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PubMed2002

Structure and function of an early divergent form of laminin in hydra: a structurally conserved ECM component that is essential for epithelial morphogenesis.

As a major component of the extracellular matrix (ECM), laminin has been found in many vertebrate and invertebrate organisms. Its molecular structure is very similar across species lines and its biological function in the ECM has been extensively studied. In an effort to study ECM structure and function in hydra, we have cloned a partial hydra laminin alpha chain and the full-length hydra laminin beta chain using ECM-enriched cDNA libraries. Analysis of deduced amino acid sequences indicated that both polypeptides have high sequence similarity to a number of invertebrate and vertebrate laminin alpha and beta subunits. Rotary shadow analysis of isolated hydra laminin indicates it has a heterotrimeric organization that is characteristic of vertebrate laminins. A putative integrin-class protein was also identified using a cell-binding peptide sequence from the laminin beta chain as an affinity probe, indicating that integrins are possible cell surface receptors in hydra. In agreement with previous results for the hydra laminin beta chain, in situ hybridization experiments revealed that hydra laminin alpha chain mRNA is restricted to endodermal cells. As with a number of other hydra ECM components, higher levels of laminin alpha chain mRNA are localized to regions where cell migration and differentiation are actively undertaken such as the base of tentacles, the peduncle region, buds, regenerating tentacles, and at the head end during regeneration. The role of laminin in morphogenesis was studied using an antisense approach and the results indicated that translation of the laminin alpha chain is required for head regeneration.

Amino Acid Sequence↗
PubMed1995

CD18 (beta 2 leukocyte integrin) promoter requires PU.1 transcription factor for myeloid activity.

Normal cellular differentiation is linked to tightly regulated gene transcription. However, the DNA elements and trans-acting factors that regulate transcription in myeloid cells are poorly defined. CD18, the beta chain of the leukocyte integrins, is transcriptionally regulated during myeloid differentiation. The CD18 promoter is active after transfection into myeloid cells. We demonstrate that a region of the CD18 promoter that contains two binding sites for the PU.1 transcription factor is required for activity in myeloid cells. These sites are bound by in vitro translated PU.1 and by PU.1 from myeloid nuclear extracts. Mutagenesis of these sites abrogates binding by PU.1 and substantially decreases promoter activity in myeloid cells. Thus, the leukocyte-specific transcription factor PU.1 is required for myeloid activity of CD18.

Base Sequence↗
PubMed1995

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

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

Animals↗
PubMed1991

Expression of a cell adhesion protein (VLA beta) in normal and diseased skin.

Biopsies from normal skin (n = 17) and various cutaneous disorders (n = 83) were examined immunohistologically for reactivity with an antibody (CD29) against the common beta chain of the VLA integrin family. In normal skin, CD29 recognized a number of cell types, i.e. endothelial cells, fibroblasts, T lymphocytes and basal keratinocytes. Similar cells were positive in diseased skin, but the expression of VLA beta was upregulated on keratinocytes. The phenotype of the VLA beta-positive T cells was examined in more detail by staining with anti-T-cell antibodies, i.e. CD3, CD4, CD8, CD45RO (UCHL1) and CD45R (2H4). These studies showed that most of the T cells in normal skin, benign cutaneous conditions and early cutaneous T-cell lymphomas (CTCL) expressed a similar phenotype and resembled antigen committed 'memory' (helper/inducer) cells (CD4+, CD29+, CD45RO+, CD45R-). In advanced CTCL, expression of these antigens was more variable, and many of these infiltrates showed aberrant (or unusual) expression of CD29, CD45RO, CD45R and other T-cell antigens. It is concluded that several cells involved in cutaneous immune reactions express a molecule (VLA beta) which acts as a receptor for extracellular matrix components. This molecule is important for the attachment of cells to connective tissue constituents and may act to facilitate the migration of lymphocytes (and other cells) during immune reactions in normal and diseased cutaneous conditions. Advanced CTCL differ from the early lesions and it is possible that there is a progressive accumulation of increasingly malignant (or transformed) cells in these conditions.

