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PubMed2006

Integrin regulation by vascular endothelial growth factor in human brain microvascular endothelial cells: role of alpha6beta1 integrin in angiogenesis.

The precise role of vascular endothelial growth factor (VEGF) in regulating integrins in brain microvascular endothelial cells is unknown. Here, we analyzed VEGF effects on integrin expression and activation in human brain microvascular endothelial cells (HBMECs). Using human cDNA arrays and ribonuclease (RNase) protection assays, we observed that VEGF up-regulated the mRNA expression of alpha(6) integrin in HBMECs. VEGF significantly increased alpha(6)beta(1) integrin expression, but not alpha(6)beta(4) integrin expression in these cells. Specific down-regulation of alpha(6) integrin expression by small interfering RNA (siRNA) oligonucleotides inhibited both the capillary morphogenesis of HBMECs and their adhesion and migration. Additionally, VEGF treatment resulted in activation of alpha(6)beta(1) integrins in HBMECs. Functional blocking of alpha(6) integrin with its specific antibody inhibited the VEGF-induced adhesion and migration as well as in vivo angiogenesis, and markedly suppressed tumor angiogenesis and breast carcinoma growth in vivo. Thus, VEGF can modulate angiogenesis via increased expression and activation of alpha(6)beta(1) integrins, which may promote VEGF-driven tumor angiogenesis in vivo.

Animals↗
PubMed2000

Integrin dynamics and matrix assembly: tensin-dependent translocation of alpha(5)beta(1) integrins promotes early fibronectin fibrillogenesis.

Fibronectin matrix assembly is a multistep, integrin-dependent process. To investigate the role of integrin dynamics in fibronectin fibrillogenesis, we developed an antibody-chasing technique for simultaneous tracking of two integrin populations by different antibodies. We established that whereas the vitronectin receptor alpha(v)beta(3) remains within focal contacts, the fibronectin receptor alpha(5)beta(1) translocates from focal contacts into and along extracellular matrix (ECM) contacts. This escalator-like translocation occurs relative to the focal contacts at 6.5 +/- 0.7 microm/h and is independent of cell migration. It is induced by ligation of alpha(5)beta(1) integrins and depends on interactions with a functional actin cytoskeleton and vitronectin receptor ligation. During cell spreading, translocation of ligand-occupied alpha(5)beta(1) integrins away from focal contacts and along bundles of actin filaments generates ECM contacts. Tensin is a primary cytoskeletal component of these ECM contacts, and a novel dominant-negative inhibitor of tensin blocked ECM contact formation, integrin translocation, and fibronectin fibrillogenesis without affecting focal contacts. We propose that translocating alpha(5)beta(1) integrins induce initial fibronectin fibrillogenesis by transmitting cytoskeleton-generated tension to extracellular fibronectin molecules. Blocking this integrin translocation by a variety of treatments prevents the formation of ECM contacts and fibronectin fibrillogenesis. These studies identify a localized, directional, integrin translocation mechanism for matrix assembly.

Biological Transport↗
PubMed2006

[Construction of a recombinant adenoviral vector carrying integrin-alpha v and the influence of integrin-alpha on the adhesion characteristics of SMMC-7721 cells].

OBJECTIVE: To establish human integrin-alpha v adenovirus expressed in human liver cancer SMMC-7721 cells and analyze the characteristics of integrin-alpha adhesion to liver cancer cells. METHODS: Human integrin-alpha v cDNA was cloned into the plasmid pAdTrack-CMV. Then, pAdTrack-integrin-alpha v was cotransformed with adenoviral backbone vector into E. coli strain BJ5183. The recombinant adenoviral plasmid was identified by restriction analysis with Pac I and transfected into HEK-293A cells to package and amplify recombinant adenovirus particles. Western blot showed that integrin-alpha v gene was exactly transcript and expressed in SMMC-7721 cells. Twenty four hours after transfection, the effect of integrin-alpha on adhesion of SMMC-7721 cells was detected by adhesion experiment. RESULTS: Recombinant adenovirus vector of integrin-alpha v gene was successfully constructed and high titers of recombinant adenovirus was obtained. Adhesion cell count was significantly higher in integrin-alpha v transfected cells than in untransfected and Ad-null-transfected cells (P<0.01). CONCLUSION: Over expression of integrin-alpha v promotes adhesion of SMMC-7721 cells, is an important molecular mechanism of tumor metastasis.

