particularly in 3D form, also augment the DNA synthesis of preactivated lymphocytes above the magnitude on serum-coated plastic. The nature of the substratum determines IL-1 production. Accordingly, the spontaneous IL-1 production by mononuclear cells is substantially lower on collagen substrata than on plastic surfaces coated with serum or BSA. However, factors which induce IL-1 production (e.g. Con A or LPS) are more effective on collagen than on serum-coated plastic. Abrogation of cell aggregation, induction of morphogenesis and motile behaviour as well as control of IL-1 synthesis thus constitute major effects of ECM substrata on cells of the immune system. An additional but relatively minor influence of ECM substrata on these cells, as suggested by the present results, is exerted via modulation of DNA synthesis.

Antigens, CD↗
PubMed1991

An abundant chick gizzard integrin is the avian alpha 1 beta 1 integrin heterodimer and functions as a divalent cation-dependent collagen IV receptor.

The alpha-subunit of an abundant chick gizzard integrin was isolated (T. Kelly, L. Molony, and K. Burridge, 1987, J. Biol. Chem. 262, 17,189-17,199) and fragmented by proteolytic digestion. The N-terminal sequences of the intact polypeptide and of several internal peptides were determined and were found to be highly homologous to the mammalian integrin alpha 1-subunit. Monoclonal antibodies to the chick integrin beta 1-chain react on immunoblots with the gizzard integrin beta-subunit (U. Hofer, J. Syfrig, and R. Chiquet-Ehrismann, 1990, J. Biol. Chem. 265, 14,561-14,565). The chain composition of the abundant chick gizzard integrin is therefore alpha 1 beta 1. Polyclonal antibodies to the avian integrin alpha 1-subunit block attachment of embryonic gizzard cells to human and chick collagen IV completely and inhibit attachment to mouse Engelbreth-Holm-Swarm (EHS) tumor laminin partially. In ELISA-style receptor assays, the isolated alpha 1 beta 1 integrin bound to human and chick collagen IV and to mouse EHS tumor and chick heart laminin. While the binding to collagen IV was abolished by removal of divalent cations, the binding to laminin was not sensitive to EDTA under the conditions used. Collagen I bound the isolated avian alpha 1 beta 1 integrin only weakly. As collagen IV was the only extracellular matrix protein for which a consistent, divalent cation-dependent, binding to the avian alpha 1 beta 1 integrin could be demonstrated in both cellular and molecular assays we suggest that it is a preferred ligand for this integrin.

Amino Acid Sequence↗
PubMed2004

Integrin alphavbeta8 functions as a receptor for foot-and-mouth disease virus: role of the beta-chain cytodomain in integrin-mediated infection.

Field isolates of foot-and-mouth disease virus (FMDV) have been shown to use three alphav integrins, alphavbeta1, alphavbeta3, and alphavbeta6, as cellular receptors. Binding to the integrin is mediated by a highly conserved RGD motif located on a surface-exposed loop of VP1. The RGD tripeptide is recognized by several other members of the integrin family, which therefore have the potential to act as receptors for FMDV. Here we show that SW480 cells are made susceptible to FMDV following transfection with human beta8 cDNA and expression of alphavbeta8 at the cell surface. The involvement of alphavbeta8 in infection was confirmed by showing that virus binding and infection of the transfected cells are inhibited by RGD-containing peptides and by function-blocking monoclonal antibodies specific for either the alphavbeta8 heterodimer or the alphav chain. Similar results were obtained with a chimeric alphavbeta8 including the beta6 cytodomain (alphavbeta8/6), showing that the beta6 cytodomain can substitute efficiently for the corresponding region of beta8. In contrast, virus binding to alphavbeta6 including the beta8 cytodomain (alphavbeta6/8) was lower than that of the wild-type integrin, and this binding did not lead to infection. Further, the alphavbeta6 chimera was recognized poorly by antibodies specific for the ectodomain of alphavbeta6 and displayed a relaxed sequence-binding specificity relative to that of wild-type integrin. These data suggest that the beta6 cytodomain is important for maintaining alphavbeta6 in a conformation required for productive infection by FMDV.