Antigens, CD↗
PubMed1998

T cell immunobiology of alloimmune thrombocytopenias.

Allorecognition and generation of alloantisera depend on T cell help. Here we summarize our recent work on identifying the T cells that recognize a specific platelet alloantigen generated by a Pro to Leu polymorphism in beta-chain of the platelet integrin alphaIIb beta3. The ability to generate alloantibodies is restricted by HLA-DRB3*0101. By measuring peptide binding to HLA-DRB3*0101, we have shown that the polymorphism controls the generation of the T cell epitope. This is not a result of the polymorphism changing a T cell contact residue, but rather by its generating a peptide anchor. The result is a directional antibody response in which only the beta-chain that is antigenic is the one that produces a peptide that binds to the HLA-DR. This mechanism of generating alloantibodies may be a paradigm for a whole class of responses.

Animals↗
PubMed1995

F-actin is involved in control of bovine cumulus expansion.

Previously, we showed that the gonadotropin-induced expansion of bovine cumulus oophorus occurs concomitantly with the rearrangement of microfilaments (MFs) inside cumulus cell cytoplasm (Sutovský et al., 1993: Biol Reprod 49:1277-1287; Sutovský et al., 1994: Reprod Nutr Dev 34:415-425) and that cumulus expansion in cattle is accompanied by the increased expression of extracellular matrix (ECM) glycoproteins laminin and type IV collagen as well as of their actin-linked membrane receptors, integrin subunits alpha-6 and beta-1 (Sutovský and Motlík: 1994). The present study was undertaken to determine the spatial and temporal relationship between cytoskeletal rearrangement and ECM synthesis during cumulus expansion. Using electron microscopy and confocal (LSCM) and conventional fluorescence microscopy, we compared the expression of the above integrins and ECM proteins and the rearrangement of cytoskeleton in the gonadotropin-stimulated bovine oocyte cumulus complexes (OCCs) with those exposed to gonadotropin stimulation and to ECM synthesis inhibitor 6-diazo-5-oxo-L-norleucin (DON), or MF-disorganizing drug cytochalasin B (CB). In control OCCs, the 24-hr culture in the presence of follicle stimulating hormone/luteinizing hormone (FSH/LH) caused the expansion of cumuli oophori and an extensive rearrangement of MFs in the cytoplasm of cumulus cells. Concomitantly, we observed an increased deposition of laminin and type IV collagen in the intercellular spaces among cumulus cells. The redistribution of microtubules (MTs), intermediate filaments (IFs), and integrin chains alpha-6 and beta-1 also occurred at this time. The addition of 20 micrograms/ml of CB prevented cumulus expansion and accumulation of laminin and type IV collagen in the OCCs. Moreover, cytochalasin treatment blocked the redistribution of MTs and IFs, and caused the disorganization of MFs and dispersion of integrins in cumulus cells. In contrast, the distribution of integrins and cytoskeletal elements was not affected when we blocked cumulus expansion and ECM protein accumulation by DON. These data suggest that F-actin acts upstream of ECM synthesis in the cascade of events leading to the expansion of bovine cumulus ooophorus.

Actins↗
PubMed2001

The NITY motif of the beta-chain cytoplasmic domain is involved in stimulated internalization of the beta3 integrin A isoform.

