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Results for “Cell Adhesion”

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PubMed2000

Kinetics and mechanics of cell adhesion.

Cell adhesion is mediated by specific interaction between receptors and ligands. Such interaction provides not only physical linkage but also communication between the cell and its environment. The kinetics and mechanics of cell adhesion are coupled, because force can influence the formation and dissociation of receptor-ligand bonds. The kinetic rates and their force dependence determine how likely, how rapidly and how strongly cells bind as well as how long they remain bound. Since adhesion molecules are linked to apposing cellular membranes, their interaction is governed by two-dimensional (2D) kinetics. This is in contrast to the three-dimensional (3D) binding of soluble ligands to cell surface receptors. Unlike the 3D case in which many methods are available for measuring kinetic rates, not until recently have the 2D kinetic rates become experimentally measurable. In this review, I will discuss the recent progress in the experimental methods that enable quantification of the relevant kinetic and mechanical parameters, the fundamental concepts that underlie the physics of the biological phenomena, and the mathematical models that relate functions to the intrinsic properties of the adhesion molecules.

Animals↗

PubMed1988

Characterization of the molecules involved in thymocyte thymic epithelial cell adhesion.

Cell to cell adhesion is important for mechanisms of cellular recognition, growth, and differentiation. The identification of molecules involved in these interactions is necessary in order to understand the molecular basis of these processes. We have previously described the development of two different thymic epithelial cell lines (TECS and TECL). Using an assay with radiolabeled thymocytes we found that thymocytes can adhere specifically to these thymic epithelial cells. This adhesion is trypsin sensitive, suggesting that involvement of specific cell surface proteins. In the present study we further characterize and begin identification of the molecules involved in this interaction. We found that thymocyte binding to thymic epithelial cells requires the presence of Ca2+ and Mg2+ and is mediated by a molecule greater than 10,000 MW. Also, we identified several antibodies which inhibit the adhesion of thymocytes to TECS. The membrane nature of the molecule mediating this interaction was confirmed by the ability of thymocyte membranes to block the inhibitory antibodies.

Animals↗

PubMed2006

Altered cell adhesion and cell viability in a p38alpha mitogen-activated protein kinase-deficient mouse embryonic stem cell line.

p38 mitogen-activated protein (MAP) kinase alpha (p38alpha) is a broadly expressed protein kinase that regulates growth and development. Most studies of p38alpha have been in somatic cells. Little is known about its function in embryonic stem (ES) cells. Using a ES cell line isolated from p38alpha knockout mouse embryos (p38alpha (-/-) ES cells), we investigated roles of p38alpha in the regulation of ES cell activities. p38alpha (-/-) ES cells displayed several altered features different from wild-type cells. The major findings are that p38alpha (-/-) ES cells have significantly increased cell adhesion to several extracelluar matrix proteins, correlating with elevated phosphorylation of focal adhesion kinase and paxillin. p38alpha (-/-) ES cells also showed increased cell viability, correlating with increased expression of survivin and activation of AKT (protein kinase B), two molecules that are known to improve cell viability. p38alpha (-/-) ES cells reach confluence faster than wild-type cells in routine cell culture. However, this is not due to a higher cell proliferation rate in p38alpha (-/-) ES cells, but rather is likely a result of improved cell adhesion and/or cell viability. Together our results indicated that p38alpha may negatively regulate mouse ES cell adhesion and viability.

Animals↗

PubMed2004

Phagocytosis, an alternative model system for the study of cell adhesion.

Cell adhesion encompasses a variety of cell-cell and cell-matrix adhesive interactions. Whereas ligation of most adhesion receptors activate Rho-family GTP-binding proteins and the subsequent reorganization of the actin cytoskeleton, the molecular mechanisms involved remain poorly understood. Because phagocytosis is a spatially restricted adhesion process, it represents a simplified model system to investigate the spatio-temporal regulation of the signalling pathways that link surface adhesion receptors, small GTPases and the actin cytoskeleton. This review highlights some of the similarities between the formation and maintenance of adhesive contacts and phagocytic uptake and discusses why the study of phagocytosis can help understand more complex adhesion processes.

Actins↗

PubMed2002

Role of galectin-8 as a modulator of cell adhesion and cell growth.

