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PubMed2006

Examination of actin and microtubule dependent APC localisations in living mammalian cells.

BACKGROUND: The trafficking of the adenomatous polyposis coli (APC) tumour suppressor protein in mammalian cells is a perennially controversial topic. Immunostaining evidence for an actin-associated APC localisation at intercellular junctions has been previously presented, though live imaging of mammalian junctional APC has not been documented. RESULTS: Using live imaging of transfected COS-7 cells we observed intercellular junction-associated pools of GFP-APC in addition to previously documented microtubule-associated GFP-APC and a variety of minor localisations. Although both microtubule and junction-associated populations could co-exist within individual cells, they differed in their subcellular location, dynamic behaviour and sensitivity to cytoskeletal poisons. GFP-APC deletion mutant analysis indicated that a protein truncated immediately after the APC armadillo repeat domain retained the ability to localise to adhesive membranes in transfected cells. Supporting this, we also observed junctional APC immunostaining in cultures of human colorectal cancer cell line that express truncated forms of APC. CONCLUSION: Our data indicate that APC can be found in two spatially separate populations at the cell periphery and these populations can co-exist in the same cell. The first localisation is highly dynamic and associated with microtubules near free edges and in cell vertices, while the second is comparatively static and is closely associated with actin at sites of cell-cell contact. Our imaging confirms that human GFP-APC possesses many of the localisations and behaviours previously seen by live imaging of Xenopus GFP-APC. However, we report the novel finding that GFP-APC puncta can remain associated with the ends of shrinking microtubules. Deletion analysis indicated that the N-terminal region of the APC protein mediated its junctional localisation, consistent with our observation that truncated APC proteins in colon cancer cell lines are still capable of localising to the cell cortex. This may have implications for the development of colorectal cancer.

Actins↗
PubMed1998

[The development of endothelial cell-to-cell junctions].

The endothelium forms the main barrier to the passage of macromolecules and circulating cells from blood to tissues. Endothelial permeability is in large part regulated by intercellular junction. The article here dicusses the development of endothelial cell-to-cell junction. The types of endothelial junctions, transduction, regulation of changes of endothelial cell-to-cell junction, the effects of the flow in vasculature and the leukocytic extravasation have been discussed. It was emphasized that the changes of endothelial junctions and skeleton were important in regulating endothelial permeability, leukocyte extravasation and reorganization of vascular endothelial cell-to-cell junction.

Adherens Junctions↗
PubMed1989

A 220 kDa polypeptide, immunolocalized to epithelial tight junctions, is associated with brain clathrin preparations.

Antibodies were raised in rabbits to highly purified preparations of bovine brain clathrin. The serum stained by immunofluorescence rat liver sections at tight junctions in a pattern that was identical to that previously reported (B. R. Stevenson et al.: J. Cell Biol. 103, 755-766 (1986] in which a monoclonal antibody specific to a 220 kDa (ZO-1) liver tight junction component was used. The serum also stained regions of the cell surface corresponding to the positions of intercellular junctions in confluent MDCK and HepG-2 cell cultures. Analysis of brain clathrin preparations resolved by polyacrylamide gel electrophoresis by immunoblotting with the serum indicated reaction with clathrin heavy and light chains as well as towards a 220 kDa polypeptide that was a minor component. Affinity purification of the serum provided antibodies directed mainly to clathrin light chains and these antibodies, as well as an independent antiserum to clathrin heavy chains, immunofluorescently stained liver tissue and cells in a manner typical of coated membranes/vesicles. These results suggested, by difference, that antibodies to a 220 kDa polypeptide, a minor constituent in brain clathrin preparations, were responsible for staining intercellular tight junctions in epithelia. The 220 kDa polypeptide present in brain clathrin preparations was demonstrated to be immunologically distinct from liver myosin heavy chain as well as erythrocyte and brain ankyrin. Comparison by two-dimensional mapping of the 220 kDa in brain clathrin with the clathrin heavy chain (180 kDa) polypeptide showed they were different proteins, but the 220 kDa polypeptide present in rat liver tight junctions was highly similar to the 220 kDa present in bovine brain clathrin preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

A novel four transmembrane spanning protein, CLP24. A hypoxically regulated cell junction protein.

