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143
Disruption of Epithelial Cell-Matrix Interactions Induces Apoptosis
"... Abstract. Cell-matrix interactions have major effects upon phenotypic features such as gene regulation, cytoskeletal structure, differentiation, and aspects of cell growth control. Programmed cell death (apoptosis) is crucial for maintaining appropriate cell number and tissue organization. It was th ..."
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Cited by 157 (1 self)
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Abstract. Cell-matrix interactions have major effects upon phenotypic features such as gene regulation, cytoskeletal structure, differentiation, and aspects of cell growth control. Programmed cell death (apoptosis) is crucial for maintaining appropriate cell number and tissue organization. It was therefore of interest to determine whether cell-matrix interactions affect apoptosis. The present report demonstrates that apoptosis was induced by disruption of the interactions between normal epithelial cells and extracellular matrix. We have termed this phenomenon "anoikis " Overexpression of bcl-2 protected cells againstanoikis. Cel-lular sensitivity to anoikis was apparently regulated: (a) anoikis did not occur in normal fibroblasts; (b) it was abrogated in epithelial cells by transformation with v-Ha-ras, v-src, or treatment with phorbol ester; (c) sensitivity to anoikis was conferred upon HTI080 cells or v-Ha-ms-transformed MDCK ceils by reversetransformation with adenovirus Ela; (d) anoikis in MDCK cells was alleviated by the motility factor, scatter factor. The results suggest that the circumvention of anoikis accompanies the acquisition of anchorage independence or cell motility. C ELL-matrix interactions have major effects upon phenotypic features such as gene regulation; cytoskeletal structure, differentiation, and aspects of cell growth control (Adams and Watt, 1993; Blau and Baltimore, 1991; Ingber, 1993). In particular, determination of anchorage dependence is an important function of cell-matrix interactions. The restriction of cell proliferation to matrixinteracting cells serves to prevent dysplasia; the circumvention of anchorage dependence plays an important role in tumorigenesis (Stoker et al., 1968). In previous studies, the growth arrest induced by suspension of fibroblasts was found to be reversible (Folkman and Moscona, 1978; Ben-Ze'ev et al., 1980). However, the fate of other cell types challenged similarly was not examined.
The small GTPases Rho and Rac are required for the establishment of cadherindependent cell–cell contacts
- J. Cell
, 1997
"... Abstract. Cadherins are calcium-dependent cell–cell adhesion molecules that require the interaction of the cytoplasmic tail with the actin cytoskeleton for adhesive activity. Because of the functional relationship between cadherin receptors and actin filament organization, we investigated whether me ..."
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Cited by 95 (3 self)
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Abstract. Cadherins are calcium-dependent cell–cell adhesion molecules that require the interaction of the cytoplasmic tail with the actin cytoskeleton for adhesive activity. Because of the functional relationship between cadherin receptors and actin filament organization, we investigated whether members of the Rho family of small GTPases are necessary for cadherin adhesion. In fibroblasts, the Rho family members Rho and Rac regulate actin polymerization to produce stress fibers and lamellipodia, respectively. In epithelial cells, we demonstrate that Rho and Rac are required for the establishment of cadherin-mediated cell–cell adhesion and the actin reorganization necessary to stabilize the receptors at sites of intercellular junctions. Blocking endogenous Rho or Rac selectively removed cadherin
Control of mammary epithelial differentiation: basement membrane induces tissue-specific gene expression in the absence of cell-cell interaction and morphological polarity
- J
, 1991
"... Abstract. Functional differentiation in mammary epithelia requires specific hormones and local environmental signals. The latter are provided both by extracellular matrix and by communication with adjacent cells, their action being intricately connected in what appears to be a cascade of events lead ..."
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Cited by 94 (9 self)
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Abstract. Functional differentiation in mammary epithelia requires specific hormones and local environmental signals. The latter are provided both by extracellular matrix and by communication with adjacent cells, their action being intricately connected in what appears to be a cascade of events leading to milk production. To distinguish between the influence of basement membrane and that of cell-cell contact in this process, we developed a novel suspension culture assay in which mammary epithelial cells were embedded inside physiological substrata. Single cells, separated from each other, were able to assimilate information from a laminin-rich basement membrane substratum and were induced to express 0-casein. In contrast, a stromal environment of collagen I was not sufficient to induce milk synthesis unless accompanied by cell-cell
Recycling of E-cadherin: a potential mechanism for regulating cadherin dynamics
- J. Cell
, 1999
"... Abstract. E-Cadherin plays critical roles in many aspects of cell adhesion, epithelial development, and the establishment and maintenance of epithelial polarity. The fate of E-cadherin once it is delivered to the basolateral cell surface, and the mechanisms which govern its participation in adherens ..."