Adenoviridae↗
PubMed1995

Polymorphonuclear leucocyte migration through human dermal fibroblast monolayers is dependent on both beta 2-integrin (CD11/CD18) and beta 1-integrin (CD29) mechanisms.

Accumulation of leucocytes in inflammation involves their migration through vascular endothelium and then in the connective tissue. We investigated human polymorphonuclear leucocyte (PMNL) migration through a biological barrier of human dermal fibroblasts grown on microporous filters, as a model of PMNL migration in the connective tissue. PMNL did not migrate through a fibroblast monolayer unless a chemotactic factor, e.g. C5a, interleukin-8 (IL-8) or zymosan-activated plasma (ZAP; C5adesArg), was added. This migration was partially inhibited (35-70%, depending on the stimulus) by treatment of PMNL with monoclonal antibody (mAb) to CD18 (beta 2-integrins). Most of the CD18-independent migration was inhibited by mAb to beta 1-integrins (CD29). Inhibition by mAb to beta 1 was observed when the PMNL, but not the fibroblasts, were treated with mAb. The role of beta 1-integrins in PMNL transfibroblast migration was detectable only when the function of the CD11-CD18 complex was blocked, because mAb to beta 1-integrin alone had no significant effect on PMNL migration. Migration induced by C5a was more CD18-independent compared to IL-8 or C5adesArg. The CD18-independent migration was also inhibited by mAb to the beta 1-integrin subunits alpha 5 (of very late antigens-5; VLA-5) and alpha 6 (of VLA-6). Treatment of the fibroblasts (4 hr) with tumour necrosis factor-alpha (TNF-alpha) or IL-1 alpha enhanced C5a-induced PMNL transfibroblast migration and increased the proportion of migration utilizing the CD11-CD18 mechanism. However, TNF-alpha treatment had no effect on the degree of beta 1-integrin-dependent migration. These findings suggest that in response to the chemotactic factors C5a, IL-8 and C5adesArg, PMNL migration in the connective tissue is mediated by both CD11-CD18 (beta 2) and beta 1-integrins on the PMNL. The VLA-5 and VLA-6 members of beta 1-integrins are involved in this process. This is in contrast to PMNL migration across endothelium in this system, which is virtually all CD18 dependent with no significant role for beta 1-integrins.

CD18 Antigens↗
PubMed2005

The crystal structure of the plexin-semaphorin-integrin domain/hybrid domain/I-EGF1 segment from the human integrin beta2 subunit at 1.8-A resolution.

Integrins are modular (alphabeta) heterodimeric proteins that mediate cell adhesion and convey signals across the plasma membrane. Interdomain motions play a key role in signal transduction by propagating structural changes through the molecule, thus controlling the activation state and adhesive properties of the integrin. We expressed a soluble fragment of the human integrin beta2 subunit comprising the plexin-semaphorin-integrin domain (PSI)/hybrid domain/I-EGF1 fragment and present its crystal structure at 1.8-A resolution. The structure reveals an elongated molecule with a rigid architecture stabilized by nine disulfide bridges. The PSI domain is located centrally and participates in the formation of extended interfaces with the hybrid domain and I-EGF1 domains, respectively. The hybrid domain/PSI interface involves the burial of an Arg residue, and contacts between PSI and I-EGF1 are mainly mediated by well conserved Arg and Trp residues. Conservation of key interacting residues across the various integrin beta subunits sequences suggests that our structure represents a good model for the entire integrin family. Superposition with the integrin beta3 receptor in its bent conformation suggests that an articulation point is present at the linkage between its I-EGF1 and I-EGF2 modules and underlines the importance of this region for the control of integrin-mediated cell adhesion.