A novel hypoxically regulated intercellular junction protein (claudin-like protein of 24 kDa, CLP24) has been identified that shows homology to the myelin protein 22/epithelial membrane protein 1/claudin family of cell junction proteins, which are involved in the modulation of paracellular permeability. The CLP24 protein contains four predicted transmembrane domains and a C-terminal protein-protein interaction domain. These domains are characteristic of the four transmembrane spanning (tetraspan) family of proteins, which includes myelin protein 22, and are involved in cell adhesion at tight, gap and adherens junctions. Expression profiling analyses show that CLP24 is highly expressed in lung, heart, kidney and placental tissues. Cellular studies confirm that the CLP24 protein localizes to cell-cell junctions and co-localizes with the beta-catenin adherens junction-associated protein but not with tight junctions. Over-expression of CLP24 results in decreased adhesion between cells, and functional paracellular flux studies confirm that over-expression of the CLP24 protein modulates the junctional barrier function. These data therefore suggest that CLP24 is a novel, hypoxically regulated tetraspan adherens junction protein that modulates cell adhesion, paracellular permeability and angiogenesis.

Alternative Splicing↗
PubMed2003

Regulation of the blood-biliary barrier: interaction between gap and tight junctions in hepatocytes.

Hepatocytes tightly connect with each other by intercellular junctions to form liver cell plates. The junctions composed of gap, tight, and adherens junctions and desmosomes concentrate around bile canaliculi. In particular, tight junctions serve as a barrier to keep bile in bile canaliculi away from the blood circulation. Thus, it is very reasonable to call tight junctions of hepatocytes the blood-biliary barrier. On the other hand, gap junctions of hepatocytes are considered to enable ordered contraction of bile canaculi from centrizonal to periportal hepatocytes by their function of intercellular communication. Gap and tight junctions may thus play a crucial role in bile secretion, one of the most differentiated functions of the liver. In intrahepatic cholestasis, a common pathological condition of the liver, downregulation of gap and tight junctional functions is seen, which results in impaired intercellular communication and in leaky tight junctions. Although the changes in gap and tight junctions had been considered to be independent of each other, recent findings that the tight junction-associated proteins ZO-1 and occludin bind to connexins indicate the possibility of either coordinate or reciprocal regulation of macromolecular complexes containing gap- and tight-junction proteins. In this review, we introduce the interaction and regulation between gap and tight junctions of hepatocytes in vitro and discuss the regulatory mechanisms of the "blood-biliary barrier" to study the molecular pathogenesis of cholestasis.

Actins↗
PubMed2005

Involvement of nectins in the formation of puncta adherentia junctions and the mossy fiber trajectory in the mouse hippocampus.

Synapses are specialized intercellular junctions whose specificity and plasticity are mediated by synaptic cell adhesion molecules. In hippocampus, the mossy fibers form synapses on the apical dendrites of the CA3 pyramidal cells where synaptic and puncta adherentia junctions (PAJs) are highly developed. Synaptic junctions are the sites of neurotransmission, while PAJs are regarded as mechanical adhesion sites. Cell-cell adhesion molecules nectin-1 and nectin-3 asymmetrically localize at the pre- and post-synaptic sides of PAJs, respectively. To reveal the definitive role of nectins, we analyzed nectin-1-/- and nectin-3(-/-) mice. In both the mutant mice, the number of PAJs at the synapses between the mossy fiber terminals and the dendrites of the CA3 pyramidal cells was reduced. In addition, the abnormal mossy fiber trajectory was observed. These results indicate that nectins are involved in the formation of PAJs, which maintain the proper mossy fiber trajectory.

Animals↗
PubMed2000

Vascular endothelial junction-associated molecule, a novel member of the immunoglobulin superfamily, is localized to intercellular boundaries of endothelial cells.