Galectin-8 belongs to the family of tandem-repeat type galectins. It consists as several isoforms, each made of two domains of approximately 140 amino-acids, both having a carbohydrate recognition domain (CRD). These domains are joined by a 'link peptide' of variable length. The human galectin-8 gene covers 33 kbp of genomic DNA. It is localized on chromosome 1 (1q42.11) and contains 11 exons. The gene produces by alternative splicing 14 different transcripts, altogether encoding 6 proteins. Galectin-8, like other galectins, is a secreted protein. Upon secretion galectin-8 acts as a physiological modulator of cell adhesion. When immobilized, it functions as a matrix protein equipotent to fibronectin in promoting cell adhesion by ligation and clustering of a selective subset of cell surface integrin receptors. Complex formation between galectin-8 and integrins involves sugar-protein interactions and triggers integrin-mediated signaling cascades such as Tyr phosphorylation of FAK and paxillin. In contrast, when present in excess as a soluble ligand, galectin-8 (like fibronectin) forms a complex with integrins that negatively regulates cell adhesion. Such a mechanism allows local signals emitted by secreted galectin-8 to specify territories available for cell adhesion and migration. Due to its dual effects on the adhesive properties of cells and its association with fibronectin, galectin-8 might be considered as a novel type of a matricellular protein. Galectin-8 levels of expression positively correlate with certain human neoplasms, prostate cancer being the best example studied thus far. The overexpressed lectin might give these neoplasms some growth and metastasis related advantages due to its ability to modulate cell adhesion and cellular growth. Hence, galectin-8 may modulate cell-matrix interactions and regulate cellular functions in a variety of physiological and pathological conditions.

Animals↗

PubMed1998

Matrix-dependent Tiam1/Rac signaling in epithelial cells promotes either cell-cell adhesion or cell migration and is regulated by phosphatidylinositol 3-kinase.

We previously demonstrated that both Tiam1, an activator of Rac, and constitutively active V12Rac promote E-cadherin-mediated cell-cell adhesion in epithelial Madin Darby canine kidney (MDCK) cells. Moreover, Tiam1 and V12Rac inhibit invasion of Ras-transformed, fibroblastoid MDCK-f3 cells by restoring E-cadherin-mediated cell-cell adhesion. Here we show that the Tiam1/Rac-induced cellular response is dependent on the cell substrate. On fibronectin and laminin 1, Tiam1/Rac signaling inhibits migration of MDCK-f3 cells by restoring E-cadherin-mediated cell- cell adhesion. On different collagens, however, expression of Tiam1 and V12Rac promotes motile behavior, under conditions that prevent formation of E-cadherin adhesions. In nonmotile cells, Tiam1 is present in adherens junctions, whereas Tiam1 localizes to lamellae of migrating cells. The level of Rac activation by Tiam1, as determined by binding to a glutathione-S-transferase- PAK protein, is similar on fibronectin or collagen I, suggesting that rather the localization of the Tiam1/Rac signaling complex determines the substrate-dependent cellular responses. Rac activation by Tiam1 requires PI3-kinase activity. Moreover, Tiam1- but not V12Rac-induced migration as well as E-cadherin-mediated cell- cell adhesion are dependent on PI3-kinase, indicating that PI3-kinase acts upstream of Tiam1 and Rac.

Animals↗

PubMed1993

Responses to Wnt signals in vertebrate embryos may involve changes in cell adhesion and cell movement.

Wnt genes encode secreted glycoproteins, and, because of their homology with the Drosophila segment polarity gene wingless, are likely to play important roles as modulators of local intercellular signalling during embryonic development. Although little is known of the mechanisms by which Wnts signal in an autocrine or paracrine manner, it is increasingly clear that cells can respond rapidly to Wnt signals in the absence of transcription, and that these responses may include changes in cell adhesion and cell movement. We review recent evidence from studies on Xenopus laevis and other systems, which demonstrate that (1) a subset of Wnts modulate gap junctional permeability, which may be a reflection of changes in cadherin-mediated cell adhesion, (2) embryos express beta-catenin and plakoglobin, which are homologs of the armadillo gene products, known to be involved in the wingless signalling pathway, and known to be found at cell junctions, and (3) overexpression of specific Wnts in Xenopus embryos leads to clear changes in cell behavior and movement.

Animals↗

PubMed2006

Small GTPase RacF2 affects sexual cell fusion and asexual development in Dictyostelium discoideum through the regulation of cell adhesion.

Cells of Dictyostelium discoideum become sexually mature when submerged and in darkness, and fuse with opposite mating-type cells as gametes. The gene for a Rho GTPase, RacF2, is one of the extremely gamete-enriched genes (>100-fold) identified by us previously. Here, we isolated knockout, overexpression, constitutively active and dominant negative mutants of RacF2, and analyzed their phenotypes. These mutants showed anomalies in the extent of sexual cell fusion and asexual development as well as in EDTA-sensitive cell-cell adhesion. It is suggested that RacF2 controls the process of sexual and asexual development through the regulation of cellular adhesiveness. An analysis of the expression of all 18 rac family genes by real-time polymerase chain reaction revealed that four additional genes, rac1b, rac1c, racF1 and racG, were induced during maturation, suggesting their possible involvement in sexual cell interactions.