Amino Acid Sequence↗
PubMed1996

Fibronectin receptor functions in embryonic cells deficient in alpha 5 beta 1 integrin can be replaced by alpha V integrins.

alpha 5 beta 1 integrin mediates cell adhesion to extracellular matrix by interacting with fibronectin (FN). Mouse lines carrying null mutations in genes encoding either the alpha 5 integrin subunit or FN have been generated previously. Both mutations are embryonic lethal with overlapping defects, but the defects of alpha 5-null embryos are less severe. Primary embryonic cells lacking alpha 5 beta 1 are able to adhere to FN, form focal contacts, migrate on FN, and assemble FN matrix. These results suggest the involvement of (an)other FN receptors(s). In this study, we examined functions of alpha 4 beta 1 and alpha V integrins in embryonic cells lacking alpha 5 beta 1. Our analysis of cells lacking both alpha 4 beta 1 and alpha 5 beta 1 showed that alpha 4 beta 1 is also not required for these FN-dependent functions. Using alpha V-specific blocking reagents, we showed that alpha V integrins are required for alpha 5-null cells, but not wild-type cells, to adhere and spread on FN. Our data also showed that, although the expression levels of alpha V integrins on the wild-type and alpha 5-null cells are similar, there is an increase in recruitment of alpha V integrins into focal contacts in alpha 5-null cells plated on FN, indicating that alpha V integrins can compensate functionally for the loss of alpha 5 beta 1 in focal contacts of alpha 5-null cells. Finally, our data suggested possible roles for alpha V integrins in replacing the role of alpha 5 beta 1 in FN matrix assembly in vitro and in FN-dependent embryonic functions in vivo.

Animals↗
PubMed2003

Talin binding to integrin beta tails: a final common step in integrin activation.

Control of integrin affinity for ligands (integrin activation) is essential for normal cell adhesion, migration, and assembly of an extracellular matrix. Integrin activation is usually mediated through the integrin beta subunit cytoplasmic tail and can be regulated by many different biochemical signaling pathways. We report that specific binding of the cytoskeletal protein talin to integrin beta subunit cytoplasmic tails leads to the conformational rearrangements of integrin extracellular domains that increase their affinity. Thus, regulated binding of talin to integrin beta tails is a final common element of cellular signaling cascades that control integrin activation.

Amino Acid Sequence↗
PubMed1993

Alpha 4 beta 7 integrin mediates B cell binding to fibronectin and vascular cell adhesion molecule-1. Expression and function of alpha 4 integrins on human B lymphocytes.

Cell-cell and cell-extracellular matrix interactions are mediated by a wide array of cell surface molecules known as adhesion receptors, including the integrin family that comprises numerous alpha beta heterodimers. A new integrin group, the beta 7 subfamily, has been recently defined. Its two members, alpha 4 beta 7 and alpha H beta 7, are involved in the lymphocyte migration to the Peyer's patches and the intestinal mucosa, respectively. We have analyzed the expression of alpha 4 beta 7 integrin on B cells from different cellular compartments and at different activation states. Resting peripheral blood B lymphocytes constitutively express large amounts of alpha 4 beta 7. By contrast, alpha 4 beta 7 integrin, which is absent on resident B cells from different lymphoid tissues, is induced upon activation. Functional studies indicates that alpha 4 beta 7 is mediating B cell attachment to fibronectin and vascular cell adhesion molecule-1 through distinct epitopes on this integrin. Furthermore, the alpha 4 beta 7 integrin is also implicated in intercellular interactions as deduced by the ability of anti-alpha 4 beta 7 mAb to trigger homotypic B cell aggregation. Finally, alpha 4 beta 7 and alpha 4 beta 1 integrins redistribute at the cell membrane in a similar clustering pattern when B cells attach to fibronectin- and vascular cell adhesion molecule-1-coated surfaces. Our studies demonstrate the differential regulation on the expression and function of alpha 4 beta 7 integrin among different human B cell populations.

