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Results for “Integrin beta Chains”

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At least 19 recordsLinked to original sources
PubMed1994

The integrin chains beta 1 and alpha 6 associate with the chaperone calnexin prior to integrin assembly.

Integrins are alpha beta heterodimers that mediate cell-cell adhesion, as well as cell-substrate adhesion. The largest subclass is formed by 10 heterodimers (the very late antigens) that all share the beta 1-chain. We have found a 90-kDa protein that co-isolates with mouse integrin beta 1-chain. This 90-kDa protein was identified as the mouse homolog of calnexin, a membrane-bound chaperone and resident protein of the endoplasmic reticulum. First, the sequence of the 15 NH2-terminal amino acids of the 90-kDa protein is 80% and 87% identical to the corresponding sequences of canine and human calnexin, respectively. Second, the 90-kDa protein was recognized by a monoclonal antibody against calnexin/IP90. Association of calnexin with the integrin beta 1-chain was directly demonstrated by chemical cross-linking. As pulse-chase experiments revealed, the association of the beta 1-chain with calnexin occurred prior to the assembly with integrin alpha 6-chain. Additionally, the alpha 6-chain bound to calnexin before integrin assembly and dissociated again at the time of integrin-assembly. Our data suggest that calnexin is involved in the assembly of beta 1 integrins, as well as in the retention of a pool of immature integrin beta 1-chains in the ER.

Amino Acid Sequence↗
PubMed1993

A monoclonal antibody against an activation epitope on mouse integrin chain beta 1 blocks adhesion of lymphocytes to the endothelial integrin alpha 6 beta 1.

We have generated a monoclonal antibody (mAb), 9EG7, against mouse endothelial cells that blocks adhesion of lymphocytes to endothelial cells. Sequencing of four tryptic peptides of the purified antigen revealed its identity with the integrin chain beta 1. The only beta 1 integrin that is known to mediate cell-cell adhesion is alpha 4 beta 1 (VLA-4). This is not the integrin that is functionally defined by the mAb 9EG7 on endothelial cells. First, alpha 4 is not present on the analyzed endothelial cells. Second, mAb 9EG7 does not block the cell-adhesion function of alpha 4 beta 1 on the nonactivated mouse lymphoma L1-2. Thus, the mAb 9EG7 can functionally distinguish between different beta 1 integrins and defines a beta 1 integrin other than alpha 4 beta 1 as a newly discovered cell-cell adhesion molecule. This integrin is most likely alpha 6 beta 1, since an antibody against the alpha 6 chain blocks lymphocyte adhesion to the same degree as the mAb 9EG7, the effect of both antibodies is not additive, and the alpha 6 chain is coprecipitated with beta 1 in 9EG7 immunoprecipitations. Surprisingly, activation of alpha 4 beta 1 on L1-2 cells with phorbol ester or Mn2+ allows blocking of alpha 4 beta 1-mediated adhesion of L1-2 cells to endothelial cells with mAb 9EG7. Furthermore, only the activated alpha 4 beta 1 heterodimer, but not the unactivated complex, is detectable with 9EG7 in immunoprecipitations and by flow cytometry. Thus, mAb 9EG7 defines an epitope on integrin chain beta 1, which is accessible on the alpha 4 beta 1 heterodimer only after activation of this integrin.

Animals↗
PubMed2002

The anchoring protein RACK1 links protein kinase Cepsilon to integrin beta chains. Requirements for adhesion and motility.

Integrin affinity is modulated by intracellular signaling cascades, in a process known as "inside-out" signaling, leading to changes in cell adhesion and motility. Protein kinase C (PKC) plays a critical role in integrin-mediated events; however, the mechanism that links PKC to integrins remains unclear. Here, we report that PKCepsilon positively regulates integrin-dependent adhesion, spreading, and motility of human glioma cells. PKCepsilon activation was associated with increased focal adhesion and lamellipodia formation as well as clustering of select integrins, and it is required for phorbol 12-myristate 13-acetate-induced adhesion and motility. We provide novel evidence that the scaffolding protein RACK1 mediates the interaction between integrin beta chain and activated PKCepsilon. Both depletion of RACK1 by antisense strategy and overexpression of a truncated form of RACK1 which lacks the integrin binding region resulted in decreased PKCepsilon-induced adhesion and migration, suggesting that RACK1 links PKCepsilon to integrin beta chains. Altogether, these results provide a novel mechanistic link between PKC activation and integrin-mediated adhesion and motility.