Animals↗

PubMed2000

Modeling concurrent binding of multiple molecular species in cell adhesion.

Cell adhesion provides not only physical linkage but also communication between the cell and its environment. As such, it is important to many cellular functions. Recently, the probability distribution of forming a low number of specific adhesive bonds in a short-duration contact has been described (Chesla et al., Biophys. J. , 1998, 75:1553-1572). This model assumes that binding occurs between a single receptor species and a single ligand species. However, cell adhesion molecules rarely work alone in physiological settings. To account for these in vivo situations, we extended the previous model to include concurrent interactions of multiple receptor-ligand species, introducing the concept of independent binding. Closed-form solutions have been obtained for cases where competition is absent or can be neglected. In two companion papers (Williams et al., Biophys. J., 2000, 79:1858-1866; 2000, 79:1867-1875), the model developed herein has been applied to analyze two sets of experiments designed such that the validity of the theory was also tested.

Animals↗

PubMedDate not supplied

Integrin dimerization and ligand organization: key components in integrin clustering for cell adhesion.

Cell adhesion requires both integrin occupancy and integrin clustering. In this work, we investigate a mechanism based on organizing ligand into islands and integrin dimerization for the initiation of integrin clustering. To study integrin clustering and integrin occupancy we develop a two-dimensional Monte Carlo lattice description of the cell-substrate interface to simulate the diffusion and reaction of integrins. We demonstrate that integrin dimerization can drive integrins into clusters of sizes greater than two. Ligand organization or integrin dimerization alone is unable to increase the number of bound integrins, but when both are present they cooperate to increase both binding and clustering of integrins. In addition, when integrin dimerization and ligand organization are both present large integrin clusters, which may act as nucleation sites for the formation of adhesion complexes, are observed. These results describe a potential mechanism for the clustering of integrin receptors and avidity modulation in cellular adhesion and have implications for the designs of surfaces to control cell responses to external ligands and to manipulate cell adhesion for tissue-engineering applications.

Biomimetic Materials↗

PubMed1998

Multiple roles of neural cell adhesion molecule, neural cell adhesion molecule-polysialic acid, and L1 adhesion molecules during sensory innervation of the otic epithelium in vitro.

To explore the role of cell adhesion molecules in the innervation of the inner ear, antibody perturbation was used on histotypic co-cultures of the ganglionic and epithelial anlagen derived from the otocyst. When unperturbed, these tissues survived and differentiated in this culture system with outgrowth of fasciculated neuronal fibers which expressed neural cell adhesion molecule and L1. The fibers exhibited target choice and penetration, then branching and spreading within the otic epithelium as individual axons. Treatment of the co-cultures, or of the ganglionic anlagen alone, with anti-neural cell adhesion molecule or anti-L1 Fab fragments produced a defasciculation of fibers but did not affect neurite outgrowth. In the co-cultures this defasciculation was accompanied by a small increase in the number of fibers found in inappropriate tissues. However, the antibodies did not prevent fiber entry to the otic epithelium. In contrast, removal of polysialic acid from neural cell adhesion molecule with endoneuraminadase-N, while producing a similar fiber defasciculation, also increased the incidence of fibers entering the epithelium. Nevertheless, once within the target tissue, the individual fibers responded to either Fab or to desialylation by spreading out more rapidly, branching, and growing farther into the epithelium. The findings suggest that fasciculation is not essential for specific sensory fibers to seek out and penetrate the appropriate target, although it may improve their tracking efficiency. Polysialic acid on neural cell adhesion molecule appears to limit initial penetration of the target epithelium. Polysialic acid as well as neural cell adhesion molecule and L1 function are involved in fiber-target interactions that influence the arborization of sensory axons within the otic epithelium.

Animals↗

PubMedDate not supplied

Dextran sulfate suppresses cell adhesion and cell cycle progression of melanoma cells.