Antigens, Neoplasm↗
PubMed1995

Migration of human polymorphonuclear leukocytes through a synovial fibroblast barrier is mediated by both beta 2 (CD11/CD18) integrins and the beta 1 (CD29) integrins VLA-5 and VLA-6.

Polymorphonuclear leukocytes (PMNL) accumulate in joint fluid in inflammatory arthritides. We investigated the molecular mechanisms required for PMNL migration through a barrier of human synovial fibroblasts (HSF) grown on microporous filters, as a model of PMNL migration through synovial connective tissue and compared this process with PMNL migration through human dermal fibroblast (HDF) barriers and through human umbilical vein endothelium (HUVE). A small amount of PMNL migration occurred spontaneously only through the synovial fibroblast/filter unit (6-10%). Migration markedly increased through all cell monolayers when the chemotactic factors C5a, IL-8, or zymosan-activated plasma (containing C5adesArg) were added to form a chemotactic gradient. The migration induced by C5a, IL-8, or C5adesArg across HSF was partially inhibited (25-76% depending on stimulus) by mAb to CD18 (beta 2 integrin). The CD18-independent migration induced by IL-8 or C5adesArg was almost completely inhibited by mAbs to beta 1 integrin, but with C5a, inhibition by mAb to beta 1 integrin was only partial (40-50%). Inhibition by mAb to beta 1 integrin required treatment of the PMNL, but not the HSF and was only observed when the function of CD11/CD18 on PMNL was also blocked by a mAb. Treatment of PMNL with mAb to alpha 5 (VLA-5) plus alpha 6 (VLA-6) in combination, was required to inhibit CD18-independent migration through HSF to the degree observed with mAb to beta 1 integrin. There was no qualitative difference in the mechanisms utilized by PMNL for migration through HSF or HDF in response to chemotactic factors. In contrast, PMNL migration across HUVE was almost completely CD18-dependent (85%) with no role for beta 1 integrins. The results suggest that (a) PMNL migration through HSF in response to chemotactic factors utilizes both CD11/CD18 and beta 1 (CD29) integrins; (b) the VLA-5 and VLA-6 members of beta 1 integrins are involved in mediating migration; and (c) PMNL utilize similar mechanisms for migration through HSF and HDF, which are distinct from migration through HUVE.

Antibodies, Monoclonal↗
PubMed1993

Maturation induced internalization of beta 1-integrin by Xenopus oocytes and formation of the maternal integrin pool.

A pool of beta 1-integrin, ready to be inserted into the cleavage membranes, is present in the cytoplasm of the Xenopus egg, while its plasma membrane is devoid of this membrane protein (Gawantka et al., 1992). The underlying mechanisms that lead to this specific pattern of beta 1-integrin distribution in the egg have been investigated. beta 1-Integrin is present on the oocyte membrane throughout oogenesis. During maturation the oocyte membrane is cleared of beta 1-integrin via internalization of the protein by the oocyte. Synthesis of beta 1-integrin precursor is stimulated moderately in the maturing oocyte. At the same time processing of the precursor into the mature form of beta 1-integrin and its complexing with a putative alpha-chain is greatly accelerated. This way a maternal integrin pool accumulates in the mature oocyte. It is localized in conspicuous yolk free patches which contain large amounts of endoplasmic reticulum, Golgi complexes and smooth vesicles. We suggest that membrane vesicles harbouring the beta 1-integrin are generated in these cytoplasmic regions and that this store of vesicles provides the material source for the rapid membrane formation during cleavage.

Animals↗
PubMed2005

ADP-ribosylation of integrin alpha7 modulates the binding of integrin alpha7beta1 to laminin.