During the process of lymphocyte homing to secondary lymphoid organs, such as lymph nodes and tonsils, lymphocytes interact with and cross a specialized microvasculature, known as high endothelial venules. There is a great deal of information available about the first steps in the homing cascade, but molecular understanding of lymphocyte transmigration through the intercellular junctions of high endothelial venules is lacking. In analyzing expressed sequence tags from a cDNA library prepared from human tonsillar high endothelial cells, we have identified a cDNA encoding a novel member of the immunoglobulin superfamily. The protein, which we have termed VE-JAM ("vascular endothelial junction-associated molecule"), contains two extracellular immunoglobulin-like domains, a transmembrane domain, and a relatively short cytoplasmic tail. VE-JAM is prominently expressed on high endothelial venules but is also present on the endothelia of other vessels. Strikingly, it is highly localized to the intercellular boundaries of high endothelial cells. VE-JAM is most homologous to a recently identified molecule known as Junctional Adhesion Molecule, which is concentrated at the intercellular boundaries of both epithelial and endothelial cells. Because the Junctional Adhesion Molecule has been strongly implicated in the processes of neutrophil and monocyte transendothelial migration, an analogous function of VE-JAM during lymphocyte homing is plausible.

Amino Acid Sequence↗
PubMed1990

Effect of 12-O-tetradecanoylphorbol-13-acetate on intercellular communication in various clones of mouse epidermal JB6 cells.

We studied gap junctional intercellular communication (IC) in various clones of mouse epidermal JB6 cells and the effect of the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA) on such communication. JB6 clones used included nonpromotable, promotable, and transformed clones, representing a spectrum in susceptibility to transformation from nontransformed, to initiated (postinitiated), to transformed cells. We used the dye transfer assay and the radioisotope transfer assay, and quantified IC both in homologous pairings, where IC among cells of a single clone was examined, and heterologous pairings, where cells of initiated or transformed clones were paired with cells of a nonpromotable clone. Both pairings showed good IC in the absence of TPA and poor IC in the presence of TPA. However, suppression of IC by TPA was more effective when cells had advanced in promotability. IC was more suppressed by TPA in heterologous pairing than in homologous pairing. These results implied that in advanced stages of promotion, the capability to retain IC with each other (homologous IC) and especially with their nontransformed counterpart (heterologous IC) is progressively lost. Thus we conclude that the interaction of initiated cells and transformed cells with nontransformed cells decreases progressively in this model system for tumor promotion and progression.

Animals↗
PubMed1987

Formation of heterotypic adherens-type junctions between L-CAM-containing liver cells and A-CAM-containing lens cells.

Cultured cells from either chicken lens or liver plated on solid substrates form flat epithelial sheets with adherens-type junctions between them. In lens cells these junctions contain A-CAM, while the same type of intercellular junctions in liver cells contain another cell adhesion molecule, L-CAM. Coculturing of lens and liver cells in the same dish resulted in the formation of mixed (heterotypic) adherens junctions. Double immunofluorescent labeling for both A-CAM and L-CAM indicated that the mixed junctions contained both molecules, each of which was present on one of the two partner cells. Moreover, the formation of the heterotypic junctions could be effectively inhibited by both anti-A-CAM and anti-L-CAM antibodies. It has thus been proposed that A-CAM and L-CAM share significant functional homology and may be involved in heterophilic interactions leading to the establishment of molecularly and cellularly asymmetrical adherens-type junctions.

Animals↗
PubMed2002

Downregulation of connexin 43 expression by high glucose reduces gap junction activity in microvascular endothelial cells.