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Cited by 74 (5 self)
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Abstract. E-Cadherin plays critical roles in many aspects of cell adhesion, epithelial development, and the establishment and maintenance of epithelial polarity. The fate of E-cadherin once it is delivered to the basolateral cell surface, and the mechanisms which govern its participation in adherens junctions, are not well understood. Using surface biotinylation and recycling assays, we observed that some of the cell surface E-cadherin is actively internalized and is then recycled back to the plasma membrane. The pool of E-cadherin undergoing endocytosis and recycling was markedly increased in cells without stable cell-cell contacts, i.e., in preconfluent cells and after cell contacts were disrupted by depletion of extracellular Ca 2 � , suggesting that endocytic trafficking of E-cadherin is regulated by cell-cell
Molecular organization of the uvomorulin–catenin complex
- J. Cell
, 1992
"... Abstract. The Cal+-dependent cell adhesion molecule uvomorulin is a member of the cadherin gene family. Its cytoplasmic region complexes with structurally defined proteins termed a-, ß-, and y-catenins. Here we show that A-CAM (N-cadherin), another member of this gene family, also associates with ca ..."
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Cited by 64 (3 self)
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Abstract. The Cal+-dependent cell adhesion molecule uvomorulin is a member of the cadherin gene family. Its cytoplasmic region complexes with structurally defined proteins termed a-, ß-, and y-catenins. Here we show that A-CAM (N-cadherin), another member of this gene family, also associates with catenins suggesting that this complex formation may be a general property of the cadherins. For uvomorulin it has been found that this association with catenins is of crucial importance for the adhesive function, but little is known about the molecular organization of the uvomorulin-catenin complex. Using a combination of biochemical analyses we show that a single complex is composed of one molecule of uvomorulin, one or two molecules of ß-catenin, and one molecule of a-catenin. Furthermore,
E-cadherin suppresses cellular transformation by inhibiting �-catenin signaling in an adhesion-independent manner
- J. Cell
, 2001
"... Abstract. E-cadherin is a tumor suppressor protein with a well-established role in cell–cell adhesion. Adhesion could contribute to tumor suppression either by physically joining cells or by facilitating other juxtacrine signaling events. Alternatively, E-cadherin tumor suppressor activity could res ..."
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Cited by 58 (8 self)
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Abstract. E-cadherin is a tumor suppressor protein with a well-established role in cell–cell adhesion. Adhesion could contribute to tumor suppression either by physically joining cells or by facilitating other juxtacrine signaling events. Alternatively, E-cadherin tumor suppressor activity could result from binding and antagonizing the nuclear signaling function of �-catenin, a known proto-oncogene. To distinguish between an adhesion-versus a �-catenin signaling–dependent mechanism, chimeric cadherin constructs were expressed in the SW480 colorectal tumor cell line. Expression of wild-type E-cadherin significantly inhibits the growth of this cell line. Growth inhibitory activity is retained by all constructs that have the �-catenin binding region of the cytoplasmic domain but not by E-cadherin constructs that exhibit adhesive activity, but lack the �-catenin binding region. This growth suppression correlates with a reduction in �-catenin/T cell factor (TCF) reporter gene activity. Importantly, direct inhibition of �-catenin/TCF signaling inhibits the growth of SW480 cells, and the growth inhibitory activity of E-cadherin is rescued by constitutively activated forms of TCF. Thus, the growth suppressor activity of E-cadherin is adhesion independent and results from an inhibition of the �-catenin/TCF signaling pathway, suggesting that loss of E-cadherin expression can contribute to upregulation of this pathway in human cancers. E-cadherin–mediated growth suppression was not accompanied by overall depletion of �-catenin from the cytosol and nucleus. This appears to be due to the existence of a large pool of cytosolic �-catenin in SW480 cells that is refractory to both cadherin binding and TCF binding. Thus, a small pool of �-catenin that can bind TCF (i.e., the transcriptionally active pool) can be selectively depleted by E-cadherin expression. The existence of functionally distinct pools of cytosolic �-catenin suggests that there are mechanisms to regulate �-catenin signaling in addition to controlling its level of accumulation. Key words: E-cadherin • tumor suppressor • adhesion • �-catenin • T cell factor
Assembly of the tight junction: the role of diacylglycerol
- J. Cell
, 1993
"... Abstract. Extracellular Ca 2 ÷ triggers assembly and sealing of tight junctions (TJs) in MDCK cells. These events are modulated by G-proteins, phospholipase C, protein kinase C (PKC), and calmodulin. In the present work we observed that 1,2-dioctanoylglycerol (diC8) promotes the assembly of TJ in lo ..."