The extracellular domain of integrin alpha7 is ADP-ribosylated by an arginine-specific ecto-ADP-ribosyltransferase after adding exogenous NAD+ to intact C2C12 skeletal muscle cells. The effect of ADP-ribosylation on the structure or function of integrin alpha7beta1 has not been explored. In the present study, we show that ADP-ribosylation of integrin alpha7 takes place exclusively in differentiated myotubes and that this post-translational modification modulates the affinity of alpha7beta1 dimer for its ligand, laminin. ADP-ribosylation in the 37-kDa 'stalk' region of alpha7 that takes place at micromolar NAD+ concentrations increases the binding of the alpha7beta1 dimer to laminin. Increased in vitro binding of integrin alpha7beta1 to laminin after ADP-ribosylation of the 37-kDa fragment of alpha7 requires the presence of Mn2+ and it is not observed in the presence of Mg2+. In contrast, ADP-ribosylation of the 63-kDa N-terminal region comprising the ligand-binding site of alpha7 that occurs at approx. 100 microM NAD+ inhibits the binding of integrin alpha7beta1 to laminin. Furthermore, incubation of C2C12 myotubes with NAD+ increases the expression of an epitope on integrin beta1 subunit recognized by monoclonal antibody 9EG7. We discuss our results based on the current models of integrin activation. We also hypothesize that ADP-ribosylation may represent a mechanism of regulation of integrin alpha7beta1 function in myofibres in vivo when the continuity of the membrane is compromised and NAD+ is available as a substrate for ecto-ADP-ribosylation.

Adenosine Diphosphate Ribose↗
PubMed2001

Phospholipase Cgamma binds alpha1beta1 integrin and modulates alpha1beta1 integrin-specific adhesion.

Integrin adhesion receptors have been implicated in bidirectional signal transduction. The dynamic regulation of integrin affinity and avidity as well as post-ligand effects involved in outside-in signaling depends on the interaction of integrins with cytoskeletal and signaling proteins. In this study, we attempted to identify cytoplasmic binding partners of alpha(1)beta(1) integrin. We were able to show that cell adhesion to alpha(1)beta(1)-specific substrates results in the association of phospholipase Cgamma (PLCgamma) with the alpha(1)beta(1) integrin independent of PLCgamma tyrosine phosphorylation. Using peptide-binding assays, the membrane proximal sequences within the alpha(1)beta(1) integrin subunits were identified as binding sites for PLCgamma. In particular, the conserved sequence of beta(1) subunit binds the enzyme very efficiently. Because purified PLCgamma also binds the integrin peptides, binding seems to be direct. Inhibition of PLC by leads to reduced cell adhesion on alpha(1)beta(1)-specific substrates. Cells lacking the conserved domain of the alpha(1) subunit fail to respond to the PLC inhibition, indicating that this domain is necessary for PLC-dependent adhesion modulation of alpha(1)beta(1) integrin.

Amino Acid Motifs↗
PubMed2001

Adenoviral transduction efficiency of ovarian cancer cells can be limited by loss of integrin beta3 subunit expression and increased by reconstitution of integrin alphavbeta3.

Recombinant adenoviruses expressing a therapeutic gene are currently used in clinical studies for treatment of advanced ovarian cancer. We therefore tested whether the expression level of primary (CAR) and secondary adenovirus receptors (integrins) was predictive of the efficacy of adenoviral gene transfer in ovarian cancer cells. Adenoviral transduction efficiency (ATE) was determined with an E1-deleted adenovirus type 5 expressing beta-galactosidase under a CMV promoter (AdGal). ATE was studied in relationship to the expression level of both CAR (coxsackie and adenovirus receptor) and integrins. A representative sample of 25 permanent human cell lines established from advanced ovarian cancer in our laboratory and the OV-2774 cell line were tested. Overall, ATE increased with increasing titers of AdGal. At a given titer of 50 infectious units per cell, transduction efficiency varied from 6 to 94% among the individual cell lines. All cell lines expressed CAR and integrin alpha(v)beta(5), but no relation between ATE and expression level of CAR or alpha(v)beta(5) integrin was observed. In contrast, cell lines with poor ATE, despite expressing high levels of CAR, lacked expression of integrins alpha(v)beta(3) and alpha(5)beta(1). Reconstitution of alpha(v)beta(3) integrin by reexpressing the beta(3) subunit significantly enhanced ATE of ovarian cancer cells. In ovarian cancer, neither integrins nor CAR alone appear to be potentially useful predictive markers for ATE by serotype 5 adenovirus in clinical gene therapy. A minimum level of CAR necessary for binding of adenoviruses was observed in all tested ovarian cancer cell lines. Loss of alpha(v)beta(3) integrin is frequently associated with advanced stages of ovarian cancer and can significantly reduce ATE.