Impairment of retinal vascular homeostasis is associated with the development and progression of diabetic retinopathy involving gap junction intercellular communication (GJIC) activity. The principal gap junction protein of intercellular communication, connexin, was investigated to determine the effects of high glucose concentrations on the expression of endothelial-specific connexins (Cx37, Cx40, and Cx43), connexin phosphorylation pattern, and GJIC activity. Rat microvascular endothelial (RME) cells grown in high (30 mmol/l)-glucose medium for 9 days had reduced Cx43 expression: Cx43 mRNA (68 +/- 13% of control; P = 0.019, n = 5) and protein (55.6 +/- 16% of control; P = 0.003, n = 5) levels were reduced; however, Cx37 and Cx40 expression was not affected. Using alkaline phosphatase and Western blot analyses, we identified three forms of Cx43: a nonphosphorylated form (P0) and two phosphorylated forms (P1 and P2). Expression of all three forms was decreased in cells grown in high-glucose medium: PO, 73 +/- 15% of control (P = 0.04); P1, 57 +/- 16% of control (P = 0.01); and P2, 42 +/- 22% of control (P = 0.006). Using immunofluorescence microscopy, we observed Cx43 localization at specific sites of contact (plaques) between adjacent cells. In cells grown in high-glucose medium, we observed reduced plaque counts (63 +/- 6% of control; P = 0.009) and decreased intensity of Cx43 immunofluorescence compared with cells grown in normal medium. Furthermore, using scrape load dye transfer (SLDT) technique, we found that these cells exhibited reduced GJIC activity (60% of control; P = 0.01, n = 5). The reduction in GJIC activity correlated with the decreased Cx43 protein levels (r = 0.9). These results indicate that high glucose concentrations inhibited GJIC activity by reducing Cx43 synthesis in RME cells. Impaired intercellular communication may contribute to breakdown of homeostatic balance in diabetic microangiopathy.

Adipose Tissue↗
PubMed1977

Morphological alterations and functional changes of interhepatocellular junctions induced by bile duct ligation.

The effect of bile duct ligation on the intercellular junctions of hepatocytes was investigated. The features and the arrangement of the bile canaliculi and the zonulae occludentes alter concomitant to the increase of the intracanalicular pressure. The lumen of the bile canaliculi enlarges and the microvilli disappear. The array of the zonulae occludentes becomes irregularly shaped, the number of strands diminishes and interruptions of the strands occur. With peroxidase a leakage in the bile-blood barrier is detected. Furthermore a disappearance of gap junctions between the hepatocytes after bile duct ligation is observed. The present investigation shows that the zonulae occludentes are mobile structures which are changed by increased unilateral pressure. Due to their ultrastructural alterations, a leakage of the permeability barrier between physiological compartments is found.

Animals↗
PubMed1982

Hormonal regulation of cell junction permeability: upregulation by catecholamine and prostaglandin E1.

By cellular activation with hormones, we test the proposition (Loewenstein, W.R., Physiol. Rev. 61:829, 1981) that the permeability of cell junction is upregulated through elevation of the level of cyclic AMP. Cultured rat glioma C-6 cells, with beta-adrenergic receptors, and human lung WI-38 cells, with prostaglandin receptors, were exposed to catecholamine (isoproterenol) and prostaglandin E1, respectively, while their junctions were probed with microinjected fluorescent-labelled mono-, di-, and triglutamate. Junctional permeability, as indexed by the proportion of cell interfaces transferring the probes, rose after the hormones treatments. The increase in permeability took several hours to develop and was associated with an increase in the number of gap-junctional membrane with an increase in the number of gap-junctional membrane particles (freeze-fracture electron microscopy). Such interaction between hormonal and junctional intercellular communication may provide a mechanism for physiological regulation of junctional communication and (perhaps as part of that) for physiological coordination of responses of cells in organ and tissues to hormones.

Alprostadil↗
PubMed1983

A freeze-fracture study of two types of collagen-phagocytosing cell in the post-partum rat endometrium.

