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Query: UNIPROT:P06889 (Mol)
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The development of transformed human airway epithelial cell lines has been important in advancing the understanding of the biochemical and genetic mechanisms underlying the cystic fibrosis (CF) defect. Since the most common mutation associated with CF is a phenylalanine deletion at position 508 (delta F508) in the CF transmembrane conductance regulator (CFTR) gene, a transformed airway epithelial cell line homozygous for this mutation will be important for determining the biologic significance of this mutation in the airways. We report the genotypic and phenotypic characterization of a delta F508 homozygote cell line derived from luminal epithelium in the trachea. The cells were transformed with a plasmid containing an origin of replication defective SV40 genome and have progressed through crisis. Immunocytochemical characterization of the cells shows that they express keratin, indicating epithelial cell origin, and that a calcium-dependent cell adhesion molecule, cellCAM 120/80, is present at plasma membrane junctions between cells. Electrophysiologically, the cells show no cAMP-dependent Cl transport. However, after treatment with the calcium ionophore, ionomycin, cells secrete Cl, albeit at a lower level than that observed in normal cells. Genetically, the cells express CFTR mRNA as determined by polymerase chain reaction amplification and CFTR protein as determined by Western hybridization analysis. Karyotypic analysis shows that 70% of the cells contain two copies of chromosome 7.
Am J Respir Cell Mol Biol 1993 May
PMID:An immortalized cystic fibrosis tracheal epithelial cell line homozygous for the delta F508 CFTR mutation. 768 97

We have identified a bone cell adhesion molecule, osteopontin, in the rat testis and epididymis by Northern analysis, RT-PCR, Western immunoblot analysis and immunocytochemistry. A polyclonal antibody raised against rat epididymal fluid proteins was used to detect fusion proteins produced by a testis lambda gt11 cDNA library. Sequence analysis of one of four positive cDNA clones, designated as pREP5, revealed identity with the rat osteopontin (OPN) cDNA. The partial cDNA clone pREP5 encompasses 64% of the 1,457 residues reported by Oldberg et al. (1986; Proc Natl Acad Sci USA 83:8819-8823). Immunoblot analysis with a monoclonal antibody against OPN detects the presence of immunoreactive polypeptides in rat testis homogenates as well as in epididymal fluid and sperm extracts. Immunocytochemical localization to the basal and adluminal region of the seminiferous tubule suggests that OPN could be a Sertoli cell product. Indeed, Northern blot analysis of testicular cell preparations demonstrated positive hybridization to Sertoli cell-enriched RNA, but not to RNA isolated from interstitial cell preparations or to isolated germ cell RNA preparations. OPN is also detected in the rat epididymis and on epididymal spermatozoa. This is the first report on the presence of OPN mRNA and protein in rat testis and epididymis and on the presence of OPN on the surface of epididymal spermatozoa. The characterization of this protein in other tissue suggests that OPN could play a role in testicular cell adhesion during spermatogenesis and/or epididymal maturation, although other potential functions in the male reproductive tract are discussed.
Mol Reprod Dev 1995 Jan
PMID:Identification of osteopontin (OPN) mRNA and protein in the rat testis and epididymis, and on sperm. 770 67