Beta3 integrin adhesion molecules play important roles in wound repair and the regulation of vascular development and three beta3 integrin isoforms (beta3-A, -B, -C) have been described so far. Surface expression of beta3 integrins is dynamically regulated through internalization of beta3 integrins, however, the molecular mechanisms are understood incompletely. To evaluate the role of the cytoplasmic domain of beta3 integrins for internalization, we have generated single chain chimeras with variant and mutated forms of beta3 cytoplasmic domains. Upon transient transfection into chinese hamster ovary cells, it was found that the beta3-A chimera had strongly reduced cell surface expression compared with the corresponding beta3-B, or beta3-C fusion proteins, or the tail-less constructs, whereas steady state levels of all chimeras were near identical. Studies employing cytoplasmic domain mutants showed that the NITY motif at beta3-A 756-759 is critical for plasma membrane expression of beta3-A. Furthermore, delivery of beta3-A to the cell surface was specifically modulated by the cytoplasmic protein beta3-endonexin, a previously described intracellular protein. Coexpression of the native, long form of beta3-endonexin, which does not interact with the beta3 tail, acted as a dominant negative inhibitor of beta3-A-internalization and enhanced steady-state surface expression of the beta3-A-chimera. Furthermore, anti-beta3 antibody-induced internalization of the native beta3 integrin (alpha(IIb)beta3 was dramatically reduced for the Tyr(759)-Ala substitution mutant (alpha(IIb)beta3) (Y759A) and expression of the long isoform of beta3-endonexin substantially decreased the internalization of wild-type alpha(IIb)beta3. Thus, the NITY motif of the beta-chain cytoplasmic domain is involved in stimulated internalization of the beta3 integrin A isoform and beta3-endonexin appears to couple the beta3-A isoform to a specific receptor-recycling pathway.

Amino Acid Sequence↗
PubMed1997

Resolution of CNS lesions following treatment of experimental allergic encephalomyelitis in macaques with monoclonal antibody to the CD18 leukocyte integrin.

Experimental allergic encephalomyelitis (EAE) in macaques is an acute inflammatory and demyelinating disease of the central nervous system (CNS) which has been studied extensively as a model of the human demyelinating disease multiple sclerosis (MS). The in vivo administration of monoclonal antibodies against CD18, the common beta-chain of a leukocyte integrin, at the onset of clinical disease, significantly prolonged the survival of nine of 11 macaques (82%) and in some cases completely reversed the clinical appearance of disease. Treatment with anti-CD18 mAbs dramatically reduced the extent of inflammation in brain lesions as determined by magnetic resonance imaging (MRI). These improvements confirm that anti-CD18 mAbs are powerful anti-inflammatory agents in vivo and suggest that such mAbs may provide effective treatment of both demyelinating and inflammatory CNS diseases in man.

Animals↗
PubMed1994

Increased processing of lymphocyte function-associated antigen-1 in human natural killer cells stimulated with IL-2.

Previously we reported that surface expression of lymphocyte function-associated antigen-1 (LFA-1), the primary leukocyte integrin on human natural killer (NK) and lymphokine-activated killer (LAK) cells, does not differ between NK and LAK cells. In contrast to surface expression, we now report that much higher levels of both precursor and mature forms of LFA-1 molecules were found relative to MHC class I, another membrane glycoprotein, with metabolic labeling of IL-2-stimulated LAK cells compared with native NK cells. An 85-90 kDa glycoprotein, found in much higher quantities in LAK compared with NK cells, appeared to be a precursor of the 95 kDa beta chain of the beta 2 integrin family in human LAK cells because: (i) pulse-chase experiments using LAK cells demonstrated decreased 35S-labeling of the 85-90 kDa molecule with a concomitant increase in the radioactivity of the mature 95 kDa LFA-1 beta chain, (ii) results of protease treatment revealed that the two molecules share virtually identical peptide maps, and (iii) endoglycosaminidase F treatment of LAK cell lysates immunoprecipitated with antibody against LFA-1 beta resulted in the disappearance of both the 85-90 and 96 kDa LFA-1 beta signals, and appearance of a signal at approximately 76 kDa. Digestion of the same immunoprecipitates with neuraminidase resulted in the disappearance of the 95 kDa signal and revealed a single molecular weight signal corresponding to 85-90 kDa. These data suggest that a core protein of approximately 76 kDa becomes N-glycosylated, perhaps terminally with sialic acid residues, to mature into the 95 kDa form. Moreover, the rate of maturation of LFA-1 was more rapid in LAK than NK cells, with half times of 0.8 versus 1.5 h for the alpha chain and 3.7 versus 4.9 h for the beta chain for LAK versus NK cells respectively. IL-2 treatment of NK cells therefore alters the processing of LFA-1 molecules during the transition to LAK cells, providing a larger intracellular reservoir with which to replenish the surface molecule. Together with our previous observation that LFA-1 is phosphorylated and transduces signal more effectively in LAK than NK cells, the findings support the notion that adhesion molecules contribute to the increased function of LAK cells.