In the post-partum rat endometrium, ultrastructural distinction could be made between stromal cells (fibroblast-like cells) and macrophages, especially by the freeze-fracture technic. The stromal cells were characterized by a well-developed rough-surfaced endoplasmic reticulum (RER) and intercellular junctions, while the macrophages had many vacuoles and vesicles, but no intercellular contact with each other. The freeze-fracture image showed that the stromal cells had many low linear elevations and gap junctions on the cleaved plane of the cell membranes, while the macrophages had no linear elevations or intercellular junctions. The cell membranes of the stromal cells had more intramembranous particles (IMP) (P-face 697 +/- 63/micrometers 2, E-face 303 +/- 52/micrometers 2) than those of the macrophages (P-face 467 +/- 50/micrometers 2, E-face 217 +/- 35/micrometers 2). It was confirmed that these two types of cell phagocytosed collagen fibrils.

Animals↗
PubMed1985

Cell-cell junctional interactions and characteristic plasma membrane features of cultured rat glial cells.

Mixed cultures of astrocytes and oligodendrocytes derived from cerebral hemispheres of 18-19 day old rat fetuses were studied with the freeze-fracture technique. The plasma membranes of cultured astrocytes and oligodendrocytes differ substantially in their intramembrane particle profiles, and they can be positively identified consistently. Orthogonal small particle assemblies and numerous isolated globular particles characterize astrocytic plasma membranes, whereas the plasma membranes of oligodendrocytes show numerous elongated particles and fewer large and small globular particles similar to those seen in situ. Using these distinct differential features, we can identify partners of glial cell junctions. We can identify numerous interastrocytic gap junctions, as well as heterologous astrocyte-to-oligodendrocyte gap junctions. The plasma membranes of adjacent oligodendrocytes form numerous tight junctions consisting of linear P face strands and/or rows of particles interrupted by short segments of grooves, the complementary features on the E face. "Reflexive" type tight junctions seen in situ are also observed. In addition to intercellular junctions, glial cells develop special plasma membrane structural domains. Astrocytic plasma membranes often contain groups of plasmalemmal vesicles (caveolae), a distinctive feature of astrocytes in situ. Oligodendrocytes form flattened velate processes with cytoplasm restricted to finger-like channels resembling myelin lamellae in situ. Cultured astrocytes and oligodendrocytes develop the entire range of plasma membrane structural specializations seen in situ in the absence of the normal brain tissue framework. Thus, primary glial cell cultures allow experimental study of many glial cell properties, including their plasma membrane specializations.

Animals↗
PubMed1979

Gap and tight junctions in tunicates. Study in conventional and freeze-fracture techniques.

Intercellular junctions have been investigated in epidermis and pharyngeal epithelium of larvae and adults of various species of tunicates with conventional and freeze-fracture techniques. Gap and tight junctions were found, similar to those observed in vertebrate tissues. Gap junctions were frequent in glandular epithelia and in larval tissues. They were interpreted as ways of intercellular communication in these developing tissues. They were also particularly numerous in Phallusia pharyngeal cells. Tight junctions were found preferentially in adult pharyngeal and epidermal epithelia, where they were arranged in strands of distinct particles forming a belt-like network at the apical part of cells. These junctions were interpreted as providing a tight barrier between the internal medium and the external environment. In larvae, tight junctions were found only between epidermal cells of the tail. These junctions thus characterized completely differentiated tissues, where they might play, in tunicates and in vertebrates, the same role as septate junctions do in invertebrates.

Animals↗
PubMed1981

Structure and function of the junctional complement of spontaneous and transplanted murine mammary carcinomas.