Animals↗
PubMed1992

Stimulation of neutrophil adhesion by antibodies recognizing CD15 (Le(X)) and CD15-expressing carcinoembryonic antigen-related glycoprotein NCA-160.

The carbohydrate antigen, CD15 (Le(X)), and its sialylated derivative have recently been shown to be involved in the binding of neutrophils to the endothelial lectins, E-selectin and P-selectin. Neutrophil NCA-160, a carcinoembryonic antigen (CEA)-related glycoprotein, is the major carrier of CD15, which is also expressed on the common beta 2 chain of leucocyte integrins. Rabbit IgG antibodies directed against CEA, which cross-react with neutrophil NCAs, increase the adhesion of neutrophils to plastic. This effect is also observed with F(ab')2 and Fab antibody fragments and a monoclonal antibody (mAb) recognizing the same antigen. Anti-CD15 mAbs inhibit adhesion at higher concentrations, but augment adhesion at lower concentrations. Anti-CEA and anti-CD15 antibodies cause the homotypic adhesion of neutrophils demonstrable by light microscopy and flow cytometry. Anti-(integrin beta 2 chain) mAbs inhibit both adhesion to plastic and homotypic adhesion. These results suggest that binding of ligand to NCA-160 is able to trigger neutrophil adhesion events which have been shown to be integrin mediated. Anti-CD15 mAbs do not, however, induce a respiratory burst from neutrophils.

Antibodies↗
PubMed1993

Expression of the beta 1 chain (CD29) of integrins and CD45 in alcoholic liver disease. The VA Cooperative Study Group No. 275.

OBJECTIVES: In the active stages of alcoholic liver disease (ALD), we have shown previously an enhanced expression of either CD4 or CD8 molecules on CD3+T cells. Class I and II MHC molecules expression were enhanced on lymphocytes, and on the cell membrane of hepatocytes, thus suggesting that an intrahepatic antigen-dependent lymphocyte-hepatocyte interaction occurs. Here we report the pattern of expression of several additional molecules known to participate in nonspecific cell-cell adhesion preceding alloantigen recognition i.e., the beta 1 chain of integrins (CD29) and the isoforms of the leukocyte common antigen CD45RA and CD45RO. METHODS: Frozen liver samples from 38 patients with advanced ALD were examined immunohistochemically by the avidin-biotin-peroxidase complex method using monoclonal antibodies. Nine patients with alcoholic fatty liver and six patients with only hepatitis C infection were included as controls and studied in a similar manner. RESULTS: CD29 was strongly expressed on the cell membrane of hepatocytes in 18/20 patients with cirrhosis, in 17/18 with alcoholic hepatitis without cirrhosis, in 5/9 of fatty liver and in all six with hepatitis C. CD45RA was present in 5/18 cases of alcoholic hepatitis and in 3/20 cases of cirrhosis on the hepatocytes plasma membrane, in none of the controls, and rarely on lymphocytes. CD45RO was expressed on the surface of lymphocytes in 14/18 cases of alcoholic hepatitis, 13/20 patients with cirrhosis, in 5/9 of fatty liver and in one with hepatitis C. The CD45RO lymphocytes were predominantly CD8 positive. CONCLUSIONS: Our results indicate that in ALD the hepatocytes exhibit on their plasma membrane an enhanced expression of the beta 1 chain of the integrins and less commonly CD45RA. Furthermore, the expression of only CD45RO on the surface of lymphocytes favors the postulate that the intrahepatic lymphocytes in ALD are most likely of the "memory" type. The results of this study lend further support to the contention that a cell-cell contact precedes a cell-mediated mechanism in the pathogenesis of ALD.

Antigens, CD↗
PubMed1994

Integrin expression in squamous neoplasia of the cervix.