We have reported that dextran sulfate is a possible candidate for an antimetastatic drug because it inhibits cell adhesion. It has been demonstrated that dextran sulfate can detach cancer cells adhering to the bottom of plastic flasks, and that the detached cells do not readhere or proliferate. In this study, we investigated the effects of dextran sulfate on cancer cells, focusing on cell cycle regulators as well as cell adhesion molecules. The effects of dextran sulfate on the cell cycle were examined by flow cytometry, and changes in gene expression caused by dextran sulfate were analyzed by cDNA microarray to identify changes in adhesion and cell cycle genes. By flow cytometry, treatment with dextran sulfate increased the percentage of cells in the G1/G0-phase, and decreased those in the S- and G2/M-phases. Analysis by cDNA microarray revealed decreased expression of several genes essential for progression of the G1- and S-phases. The expression of the adhesion factors involved in metastases was also suppressed. Furthermore, we confirmed these changes in the gene expression by Northern and Western blotting. Our results indicate that dextran sulfate suppresses cell adhesion and cell cycle progression, both of which are essential for metastasis, suggesting that dextran sulfate could be used as an antimetastatic agent.

Animals↗

PubMed1996

Beta4 integrin is required for hemidesmosome formation, cell adhesion and cell survival.

The integrin heterodimer alpha 6 beta 4 is expressed in many epithelia and in Schwann cells. In stratified epithelia, alpha 6 beta 4 couple with BPAG1-e and BPAG2 to form hemidesmosomes, attaching externally to laminin and internally to the keratin cytoskeleton. To explore the function of this atypical integrin, and its relation to conventional actin-associated integrins, we targeted the removal of the beta 4 gene in mice. Tissues that express alpha 6 beta 4 are grossly affected. Stratified tissues are devoid of hemidesmosomes, display only a very fragile attachment to the basal lamina, and exhibit signs of degeneration and tissue disorganization. Simple epithelia which express alpha 6 beta 4 are also defective in adherence, even though they do not form hemidesmosomes. In the absence of beta 4, alpha 6 is dramatically downregulated, and other integrins do not appear to compensate for the loss of this heterodimer. These data have important implications for understanding integrin function in cell-substratum adhesion, cell survival and differentiation, and for understanding the role of alpha 6 beta 4 in junctional epidermolysis bullosa, an often lethal human disorder with pathology similar to our mice.

Animals↗

PubMed2001

A novel C-type lectin regulating cell growth, cell adhesion and cell differentiation of the multipotent epithelium in budding tunicates.

We have isolated two Ca(2+)-dependent, galactose-binding polypeptides from the budding tunicate, Polyandrocarpa misakiensis. Based on their partial amino acid sequences, full-length cDNAs were cloned. One of them was identical with a tunicate C-type lectin (TC14-2) reported previously. The other was a novel C-type lectin, referred to as TC14-3. In living animals, they appeared to be coupled. This complex of lectins, when applied in vitro to tunicate multipotent cells of epithelial origin, blocked cell proliferation and induced cell aggregation. The aggregates expressed a homolog of the integrin alpha-chain and other differentiation markers specific for epithelial cells. Recombinant TC14-3 could reproduce all the activities of native lectins by itself, which was accelerated by recombinant TC14-2. The inhibitory activity of TC14-3 on cell growth was completely abolished by the addition of 50 microM D-galactose. Anti-TC14-3 monoclonal antibody showed that the antigen was expressed constitutively by the multipotent epithelial and mesenchymal cells. These results provide evidence that in P. misakiensis a C-type lectin plays a novel, cytostatic role in regulating cell growth, cell adhesion and cell differentiation during asexual reproduction.

Amino Acid Sequence↗

PubMed1994

Wnt-1 modulates cell-cell adhesion in mammalian cells by stabilizing beta-catenin binding to the cell adhesion protein cadherin.

Wnt-1 homologs have been identified in invertebrates and vertebrates and play important roles in cellular differentiation and organization. In Drosophila, the products of the segment polarity genes wingless (the Wnt-1 homolog) and armadillo participate in a signal transduction pathway important for cellular boundary formation in embryonic development, but functional interactions between the proteins are unknown. We have examined Wnt-1 function in mammalian cells in which armadillo (beta-catenin and plakoglobin) is known to bind to and regulate cadherin cell adhesion proteins. We show that Wnt-1 expression results in the accumulation of beta-catenin and plakoglobin. In addition, binding of beta-catenin to the cell adhesion protein, cadherin, is stabilized, resulting in a concomitant increase in the strength of calcium-dependent cell-cell adhesion. Thus, a consequence of the functional interaction between Wnt-1 and armadillo family members is the strengthening of cell-cell adhesion, which may lead to the specification of cellular boundaries.

Amino Acid Sequence↗

PubMed2004

Comparative analysis of cell adhesion molecules, cell cycle regulatory proteins, mismatch repair genes, cyclooxygenase-2, and DPC4 in carcinomas arising in inflammatory bowel disease and sporadic colon cancer.