In addition to the antigen receptor, resting T cells express a number of receptors that can be stimulated to generate proliferative signals. These "accessory" receptors require co-expression of the T cell receptor (TCR), suggesting that they channel their signals via secondary activation of the signal transduction function of the CD3-TCR complex. Little is known about how different receptors control each other's function when one or more stimuli are presented at the same time. In order to study the regulation of accessory receptors by the CD3-TCR and vice versa, we have investigated the activation of the CD2 cell adhesion molecule receptor and the pertussis toxin receptor, a 43 kDa plasma membrane protein. Both receptors can activate signal transduction pathways in T cells similar to that of the CD3-TCR, including increases in Ca2+ and phosphatidylinositol turnover. They are also similar in that they utilize the antigen receptor to transmit their signals to the cell since CD3-TCR(-) mutants cannot be activated via either CD2 or the toxin receptor. We have previously shown that submaximal stimulation of the CD3-TCR blocks second messenger generation and proliferation in response to pertussis toxin. This heterologous desensitization was unidirectional since activation of the toxin receptor had no effect on CD3-TCR function. Here we extend these studies to show that activation of both CD2 and the toxin receptor led to rapid tyrosine phosphorylation of three similar proteins. Submaximal stimulation of the CD3-TCR completely inhibited toxin receptor-stimulated tyrosine protein kinase activity but did not desensitize CD2 function as determined by activation of tyrosine protein phosphorylation. Furthermore, CD2 stimulation did not lead to desensitization of the pertussis toxin receptor. These data support a system of complex regulatory relationships between different signaling receptors and suggest a model for signal integration and inter-receptor cross-talk in T cell activation.
Mol Immunol 1995 Apr
PMID:Differential regulation of accessory mitogenic signaling receptors by the T cell antigen receptor. 773 70

The ARK (AXL, UFO) receptor is a member of a new family of receptor tyrosine kinases whose extracellular domain contains a combination of fibronectin type III and immunoglobulin motifs similar to those found in many cell adhesion molecules. ARK mRNA is expressed at high levels in the mouse brain, prevalently in the hippocampus and cerebellum, and this pattern of expression resembles that of adhesion molecules that are capable of promoting cell aggregation through homophilic or heterophilic binding. We report here the ability of the murine ARK receptor to mediate homophilic binding. Expression of the ARK protein in Drosophila S2 cells induces formation of cell aggregates consisting of ARK-expressing cells, and aggregation leads to receptor activation, with an increase in receptor phosphorylation. Homophilic binding does not require ARK tyrosine kinase activity, since S2 cells expressing a receptor in which the intracellular domain was deleted were able to undergo aggregation as well as cells expressing the wild-type ARK receptor. Similar results were obtained with NIH 3T3 and CHO cells expressing high levels of ARK, although in this case ARK expression appeared to be accompanied by constitutive activation. The purified recombinant extracellular domain of ARK can induce homotypic aggregation of coated fluorescent beads (Covaspheres), and this protein can also function as a substrate for adhesion by S2 and NIH 3T3 cells expressing ARK. These results suggest that ARK represents a new cell adhesion molecule that through its homophilic interaction may regulate cellular functions during cell recognition.
Mol Cell Biol 1995 Feb
PMID:The receptor tyrosine kinase ARK mediates cell aggregation by homophilic binding. 782 30

The distribution of high endothelial venules (HEVs) in various rat organs has been investigated immunohistochemically using two monoclonal antibodies (MoAbs), REC16-11 and REC4-1. The staining patterns observed with REC16-11 and REC4-1 were compared with those obtained with the MoAb anti-rat ICAM-1, which is a cell adhesion molecule in HEVs. REC16-11 reacted not only with HEVs but also with all vascular endothelial cells (ECs) in the tissues examined. Electronmicroscopy showed that REC16-11 and REC4-1 reacted with the cell surface antigens of ECs and immunoblot analysis of rat splenic stromal preparations showed that REC4-1 stained 42 kd and 60 kd bands. REC4-1 inhibited the binding of lymphocyte to HEVs in the mucosa-associated lymphoid tissues (MALT), but had no effects on lymphocyte binding to HEVs in peripheral (non-mucosal) lymph nodes. These findings suggested that the MoAb REC4-1 recognized the associated antigen of the lymphocyte-HEV recognition system in MALT.
Virchows Arch B Cell Pathol Incl Mol Pathol 1993
PMID:Immunohistochemical and functional studies on rat high endothelial venules using monoclonal antibodies. 810 Jan