Cells, Cultured↗
PubMed1992

Involvement of beta 2-integrins in the migration of human natural killer cells.

Human large granular lymphocytes with the NK cell phenotype (CD16+ or CD56+CD3-) were greatly enriched among the cells which migrated spontaneously through untreated or albumin-coated, 3-microns pore size polycarbonate filters for 1 to 8 h. Three days of rIL-2 treatment (300 IU/ml) and 3 to 5 wk of rIL-2 treatment (100 IU/ml) generated a 2.7 +/- 0.9-fold and 5.6 +/- 0.8-fold increase in cell migration, respectively. The adhesion and subsequent migration of freshly isolated NK cells was mainly mediated by CD11b/CD18, because migration could be inhibited by 80 +/- 8% anti-CD11b (Mac-1) antibodies but not with antibodies against CD11a (LFA-1) or CD11c (p150,95), the other alpha-chains of the beta 2-integrins. After rIL-2 activation, however, CD11a/CD18 was the major receptor utilized in migration, inasmuch as anti-CD11a antibody caused a 69 +/- 8% reduction in the number of migrated cells. Anti-CD11b antibody decreased migration by 43 +/- 12%, and together these antibodies inhibited migration by 82 +/- 7%. Anti-CD11a alone did not have any effect on adhesion, but CD11a/CD18 cooperated in the adhesion because anti-CD11b decreased adhesion by 40 +/- 11% and together these antibodies inhibited adhesion by 74 +/- 6%. The ability of large granular lymphocytes to rapidly utilize beta 2-integrins and unidentified ubiquitous ligands for binding and migration may be significant for their capacity to function in the first line of immune defense under highly variable conditions.

Antibodies, Monoclonal↗
PubMed1990

Amino acid sequence of a novel integrin beta 4 subunit and primary expression of the mRNA in epithelial cells.

Using the polymerase chain reaction, we have isolated cDNA clones that encode a new integrin beta subunit--beta 4. Its cDNA, which is 5676 bp in length, has one long coding sequence (5256 bp), a polyadenylation signal and a poly(A) tail. The deduced sequence of 1752 amino acids is unique among the integrin beta subunits. It contains a putative signal sequence as well as a transmembrane domain that divides the molecule into an extracellular domain at the N-terminal side and a cytoplasmic domain at the C-terminal side. The extracellular domain exhibits a 4-fold repeat of cysteine-rich motif similar to those of other integrin beta subunits. Certain features of the extracellular domain, however, are unique to the beta 4 subunit sequence. Of the 56 conserved cysteine residues found within the extracellular domain of other mature beta subunits, eight such residues are deleted from the beta 4 subunit sequence. The cytoplasmic domain is much larger (approximately 1000 amino acids) than those of other beta subunits (approximately 50 amino acids) and has no significant homology with them. A protein homology search revealed that the beta 4 subunit cytoplasmic domain has four repeating units that are homologous to the type III repetition exhibited by fibronectin. The beta 4 subunit mRNA was expressed primarily in epithelial cells. The restricted expression and the new structural features distinguish the integrin beta 4 subunit from other integrin beta subunits.

Amino Acid Sequence↗
PubMed2003

[Beta-1 and beta-4 integrins, and laminin 67 kDa receptors in interaction between A431 cells and laminin isoforms ].

Laminins, as basal membrane glycoproteins, are able to stimulate cell adhesion and migration, and to influence gene expression. The laminin molecule has a set of bioactive sites that interact with different integrin and nonintegrin receptors, and, as a result, the reaction of the same cell type to different laminin isoforms may be different. The aim of this study was to determine the contributions of both integrins with beta 1 and beta 4 chains and 67 kDa laminin receptor in the interaction of A431 cells with two laminin isoforms: laminin-1 and laminin-2/4. The obtained data show that integrin alpha 6 beta 4 is more specific for interaction with laminin-2/4 than with laminin-1 and takes part in the stage of attachment of A431 cells to laminin. 67 kDa receptor promotes cell spreading on laminin-2/4 and inhibits cell spreading on laminin-1. An assumption was made about the complex action of receptors for interaction of A431 cells with laminins ("integrin alpha 6 beta 4--67 kDa receptors" complex).