Epithelial cell-basement membrane interactions are important in maintaining tissue architecture and function, and the anatomical and functional relationships between epithelial cells and their basement membranes are clearly altered in malignancy. These interactions are thought to be largely mediated by the integrins, a family of heterodimeric transmembrane glycoproteins, each consisting of an alpha and a beta chain. Epithelial integrins mainly belong to the beta 1 (VLA) subfamily, which forms receptors for matrix macromolecules such as fibronectin, laminin, and collagen. There is evidence that integrin expression changes in some epithelial malignancies, possibly in relation to invasive potential. Integrin expression in cervical neoplasia was studied by immunohistochemical examination of prospectively collected colposcopic biopsies. Well-characterized monoclonal antibodies against beta 1-4, alpha 1-6, and alpha V integrins were used to examine normal, koilocytic, and dysplastic cervical squamous epithelium, and invasive squamous carcinoma. beta 1, beta 4, alpha 2, alpha 3, alpha 6, and alpha V were expressed by the basal layer of normal cervical squamous epithelium and by dysplastic cells in CIN (cervical intraepithelial neoplasia) 1 and 2, with none being lost and no new chains acquired. In CIN3, these integrins were either expressed throughout the ectocervical epithelium or restricted to the basal layer. In the latter cases, integrin expression was retained to a greater degree by dysplastic squamous epithelium within endocervical glands. These patterns could not be correlated with age or smear history in the cases examined. Patterns of integrin expression in neoplastic cervical epithelium therefore differ from those of normal cervical epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Neuritogenesis on collagen substrates. Involvement of integrin-like matrix receptors in retinal fibre outgrowth on collagen.

Extracellular matrix molecules such as laminin, fibronectin and collagen promote neurite outgrowth in vitro. We have investigated the capacity of hydrated gels of collagen types I-III and monomeric collagen types I-VI on plastic surfaces to support neuritogenesis. The attachment and survival of explants from the day 6 chick embryo were studied and neurite outgrowth measured as mean elongation rate and maximal neurite length. Collagen types I and III, both as three-dimensional gels or as native monomers supported neuritogenesis equal to or better than laminin. Collagen type V also supported neurite out-growth although less effectively. Collagen types II, IV and VI, as well as denatured collagens of all types tested, did not support outgrowth. The monoclonal anti-beta 1 integrin antibody (CSAT), as well as rabbit polyclonal antibodies directed to the integrin beta 1-chain, effectively inhibited neurite outgrowth on permissive collagenous substrata, indicating that collagen-binding integrins were involved in the neuritogenesis. These beta 1-integrins were independent of Arg-Gly-Asp (RGD) since neurite formation proceeded in the presence of synthetic RGD-containing peptides. Fluorescence immunohistochemistry revealed the presence of the integrin beta 1-chain on the outgrowing neurites. The results suggest a possible function of collagen and collagen-binding integrins in the development of the visual system.

Animals↗
PubMed2006

Morphological analysis of integrin-mediated adhesion of immature human mast cells to extracellular matrix proteins.

Specific heterodimers of alpha and beta integrins are implicated in mediating adhesion and functional activation of mast cells to extracellular matrix (ECM) proteins, determining thus homing, secretion and tissue distribution of these cells. In the present study, we have examined integrin expression and associated morphological features of mast cells adhering to ECM, also depending on cell activation and under the influence of protein kinase C (PKC) inhibitors. Unstimulated and PMA-activated human leukaemic mast cells (HMC-1 line) were allowed to adhere to fibronectin or vitronectin-coated surfaces. Cells were specifically stained for actin, beta(1, )alpha(1)-alpha(6), alpha(v) and alpha(v)beta(5 )integrins and were evaluated by fluorescence microscopy and confocal laser scan microscopy. Spontaneously adhering cells rapidly assumed an oblong shape, with pronounced formation of filopodia, whereas PMA-stimulated cells were round in shape. Clustering of integrins on filopodia and on comma-like shapes at the cell circumference in rounded cells was noted only for alpha(4), alpha(5) and beta(1 )chains in fibronectin-adhering cells, and for alpha(v) and alpha(v)beta(5) chains in vitronectin-adhering cells. On double staining, clustered integrins co-localized with each other and with actin at the cell membrane and along intracellular tension lines of actin filaments. PKC inhibitors affected the shape of cells, but adhesion was maintained. These data provide a morphological correlate to previously reported functional studies, demonstrating clustering of selected integrins during ECM adhesion at the cell membrane. This was associated with alignment of integrins along actin filaments within the cytoplasm, PKC signalling and changes in shape and activation of mast cells.

Cell Adhesion↗