Adhesive interactions between cells are essential for the organization and function of differentiated tissues and organs and are mediated by inducible cell surface glycoproteins. In normal tissues, cell adhesion molecules contribute to immune regulation, inflammation, and embryogenesis. Additionally, they play an important role in a variety of pathogenic processes. Cell adhesion molecule expression can be induced by stimuli known to activate NF-kappa B, a ubiquitous transcription factor found in a variety of cell types. To investigate the role of NF-kappa B in cell adhesion molecule expression, we treated HL-60 cells with a double-stranded oligonucleotide which specifically inhibits NF-kappa B-mediated transcription. This treatment resulted in the inhibition of phorbol 12-myristate 13-acetate (PMA)-induced cellular adhesion, morphological changes, and the expression of leukocyte integrin CD11b. In a similar fashion, expression of intercellular adhesion molecule 1 on human endothelial cells induced by PMA was specifically inhibited by the NF-kappa B antagonist. We suggest that NF-kappa B activation is a necessary event for the PMA-induced differentiation of HL-60 cells and the expression of certain activation is a necessary event for the PMA-induced differentiation of HL-60 cells and the expression of certain adhesion molecules. Furthermore, the inhibition of transcription factor functions by this generally applicable mechanism can be used to define their role in cellular differentiation and function.
Mol Cell Biol 1993 Oct
PMID:Inhibition of phorbol ester-induced cellular adhesion by competitive binding of NF-kappa B in vivo. 810 72

During angiogenesis capillary endothelial cells undergo a coordinated set of modifications in their interactions with extracellular matrix components. In this study we have investigated the effect of the prototypical angiogenic factor basic fibroblast growth factor (bFGF) on the expression and function of several integrins in microvascular endothelial cells. Immunoprecipitation experiments with antibodies to individual subunits indicated that microvascular cells express at their surface several integrins. These include the alpha 1 beta 1, alpha 2 beta 1, and alpha 3 beta 1 laminin/collagen receptors; the alpha 6 beta 1 laminin receptor; the alpha 5 beta 1 and alpha v beta 1 fibronectin receptors; the alpha 6 beta 4 basement membrane receptor; and the alpha v beta 3 and alpha v beta 5 vitronectin receptors. Treatment with bFGF caused a significant increase in the surface expression of the alpha 2 beta 1, alpha 3 beta 1, alpha 5 beta 1, alpha 6 beta 1, alpha 6 beta 4, and alpha v beta 5 integrins. In contrast, the level of expression of the alpha 1 beta 1 and alpha v beta 3 integrins was decreased in bFGF-treated cells. Immunoprecipitation of metabolically labeled cells indicated that bFGF increases the biosynthesis of the alpha 3, alpha 5, alpha 6, beta 4, and beta 5 subunits and decreases the production of the alpha v and beta 3 subunits. These results suggest that bFGF modulates integrin expression by altering the biosynthesis of individual alpha or beta subunits. In accordance with the upregulation of several integrins observed in bFGF-treated cells, these cells adhered better to fibronectin, laminin, vitronectin, and type I collagen than did untreated cells. The largest differences in beta 1 integrin expression occurred approximately 72 h after exposure to bFGF, at a time when the expression of the endothelial cell-to-cell adhesion molecule endoCAM was also significantly upregulated. In contrast, a shorter exposure to bFGF (24-48 h) was required for the maximal induction of plasminogen activator production in the same cells. Taken together, these results show that bFGF causes significant changes in the level of expression and function of several integrins in microvascular endothelial cells.
Mol Biol Cell 1993 Oct
PMID:Basic fibroblast growth factor modulates integrin expression in microvascular endothelial cells. 829 94