Basement Membrane↗
PubMed1991

Adhesion molecule expression in psoriatic skin lesions and the influence of cyclosporin A.

Normal skin of healthy individuals and both lesional and uninvolved skin from patients with psoriasis before and after receiving cyclosporin A (CsA; 2.5 or 5 mg/kg per day) was examined by immunocytochemistry for differences in expression of adhesion-relevant epitopes. Normal, lesional and uninvolved skin all showed staining of basal keratinocytes for CD29 (the common beta chain of the beta 1-integrin family). No other adhesion molecule investigated was detected on structural components of normal skin. In uninvolved skin, weak expression of CD54 (intercellular adhesion molecule 1, ICAM-1) was noted on vascular endothelium. Uninvolved keratinocytes were found to stain with anti-CD58 (leucocyte function-associated antigen 3, LFA-3) and there was weak expression of CD11b (alpha chain of complement C3bi receptor) and CD11c (alpha chain of p150, 95 molecule) but not CD11a (leucocyte function-associated antigen 1, LFA-1, alpha chain) on those cells. In lesional skin, in addition to expression of CD58, there was also enhanced expression of CD11c. Weak expression of CD54 on keratinocytes was also observed. Lesional blood vessels were found to stain strongly with anti-CD54, CD29 and CD58. CD11a was expressed only on infiltrating mononuclear cells. CsA treatment produced marked clinical improvement, accompanied by the loss of CD54 expression on keratinocytes. However, despite the loss of T cells from lesional skin with CsA treatment, CD54 persisted on blood vessels. CsA was found to have no effect on keratinocyte expression of CD29, CD58 or CD11b and c. The persistence of CD54 on vascular endothelium and of adhesion molecule expression on keratinocytes, despite resolution of the skin lesions, may explain the universal and rapid recurrence of psoriasis on cessation of CsA administration.

Adult↗
PubMed1993

Roles of soluble fibronectin and beta 1 integrin receptors in the binding of Mycobacterium leprae to nasal epithelial cells.

The mechanisms by which Mycobacterium leprae invades the human host are presently unknown. We investigated the ability of M. leprae to bind to human RPMI 2650 cells, a human nasal septal epithelial cell line, using both microscopic observation and an ELISA technique. The results demonstrated that M. leprae adheres to nasal cells after binding to soluble fibronectin. Furthermore, it was observed that M. leprae could bind to the beta 1 chain of the integrins in the absence of serum or mucus. These results demonstrated that M. leprae uses fibronectin and fibronectin receptors on the surface of epithelial cells to bind and possibly invade the nasal epithelial cells.

Amino Acid Sequence↗
PubMed2000

Fibrinogen binds to integrin alpha(5)beta(1) via the carboxyl-terminal RGD site of the Aalpha-chain.

Fibrinogen interactions with vascular endothelial cells are implicated in various physiological and pathophysiological events, including angiogenesis and wound healing. We have shown previously that integrin alpha(5)beta(1) is a fibrinogen receptor on endothelial cells [Suehiro, K., Gailit, J., and Plow, E.F. (1997) J. Biol. Chem. 272, 5360-5366]. In the present study, we have characterized fibrinogen interactions with purified alpha(5)beta(1) and have identified the recognition sequence in fibrinogen for alpha(5)beta(1). The binding of fibrinogen to immobilized alpha(5)beta(1) was selectively supported by Mn(2+). Fibrinogen bound to purified alpha(5)beta(1) in a time-dependent, specific, and saturable manner in the presence of Mn(2+), and the binding was blocked completely by Arg-Gly-Asp (RGD)-containing peptides and by anti-alpha(5) and anti-alpha(5)beta(1) monoclonal antibodies. A monoclonal antibody directed to the C-terminal RGD sequence at Aalpha572-574 significantly inhibited the binding of fibrinogen to alpha(5)beta(1), whereas monoclonal antibodies directed to either the N-terminal RGD sequence at Aalpha95-97 or the C-terminus of the gamma-chain did not. Furthermore, substituting RGE for RGD at position Aalpha95-97 in recombinant fibrinogen had a minimal effect on binding, whereas substituting RGE for RGD at position Aalpha572-574 decreased binding by 90%. These results demonstrate that the C-terminal RGD sequence at Aalpha572-574 is required for the interaction of fibrinogen with alpha(5)beta(1).