Animals↗
PubMed1993

Functionally distinct roles for glycosylation of alpha and beta integrin chains in cell-matrix interactions.

Laminin interaction with gp120/140, a B16-F10 laminin-binding protein immunologically related to alpha 6 beta 1 integrin, has been shown to be dependent on oligosaccharides from both ligand and receptor. Lectin analysis of gp120/140 led to the conclusion that this integrin is a sialoglycoprotein bearing mainly complex antennary structures. By means of exoglycosidase treatment, it was possible to identify alpha-galactosyl residues on the integrin alpha chain as the laminin-binding determinants. These residues are involved in cell adhesion to laminin. On the other hand, beta-chain complex antennary structures, whose synthesis could be inhibited by swainsonine, were associated with cell spreading rather than cell adhesion. Thus, it was possible to modulate integrin-mediated cell adhesion and spreading through changes in the glycosylation state of integrin alpha and beta chains.

Animals↗
PubMed1989

Peyer's patch-specific lymphocyte homing receptors consist of a VLA-4-like alpha chain associated with either of two integrin beta chains, one of which is novel.

Lymphocytes home to various lymphoid organs by adhering to and migrating through specialized high endothelial venules (HEV). The murine cell surface heterodimer LPAM-1 is involved in the homing of lymphocytes to mucosal sites (Peyer's patches). LPAM-1 has an alpha subunit (alpha 4m) analogous to the alpha chain of the human integrin molecule VLA-4. Here we show that the LPAM-1 beta subunit (beta p) is immunochemically and biochemically distinct from previously defined integrin beta subunits, suggesting that beta p represents a novel integrin beta subunit. Depending on the cellular source two alternative beta subunits, beta p and integrin beta 1, can be isolated in association with alpha 4m. Therefore, alpha 4m is the common subunit of the unique integrin LPAM-1 (alpha 4m beta p) and of the heterodimer LPAM-2 (alpha 4m beta 1), which is analogous to VLA-4. Antibody-blocking experiments suggest that, in addition to LPAM-1, LPAM-2 is also involved in the organ-specific adhesion of lymphocytes to Peyer's patch HEV.

Animals↗
PubMed1997

Importance of the tubulointerstitium in human glomerulonephritis. II. Distribution of integrin chains beta 1, alpha 1 to 6 and alpha V.

Accumulation of extracellular matrix is important in the progression of glomerulonephritis. Since adherent cell types utilize integrins to bind and organize extracellular matrix proteins, we have assessed expression of the beta 1 integrins in sequential sections from 85 human renal biopsies and 4 normal kidneys by immunohistochemical staining. Our results demonstrate strong correlations between expression of the alpha 5 chain within the interstitium, the alpha V chain on proximal and distal tubular epithelium and the presence of chronic histological damage. Moreover, staining for interstitial alpha 5 and proximal and distal tubular alpha V were also strongly associated with expression of certain adhesion molecules (ICAM-1, VCAM-1, E-selectin and L-selectin) and the presence of macrophages within the interstitium, which have been linked, in an earlier study, with the degree of chronic histological damage and disease progression. However, in contrast to our earlier study of adhesion molecules, there were also associations between expression of integrin chains within the glomerulus and tubulointerstitium. For example, there were strong positive associations between staining for alpha 5 on glomerular endothelium and its expression on extraglomerular vascular endothelium and between both mesangial alpha 1 and podocyte alpha 3 and tubular staining for the common beta 1 subunit. While the functional significance of these associations is obscure, they suggest some kind of communication between cells in different sites in the kidney. There were also positive associations between staining for different integrins within the glomerulus, notably mesangial cell staining for alpha 2, glomerular endothelial cells staining for alpha 5 and glomerular epithelial cell alpha 3. These results suggest that there is a coordinated upregulation of integrin expression both within the tubulointerstitium and the glomerulus and that at least some of these integrins (interstitial alpha 5 and distal tubular alpha V) are associated with the expression of other adhesion molecules, macrophage infiltration and the presence of markers of disease progression (interstitial fibrosis and tubular atrophy).