Colon carcinoma arising in inflammatory bowel disease often exhibits aggressive behavior compared to sporadic carcinomas. The rationale for the different biological behaviors of these two groups of tumors is not fully understood. In this study, we have examined carcinomas arising in inflammatory bowel disease (IBD) and sporadic carcinomas (SCA) for molecular differences that may provide clues for the behavioral disparity of these tumors. Thirty-eight colon carcinomas (12 from ulcerative colitis, 5 from Crohn's disease, and 21 SCA) were analyzed by immunohistochemistry for cell adhesion molecules (E-cadherin, beta-catenin, CD44), cell cycle regulatory proteins (cyclin D1, p27, p21), mismatch repair proteins (hMLH1, hMSH2), cyclooxygenase-2 and DPC4. Carcinomas arising in IBD showed significant decrease in expression of cell adhesion molecules, the cell cycle inhibitor protein, p21, and increased expression of cyclooxygenase-2 compared to sporadic carcinomas. No differences were observed in the expression of cell cycle regulatory proteins p27, cyclin D1, DPC4 and mismatch repair proteins between these two groups of tumors. Decreased expression of p21 as well as adhesion molecules may provide increased impetus for the aggressive behavior of tumors arising in inflammatory bowel disease.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Cell adhesion kinase beta forms a complex with a new member, Hic-5, of proteins localized at focal adhesions.

Cell adhesion kinase beta (CAKbeta/PYK2) is the second protein-tyrosine kinase of the focal adhesion kinase subfamily. We identified a cDNA that encodes a CAKbeta-binding protein. This cDNA clone encodes the human homologue of Hic-5, the cDNA of which was cloned in 1994 as transforming growth factor beta1- and hydrogen peroxide-inducible mRNA. We found that Hic-5 exclusively localized at focal adhesions in a rat fibroblast line, WFB. This localization of Hic-5 was confirmed in WFB cells expressing Myc-tagged Hic-5. The amino acid sequence of Hic-5 is highly similar to that of paxillin in the four LD motifs as well as in the four contiguous LIM domains. The Hic-5 N-terminal domain directly associated in vitro with the extreme C-terminal region (residue 801 to the end) of CAKbeta. CAKbeta was coimmunoprecipitated with Hic-5 from the WFB cell lysate. The coimmunoprecipitation of CAKbeta with Hic-5 was markedly inhibited by the addition of the extreme C-terminal region of CAKbeta. Coimmunoprecipitation of Hic-5 with CAKbeta, which was shown in COS-7 cells doubly transfected with cDNA constructs of CAKbeta and Myc-tagged Hic-5, was lost when the CAKbeta amino acid residues 741-903 were deleted. Hic-5 was tyrosine-phosphorylated in Src-transformed 3Y1 cells and in cells treated with pervanadate. Hic-5 associated with CAKbeta was selectively tyrosine-phosphorylated in WFB cells exposed to hypertonic osmotic stress. These results indicate that Hic-5 is a paxillin-related component of focal adhesions and binds to CAKbeta, implying possible involvement of Hic-5 in the downstream signaling of CAKbeta.

Amino Acid Sequence↗

PubMed1993

Carbohydrate-carbohydrate interactions of a novel acidic glycan can mediate sponge cell adhesion.

Cell recognition and adhesion were first demonstrated in marine sponges. These phenomena were later shown in Microciona prolifera sponge to be mediated by a Ca(2+)-dependent self-association of adhesion proteoglycans (APs) attached in a species-specific manner to cell-surface receptors. Using the same experimental system we now provide three lines of evidence that highly polyvalent Ca(2+)-dependent carbohydrate-carbohydrate interactions of a novel AP glycan represent the basis of AP-AP self-binding and thus of cell adhesion. 1) A specific monoclonal antibody which blocks cell aggregation and AP bead adhesion identified a highly repetitive novel carbohydrate epitope (2500 sites) in an acidic glycan of M(r) = 200 x 10(3) (g200) from AP. 2) Reconstitution of the Ca(2+)-dependent self-interaction activity of AP was achieved by cross-linking the purified protein-free g200 glycan into polymers of similar valency as the native AP. 3) Beads coated with the protein-free g200 glycan showed a Ca(2+)-dependent aggregation equivalent to that of AP beads. Carbohydrate and amino acid analyses of the g200 glycan purified by gel electrophoresis, high performance liquid chromatography gel filtration, and ion exchange chromatography yielded six components in the following proportions; 68 fucose, 32 glucuronic acid, 2 mannose, 18 galactose, 19 N-acetylglucosamine, and 1 asparagine residue. These unique chemical features together with immunological and enzymological analyses suggest that the g200 glycan is a large highly fucosylated, acidic, N-linked polysaccharide with a novel structure distinct from that of other known glycosaminoglycans.

Animals↗