In this study the morphology of intercellular junctions in a murine mammary adenocarcinoma and in a solid carcinoma which resulted from continuous transplantations of this spontaneous tumor are described employing the techniques of ultrathin-sectioning after conventional fixation and tannic acid fixation and freeze-fracturing. The acini of the original adenocarcinoma are separated from the intercellular spaces by tight junctions which form a narrow belt-like zonula around the adluminal parts of all epithelial cells. The apical-to-basal width of the tight junctions varies from 0.4 to 0.8 micrometer. Desmosomes and gap junctions are located close to the zonulae occludentes. The size of gap junctions ranges from small spots 0.2 micrometer in diameter to large areas approximately 1.5 micrometer in diameter. In the solid carcinoma these cellular junctions appear without acinar organization randomly between the cells. In addition, special contact zones can be observed. The contact zones seem to be the precursors of a formation plaque for gap or tight junction formation. The sizes of the gap junctions show a wide range of variation, from as small as 5 particles to as large as 0.5 micrometer in diameter. Tight junctions do not form continuous belt-like zonulae indicating that they have lost their significance as a permeability barrier. They are interpreted as mechanical links. In addition to isolated gap junctions and tight junctions there exist gap junctions adjacent to tight junction fibrils suggesting a probable biogenetic relationship of these two structures.

Adenocarcinoma↗
PubMed1980

Intramembrane events accompanying junction formation in a liver cell line.

To study intramembrane events leading to the establishment of intercellular junctions between epithelial cells in vitro, we examined monolayer cultures of a rat liver cell line by an in situ freeze-fracturing technique (Pauli et al., J. Cell Biol., 72:763, 1977). Our observations indicate that an early step of junction formation between liver cells consists of the differentiation of a particle-poor membrane stretch showing a honeycomb pattern of shallow P-face depressions or E-face bulges ("formation band"). This change in membrane organization precedes and accompanies the subsequent aggregation of junctional particles. The latter process results in the formation of irregular particle islands with peripheral branchings which tend to encompass the depressions in the membrane. The linear branchings grow and interconnect in a network of beaded strands, which gradually transform into smooth tight junctional fibrils, as previously described in fetal liver in vivo (Montesano et al., J. Cell Biol., 67:310, 1975), while the particle islands assume the typical configuration of mature gap junctions. Formation bands are particularly prominent between liver cells growth in the presence of hydrocortisone (5 microgram/ml) in the culture medium.

Animals↗
PubMed1995

Freeze-fracture studies of interendothelial junctions in the angle of the human eye.

PURPOSE: The aim of this study was to determine the structure and complexity of the intercellular junctions between trabecular endothelial cells and Schlemm's canal endothelial (SCE) cells as they exist in the normal human eye. Despite the probable relevance of these junctions to aqueous outflow, examination of these junctions has been limited to monkey eyes. METHODS: Human eyes (< 24 hours after death) were fixed by immersion in modified Karnovsky's fluid. Radially oriented tissue-chopper sections (190 microns) were trimmed to contain only the trabecular meshwork, Schlemm's canal, and a narrow strip of the sclera. Specimens were processed for conventional electron microscopy and freeze-fracture. Replicas were produced in a freeze-fracture apparatus operated at -115 degrees C and 10(-7) torr. Thin sections were stained with uranyl acetate and lead citrate. Micrographs were taken on a transmission electron microscope. RESULTS: The trabecular endothelial cells were joined by gap junctions and short discontinuous junctional strands that partitioned predominantly with P-face. The strand pattern varied from short and isolated undulating strands to radiating arrays of short junctional strands. No continuous zonulae occludentes were observed. The SCE cells were joined by continuous tight junctions (tj) composed of discontinuous strands that rarely branched or anastomosed. The tj strands fractured preferentially with the E-face, where they were positioned at the bases of shallow valleys. On the P-face, a complementary system of shallow ridges was observed with few particles at their crests. Often, only a single continuous strand was present for long distances, with occasional short discontinuous strands running parallel to the single strand. Less often, short lengths of remarkably complex junctions, which occasionally branched or anastomosed, were also encountered. When more than one strand was present, numerous free endings and transjunctional pathways, described in monkey eyes as "slit-pores," were evident. CONCLUSION: The overall structure of the junctions between endothelial cells of Schlemm's canal in the human eye was more complex, and thus less permeable, than that reported in the monkey eye. The role of slit-pores and other junctions of SCE and trabecular endothelial cells will require further investigation under conditions of flow and in glaucoma to determine if these junctions change in a manner that might influence outflow resistance.

Adult↗