Antigens, CD↗
PubMed2000

The LIM-only protein DRAL/FHL2 binds to the cytoplasmic domain of several alpha and beta integrin chains and is recruited to adhesion complexes.

LIM proteins contain one or more double zinc finger structures (LIM domains) mediating specific contacts between proteins that participate in the formation of multiprotein complexes. We report that the LIM-only protein DRAL/FHL2, with four and a half LIM domains, can associate with alpha(3A), alpha(3B), alpha(7A), and several beta integrin subunits as shown in yeast two-hybrid assays as well as after overexpression in human cells. The amino acid sequence immediately following the conserved membrane-proximal region in the integrin alpha subunits or the C-terminal region with the conserved NXXY motif of the integrin beta subunits are critical for binding DRAL/FHL2. Furthermore, the DRAL/FHL2 associates with itself and with other molecules that bind to the cytoplasmic domain of integrin alpha subunits. Deletion analysis of DRAL/FHL2 revealed that particular LIM domains or LIM domain combinations bind the different proteins. These results, together with the fact that full-length DRAL/FHL2 is found in cell adhesion complexes, suggest that it is an adaptor/docking protein involved in integrin signaling pathways.

3T3 Cells↗
PubMed1992

Coevolution of the vertebrate integrin alpha- and beta-chain genes.

The integrin receptors are heterodimers whose alpha and beta subunits are encoded by separate, evolutionarily unrelated multigene families. Phylogenetic analysis of DNA sequences from these two gene families showed that they have not always evolved in a parallel fashion. The integrin alpha chains that can form heterodimers with beta 1 do not constitute a monophyletic group, nor do the beta chains which can form heterodimers with alpha V. On the other hand, the vertebrate alpha chains associating with beta 2 are a monophyletic group. In the metal cation-binding region of the alpha chain, an exon exchange took place between human alpha M and alpha X approximately 40-50 Mya, homogenizing this functionally important region in these two alpha chains. When integrin beta chains of different functional classes are compared, nonsynonymous (amino acid altering) nucleotide substitutions that alter amino acid residue charge in the central region of the molecule occur at a rate significantly higher than that expected under random replacement. By contrast, when closely related beta 1 chains are compared, residue charge is conserved in this region. These results pinpoint the central region as a focus of functional divergence among integrin beta chains, perhaps relating to the ability of each beta integrin class to associate with a specific array of alpha integrins. Furthermore, they imply that positive, directional selection on this region has occurred in the evolution of the integrin beta-chain gene family.

Animals↗
PubMed1994

A calcium- or manganese-dependent epitope on the integrin beta 1 chain recognized by a unique mAb.

A calcium- or manganese-dependent epitope was demonstrated on the beta 1 integrin chain by a newly established mAb. In immunoprecipitation, the mAb was able to bind to the solubilized beta 1 integrin chain in the presence of calcium but not magnesium. Cation chelating reagents completely affected the binding of the antibody to the intact beta 1 integrin chain on a cell surface. Calcium but not magnesium restored the binding of the antibody. Quantitative analyses revealed that chelating reagents reduced the affinity of the antibody. Moreover, manganese also rescued epitope expression. These results suggested that divalent cations, particularly calcium or manganese, had a crucial role in the conformation of the beta 1 integrin chain recognized by the SG/7 antibody. This antibody would be of great use for studying the divalent cation-dependent modulation of the integrin molecules and bring another aspect to the understanding of the regulatory mechanisms of ligand binding of the integrin molecules.

Antibodies, Monoclonal↗
PubMed1998

Localisation of a novel adhesion blocking epitope on the human beta 1 integrin chain.