E-cadherin is a Ca(2+)-dependent cell adhesion molecule involved in cell-cell interaction. In its normal physiological function it plays an important role in embryonic development and tissue morphogenesis. Recent studies have shown that in cancer development E-cadherin can act as a suppressor of invasion. Indeed, in several kinds of carcinomas allelic loss of the E-cadherin/Uvomorulin locus and decreased E-cadherin expression have been described. The importance of E-cadherin in human cancer development may be substantiated by molecular analysis of the E-cadherin transcript. Therefore, we isolated and characterized the human E-cadherin cDNA. Comparison of the nucleotide and deduced amino acid sequences revealed that the human E-cadherin is highly homologous to the mouse E-cadherin (uvomorulin) and to other members of the cadherin family.
Mol Biol Rep 1993 Feb
PMID:Molecular cloning and characterization of the human E-cadherin cDNA. 845 5

Continuous progress has been achieved during recent decades in the therapy of metastasizing malignancies by improving chemotherapeutic strategies and new approaches in radiation therapy. Genetic manipulation of tumor cells and of the tumor fighting immune system is hoped to add significant contributions to curative interventions in disseminated tumors. That we are still far from eradicating death by malignant growth is due ultimately to our limited understanding of the cascade of events resulting in metastasis formation, which until recently was believed to rely on multiple rounds of mutation and selection processes. This implies an individually specific history of each metastatic tumor, which would rule out uniform diagnostic and therapeutic concepts. When it was noted in a rat tumor model that the transfer of cDNA of a single gene, a CD44 variant isoform (CD44v) covering the exons v4-v7, sufficed to initiate metastasis formation of a locally growing tumor, hope was created that a "metastogene" may have been identified. Although the idea of CD44v expression as a unifying concept for tumor progression was not sustained, the discovery of CD44v-initiated metastatic spread allowed a conceptually new hypothesis on tumor progression as a consequence of the reactivation of genetic programs of ontogeny, stem cell differentiation, and/or lymphocyte activation. Since distinct CD44 isoforms play an important role in these processes, unraveling the functions of this family of molecules can indeed provide a cornerstone in the understanding of tumor progression. This article summarizes briefly the present knowledge on known functions of CD44 isoforms with particular focus on parallels between physiological programs and tumor progression.
J Mol Med (Berl) 1995 Sep
PMID:CD44: physiological expression of distinct isoforms as evidence for organ-specific metastasis formation. 852 46

Divalent cations and various soluble stimuli can alter cell adherence by affecting the avidity of adhesion molecules. We hypothesized that beta 1 integrin function of human eosinophils may be altered by divalent cations and eosinophil-activating cytokines such as interleukin-5 (IL-5). Expression of the beta 1 integrin activation epitope recognized by monoclonal antibody (mAb) 15/7 was evaluated by flow cytometry using purified eosinophils from allergic subjects, normal subjects, and late-phase bronchoalveolar lavage (BAL) fluids. Rapid and reversible 15/7 binding on eosinophils from each source was induced in Mn2+ (0.01-1 mM) but not in buffers containing other divalent cations and occurred without affecting the total level of beta 1 integrin expression (quantified using mAb 33B6). Augmentation of eosinophil adhesion to immobilized vascular cell adhesion molecule (VCAM-1) in Mn2+ followed a similar concentration dependence as mAb 15/7 binding. Net binding to VCAM-1 in Mn2+ was completely inhibited with a mixture of alpha 4 and beta 1 integrin mAb while beta 2 integrin mAb had no effect. Exposure of eosinophils from allergic subjects to as little as 1 pg/ml IL-5 completely inhibited mAb 15/7 binding induced by Mn2+. In contrast, increased binding of mAb 15/7 in Mn2+ was not blocked by IL-5 in eosinophils from normal subjects. For eosinophils from allergic subjects, IL-5 also inhibited Mn(2+)-induced adhesion to VCAM-1. Thus, beta 1 integrins on eosinophils from allergic and nonallergic subjects are modulated differently by Mn2+ and IL-5. Altered beta 1 integrin avidity may be one mechanism involved in preferential eosinophil recruitment in vivo.
Am J Respir Cell Mol Biol 1996 Jan
PMID:Functional regulation of beta 1 integrins on human eosinophils by divalent cations and cytokines. 853 85


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