Adenoviridae↗
PubMed2002

Integrin alpha2beta1 on rat myeloma cells modulates interaction of alpha4beta1 integrin with vascular cell adhesion molecule-1 but not fibronectin.

It is well established that alpha2beta1 integrin functions as a receptor for collagen and laminin; whereas alpha4beta1 integrin binds fibronectin and vascular cell adhesion molecule-1 (VCAM-1). In the present study, we showed that rat myeloma YB2/0 cells constitutively expressed alpha4beta1 but not alpha2beta1 integrin. Transfection of cDNA of mouse a2 integrin subunit resulted in the expression of heterologous alpha2beta1 integrin on YB2/0 cells (YBmalpha2). The expression of alpha2beta1 conferred YBmalpha2 cells the ability to interact with collagen and laminin. In comparison with mock transfected YB2/0 cells (YBpF), YBmalpha2 cells exhibited increases in the binding and migration on VCAM-1; in contrast, both YBpF and YBmalpha2 were similar in their interactions with fibronectin or fibronectin fragment FN-40 that contains the binding site for alpha4beta1 integrin. The interaction of alpha4beta1 with VCAM-1 was further stimulated upon ligation with alpha2beta1-specific mAb. The use of specific inhibitory mAb demonstrated the role of alpha4beta1 in mediating the observed interactions with fibronectin and VCAM-1. Therefore, results show that expression of alpha2beta1 differentially regulated alpha4alpha1 integrin function by stimulating its interactions with VCAM-1 but not fibronectin. The in vivo significance of alpha2beta1 integrin expression was demonstrated by intravital videomicroscopy showing that ligation of alpha2beta1 enhanced alpha4beta1-mediated extravasation of YBmalpha2 cells in the liver.

Animals↗
PubMedDate not supplied

Heparin modulates integrin-mediated cellular adhesion: specificity of interactions with alpha and beta integrin subunits.

Heparin is known to influence the growth, proliferation, and migration of vascular cells, but the precise mechanisms are unknown. We previously demonstrated that unfractionated heparin (UH) binds to the platelet integrin alpha(IIb)beta(3), and enhances ligand binding. To help define the specificity and site(s) of heparin-integrin interactions, we employed the erythroleukemic K562 cell line, transfected to express specific integrins (alpha(v)beta(3), alpha(v)beta(5), and alpha(IIb)beta(3)). By comparing K562 cells expressing a common alpha subunit (Kalpha(v)beta(3), Kalpha(v)beta(5)) with cells expressing a common beta subunit (Kalpha(v)beta(3), Kalpha(IIb)beta(3)), we observed that heparin differentially modulated integrin-mediated adhesion to vitronectin. UH at 0.5-7.5 microg/ml consistently enhanced the adhesion of beta(3) expressing cells (Kalpha(v)beta(3),Kalpha(IIb)beta(3)). In contrast, UH at 0.5-7.5 microg/ml inhibited Kalpha(v)beta(5) adhesion. Experiments using integrin-blocking antibodies, appropriate control ligands, and nontransfected native K562 cells revealed that heparin's actions were mediated by the specific integrins under study. Preincubation of heparin with Kalpha(v)beta(3) cells enhanced adhesion, while preincubation of heparin with the adhesive substrate (vitronectin) had minimal effect. There was a structural specificity to heparin's effect, in that a low molecular weight heparin and chondroitin sulfate showed significantly less enhancement of adhesion. These findings suggest that heparin's modulation of integrin-ligand interactions occurs through its action on the integrin. The inhibitory or stimulatory effects of heparin depend on the beta subunit type, and the potency is dictated by structural characteristics of the glycosaminoglycan.