Members of the beta 1 integrin family mediate cellular adherence to a wide range of extracellular and cell surface associated ligands. Conformational changes have been shown to be associated with integrin activation and ligand binding. Some studies suggest that there may be a restricted region of the beta 1 integrin that serves as the target for regulatory antibodies which can inhibit or stimulate integrin function. Here we identify an inhibitory epitope that is located at a distinct sight from that suggested for other inhibitory antibodies. Three different adhesion blocking antibodies, JB1A, C30B, and D11B bind to a peptide corresponding to residues 82-87 of the mature beta 1 chain. Mn++ inhibited the binding of JB1A to purified beta 1 integrin. In contrast the binding of several other antibodies to beta 1 were not influenced by these conditions. JB1A binding to purified peptide was also inhibited by Mn++ suggesting that it related to interference with the antibody function rather than a cation dependent change in the epitope. Our data 1) directly demonstrates the peptide sequence recognised by three adhesion blocking antibodies to the human beta 1 integrin chain 2) identifies a novel epitope located at residues 82-87, distinct from that of previously described regulatory epitopes 3) characterises a Mn++ sensitive antibody integrin interaction. Collectively, these results indicate the existence of multiple regulatory sites on the beta 1 integrin molecule.

Amino Acid Sequence↗
PubMed1990

Multiple beta 1 chain integrins are receptors for invasin, a protein that promotes bacterial penetration into mammalian cells.

Mammalian cell receptors that promote entry of intracellular bacteria into nonphagocytic cells have not been identified. We show here that multiple members of the integrin superfamily of cell adhesion receptors bind the Y. pseudotuberculosis invasin protein prior to bacterial penetration into mammalian cells. Affinity chromatography of crude detergent extracts demonstrated that integrins containing the subunit structures alpha 3 beta 1, alpha 5 beta 1, and alpha 6 beta 1 bound to immobilized invasin. Furthermore, phospholipid vesicles containing isolated integrin proteins were able to attach to invasin. Specificity for invasin binding to the identified integrin receptors was also demonstrated, as immunoprobing and phospholipid reconstitution studies showed that the alpha 2 beta 1 integrin, beta 2 chain integrins, and vitronectin receptor (alpha v beta 3) were not involved in cellular attachment to invasin.

Adhesins, Bacterial↗
PubMed1993

Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1.

The mucosal vascular addressin, MAdCAM-1, is an immunoglobulin superfamily adhesion molecule for lymphocytes that is expressed by mucosal venules and helps direct lymphocyte traffic into Peyer's patches (PP) and the intestinal lamina propria. We demonstrate that the lymphocyte integrin alpha 4 beta 7, also implicated in homing to PP, is a receptor for MAdCAM-1. Certain antibodies to alpha 4 and beta 7 integrin chains but not to the beta 2 integrin LFA-1 inhibit lymphocyte binding to purified MAdCAM-1 and to MAdCAM-1 transfectants. Lymph node lymphocytes, alpha 4 beta 7+ TK1 lymphoma cells, and a beta 7-transfected variant of an alpha 4+ B cell line, 38C13, bind constitutively to MAdCAM-1. Binding is enhanced by Mn(++)-induced integrin activation. The related integrin alpha 4 beta 1 supports efficient binding to VCAM-1 but not to MAdCAM-1, even after integrin activation, indicating that MAdCAM-1 is a preferential ligand for alpha 4 beta 7. Alpha 4 beta 7 can also bind VCAM-1, but this requires greater integrin activation than binding to MAdCAM-1. The findings imply a selective role for the interaction of alpha 4 beta 7 and MAdCAM-1 lymphocyte in homing to mucosal sites.

Animals↗
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↗
PubMed1993

Bacterial internalization mediated by beta 1 chain integrins is determined by ligand affinity and receptor density.

Binding of bacteria to beta 1 chain integrin receptors results in either bacterial adherence or uptake by cultured cells (Isberg, 1991). In this report we show that Staphylococcus aureus coated with high affinity ligands for the beta 1 chain integrin family can be internalized efficiently, whereas bacteria coated with low affinity ligands are poorly internalized. Overproduction of the alpha 5 beta 1 integrin increased the efficiency of bacterial internalization, indicating that the uptake efficiency is directly related to the level of expression of the receptor. By using latex beads or S. aureus coated with mAbs directed against the alpha 5 beta 1 integrin, a roughly semi-logarithmic correlation was observed between the affinity of the receptor-ligand interaction and the rate of bacterial internalization. Evidence is presented that high affinity binding of the bacterium allows the microorganism to compete efficiently with receptor-ligand interactions at the basolateral surface of the cell.