Amino Acid Sequence↗
PubMed1996

Activated conformations of very late activation integrins detected by a group of antibodies (HUTS) specific for a novel regulatory region (355-425) of the common beta 1 chain.

The very late activation antigens (VLA) or beta 1 integrins mediate cell attachment to different extracellular matrix proteins and intercellular adhesions. The ligand binding activity of these adhesion receptors is not constitutive and can be regulated by temperature, presence of extracellular divalent cations, stimulatory monoclonal antibodies (mAbs), and cellular activation. We have generated three novel mAbs, HUTS-4, HUTS-7, and HUTS-21, recognizing specific epitopes on the common beta 1 subunit (CD29) of VLA integrins whose expression correlates with the ligand binding activity of these heterodimeric glycoproteins. This correlation has been demonstrated for several integrin heterodimers in different cell systems using a variety of extracellular and intracellular stimuli for integrin activation. Thus, the presence of micromolar concentrations of extracellular Mn2+, preincubation with the activating anti-beta 1 mAb TS2/16, and cell treatment with phorbol esters or calcium ionophores, induced the expression of the HUTS beta 1 epitopes on T lymphoblasts. Using a panel of human-mouse beta 1 chimeric molecules, we have mapped these epitopes to the 355-425 sequence of the beta 1 polypeptide. This segment represents therefore a novel regulatory region of beta 1 that is exposed upon integrin activation. Interestingly, binding of HUTS mAbs to partially activated VLA integrins results in maximal activation of these adhesion receptors and enhancement of cell adhesion to beta 1 integrin ligands collagen, laminin, and fibronectin.

Antibodies, Monoclonal↗
PubMed1991

Characterization of the alpha 4 integrin gene promoter.

A cDNA for the alpha 4 chain of the alpha 4 beta 1 integrin was described previously [Takada, Y., Elices, M. J., Crouse, C. & Hemler, M. E. (1989) EMBO J. 8, 1361-1368]. Primer extension analysis indicated that alpha 4 mRNA extended well beyond the 5' end of this cDNA. To clone this 5' sequence, a primer extension cDNA library was constructed, and a cDNA extending an additional 660 base pairs was isolated. This cDNA hybridized to multiple mRNAs in both T and B lymphocytes, but no alpha 4 mRNA was found in different tissues or in adherent cell lines. A single alpha 4 gene was detected in a genomic Southern blot when hybridization was done at high stringency; however, additional bands were observed at lower stringency, indicating the presence of alpha 4-related genes. Some of the different mRNAs that hybridize to the alpha 4 cDNA may then be the products of these related genes. Analysis of the alpha 4 genomic sequence revealed a large first exon of 958 base pairs. Interestingly, translation of alpha 4 initiates from the second ATG in this exon (nucleotide + 744). The first ATG (nucleotide +21) is followed by a termination codon 21 amino acids downstream. Such upstream ATG codons have been implicated in translational control of protooncogenes. One major transcriptional start site was identified by using S1 nuclease and primer extension mapping. Consensus sequences for DNA regulatory elements were found upstream of the gene and in exon 1 and intron 1. The alpha 4 gene 5' flanking region acted as a promoter in transfection assays. Detailed characterization of the promoter should provide insight into molecular events regulating expression and tissue specificity of alpha 4.

Amino Acid Sequence↗