Antibodies↗
PubMed1993

Co-clustering of beta 1 integrins, cytoskeletal proteins, and tyrosine-phosphorylated substrates during integrin-mediated leukocyte aggregation.

The involvement of the VLA-4 integrin in an alternative leukocyte homotypic adhesion mechanism that is LFA-1/ICAM-1 independent, has been previously reported. We describe here the localization of beta 1 and alpha 4 integrin subunits at sites of cell-cell contact, on both beta 1- and alpha 4-induced aggregates of B lymphoblastoid Ramos cells. Moreover, the distribution of different VLA-alpha subunits was also examined on beta 1-induced cell aggregates of alpha 2- and alpha 4-transfected K-562 cells. Both alpha 2 and alpha 4 integrin subunits were mainly localized at sites of intercellular boundaries, suggesting a possible role for these integrins in leukocyte intercellular adhesion. The fibronectin receptor alpha 5 subunit was either diffuse throughout the plasma membrane, or displayed some accumulation at sites of cell-cell contact. Even though homotypic aggregation of U-937 cells was induced with the anti-alpha 5 P1D6 mAb, the alpha 5 subunit showed only partial redistribution to regions of cell-cell contact, compared with the complete redistribution of the alpha 4 subunit in the alpha 4-induced aggregates. The reorganization of the actin-cytoskeleton was observed at sites of intercellular boundaries in both the anti-beta 1- and anti-alpha 4-induced cell aggregates. Hence, F-actin and the cytoskeletal protein talin co-localized with beta 1 and alpha 4 integrin clusters at sites of cell-cell contact. Signal transduction during VLA-mediated homotypic cell adhesion has also been investigated. We found co-localization of beta 1 and alpha 4 subunits with tyrosine-phosphorylated proteins at cell-cell contact regions during cell aggregation. These data indicate that VLA integrin-mediated leukocyte aggregation results in clustering of beta 1-integrins at sites of cell-cell contact, together with co-localization of cytoskeletal proteins. These results also suggest that protein tyrosine phosphorylation is an important signal transduction mechanism when VLA integrins participate in intercellular contacts.

Actins↗
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↗
PubMed1996

Altered integrin expression in rheumatoid synovial lining type B cells: in vitro cytokine regulation of alpha 1 beta 1, alpha 6 beta 1, and alpha v beta 5 integrins.

OBJECTIVE: We recently showed that in rheumatoid arthritis (RA) the extracellular matrix around the lining cells is similar to the matrix seen in osteoarthritis, whereas the cellular adhesion apparatus is very different. In hyperplastic synovial membrane there is very little of alpha 6, alpha v, and beta 5 integrin subunits, whereas in noninflammatory synovial membrane these integrins are well expressed. We studied how expression of these cell adhesion molecules is regulated in RA in vitro. METHODS: The integrin expression in 6 different synovial fibroblast strains representing the type B cells and in THP-1 cell line was examined by immunoprecipitation, flow cytometry, and Northern hybridization. RESULTS: Proinflammatory cytokines, especially interleukin 1 beta, increased the expression of alpha 1 integrin in synovial fibroblasts. When the monocyte-like THP-1 cells were induced to differentiate to adherent macrophages they started to express alpha 6 and beta 5 integrin subunits. In adherent THP-1 cells the expression of integrin alpha 6 subunit was strongly enhanced by transforming growth factor-beta and downregulated by the combination of tumor necrosis factor-alpha and interferon-gamma. CONCLUSION: Cytokines regulate the cell adhesion molecules of synovial fibroblasts and mononuclear phagocytes in vitro causing alterations in integrin expression similar to the ones seen in rheumatoid synovium in vivo.

Adult↗