Adhesins, Bacterial↗
PubMed1996

A fundamental subdivision of circulating lymphocytes defined by adhesion to mucosal addressin cell adhesion molecule-1. Comparison with vascular cell adhesion molecule-1 and correlation with beta 7 integrins and memory differentiation.

The leukocyte integrin alpha 4 beta 7 is a receptor for the vascular mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Most circulating B and T lymphocytes in man are alpha 4+, and on these cells the regulated display of the beta 7 integrin chain determines the expression of alpha 4 beta 7 and, in large part, binding to MAdCAM-1. Among CD4+ T cells, beta 7 high memory cells (including the L-selectin+ subset) bind MAdCAM-1 better than beta 7int naive cells; whereas beta 7- memory cells,including skin homing lymphocytes, interact poorly if at all. Circulating alpha E beta 7+ T cells are alpha 4 beta 7high and also bind MAdCAM-1 well. B cells are also subdivided by beta 7 expression, and beta 7+ B cells bind MAdCAM-1 better than the beta 7low/- subset. The related vascular ligand vascular cell adhesion molecule-1 (VCAM-1), expressed on endothelium primarily in nonmucosal sites of inflammation, interacts with blood lymphocytes (including beta 7high T cells) almost exclusively via alpha 4 beta 1 and binds beta 7low/-(beta 1high) better than beta 7+ B cells and memory cells better than naive CD4+ cells. beta 7-(beta 1high) memory T cells are somewhat enriched over beta 7high memory cells at low (but not at high) VCAM-1 densities. Interestingly, CD56+ NK cells, which express both alpha 4 beta 7 and alpha 4 beta 1, bind well to VCAM-1 but poorly to MAdCAM-1. The findings indicate that the display and function of alpha 4 beta 7 determine integrin-dependent blood lymphocyte interactions with MAdCAM-1, thus delineating discrete mucosal vs nonmucosal lymphocyte populations in vivo; that alpha 4 beta 1 dominates blood lymphocyte interactions with VCAM-1; and that quantitative and qualitative regulation of MAdCAM-1 vs VCAM-1 can critically control the recruitment of specialized lymphocyte subsets during inflammation.

Adult↗
PubMed2001

In situ demonstration of intraepithelial lymphocyte adhesion to villus microvessels of the small intestine.

The recirculation of lymphocytes through the intestinal mucosa is important for specific immune defense, but the origin and differentiation of intraepithelial lymphocytes (IEL) are not fully understood. The present study therefore used intravital microscopy to investigate the migration of IEL to the villus mucosa and Peyer's patches of the small intestine. IEL were separated from inverted murine small intestine and mesenteric lymph node (MLN) T cells were also isolated. The adhesion of fluorescence-labeled lymphocytes to postcapillary venules (PCV) of Peyer's patches and arcade microvessels of small intestinal villi was observed after injection. In some experiments, the effect of antibodies against adhesion molecules on cell kinetics were investigated. IEL time-dependently accumulated in villus microvessels of the small intestine, whereas few MLN cells did. Few IEL adhered to the PCV of Peyer's patches. IEL were shown to express alpha(E)beta(7)-integrin but not L-selectin. The accumulation of IEL in villus archade was significantly inhibited by antibody against beta(7)-integrin or mucosal addressin cell adhesion molecules (MAdCAM)-1, but not by alpha(E)-integrin. The combined blocking of beta(7)-integrin and MAdCAM-1 further attenuated the sticking of IEL in this area, although it did not entirely block the IEL adherence. The adherence of CD4(+) or TCRalphabeta IEL to villus microvessels was significantly greater than that of CD4(-) or TCRgammadelta IEL. It was demonstrated in situ for the first time that IEL adhered selectively to the villus microvessels of the small intestine partly via beta(7) and MAdCAM-1.

Animals↗
PubMed2001

Beta-integrin of Anopheles gambiae: mRNA cloning and analysis of structure and expression.

We have isolated an mRNA encoding a beta integrin subunit of the malaria mosquito Anopheles gambiae. Our analysis predicts a protein that is very similar to betaPS, the fruitfly orthologue. The gene is expressed during all developmental stages and it is found in all body parts, including the midgut. Finally, the expression of the gene does not seem to be modulated during blood meals, except for a substantial increase 48 h posthaematophagy, when digestion is nearly complete.

Amino Acid Sequence↗