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Cited by 52 (5 self)
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Abstract. Extracellular Ca 2 ÷ triggers assembly and sealing of tight junctions (TJs) in MDCK cells. These events are modulated by G-proteins, phospholipase C, protein kinase C (PKC), and calmodulin. In the present work we observed that 1,2-dioctanoylglycerol (diC8) promotes the assembly of TJ in low extracellular Ca 2÷, as evidenced by translocation of the TJassociated protein ZO-1 to the plasma membrane, formation of junctional fibrils observed in freeze-fracture replicas, decreased permeability of the intercellular space to [3H]mannitol, and reorganization of actin illaments to the cell periphery, visualized by fluorescence microscopy using rhodamine-phalloidin. In contrast, diC8 in low Ca 2 ÷ did not induce redistribution of the Ca-dependent adhesion protein E-cadherin (uvomoru-
Quantitative analysis of cadherin-catenin-actin reorganization during development of cell–cell adhesion
, 1996
"... Abstract. Epithelial cell--cell adhesion requires interactions between opposing extracellular domains of E-cadherin, and among the cytoplasmic domain of E-cadherin, catenins, and actin cytoskeleton. Little is known about how the cadherin-catenin-actin complex is assembled upon cell-cell contact, or ..."
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Cited by 46 (2 self)
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Abstract. Epithelial cell--cell adhesion requires interactions between opposing extracellular domains of E-cadherin, and among the cytoplasmic domain of E-cadherin, catenins, and actin cytoskeleton. Little is known about how the cadherin-catenin-actin complex is assembled upon cell-cell contact, or how these complexes initiate and strengthen adhesion. We have used timelapse differential interference contrast (DIC) imaging to observe the development of cell-cell contacts, and quantitative retrospective immunocytochemistry to measure recruitment of proteins to those contacts. We show that E-cadherin, a-catenin, and [3-catenin, but not plakoglobin, coassemble into Triton X-100 insoluble (TX-insoluble) structures at cell-cell contacts with kinetics similar to those for strengthening of E-cadherinmediated
The catenin/cadherin adhesion system is localized in synaptic junctions bordering transmitter release zones
- J. Cell
, 1996
"... Abstract. Molecular mechanisms linking pre- and postsynaptic membranes at the interneuronal synapses are little known. We tested the cadherin adhesion system for its localization in synapses of mouse and chick brains. We found that two classes of cadherin-associated proteins, aN- and 13-catenin, are ..."
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Cited by 45 (4 self)
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Abstract. Molecular mechanisms linking pre- and postsynaptic membranes at the interneuronal synapses are little known. We tested the cadherin adhesion system for its localization in synapses of mouse and chick brains. We found that two classes of cadherin-associated proteins, aN- and 13-catenin, are broadly distributed in adult brains, colocalizing with a synaptic marker, synaptophysin. At the ultrastructural level, these proteins were localized in synaptic junctions of various types, forming a symmetrical adhesion structure. These structures sharply bordered the transmitter release sites associated with synaptic vesicles, although their segregation was less clear in certain types of synapses. N-cadherin was also localized at a similar site of synaptic junctions but in restricted brain nuclei. In developing
Binding to cadherins antagonizes the signaling activity of beta-catenin during axis formation in Xenopus
- J. Cell
, 1996
"... Abstract. 13-Catenin, a cytoplasmic protein known for its association with cadherin cell adhesion molecules, is also part of a signaling cascade involved in embryonic patterning processes such as the determination of the dorsoventral axis in Xenopus and determination of segment polarity in Drosophil ..."
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Cited by 43 (13 self)
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Abstract. 13-Catenin, a cytoplasmic protein known for its association with cadherin cell adhesion molecules, is also part of a signaling cascade involved in embryonic patterning processes such as the determination of the dorsoventral axis in Xenopus and determination of segment polarity in Drosophila. Previous studies suggest that increased cytoplasmic levels of 13-catenin correlate with signaling, raising questions about the need for interaction with cadherins in this process. We have tested the role of the 13-catenin-cadherin interaction in axis formation. Using [3-catenin deletion mutants, we dem-onstrate that significant binding to cadherins can be eliminated without affecting the signaling activity. Also, depletion of the soluble, cytosolic pool of 13-catenin by binding to overexpressed C-cadherin completely inhibited [3-catenin-inducing activity. We conclude that binding to cadherins is not required for [3-catenin signaling, and therefore the signaling function of [3-catenin is independent of its role in cell adhesion. Moreover, because 13-catenin signaling is antagonized by binding to cadherins, we suggest that cadherins can act as regulators of the intracellular [3-catenin signaling pathway. C ELLS respond to environmental stimuli by generating intracellular signaling cascades, which modify cellular functions including gene expression. While soluble molecules such as growth factors are classical examples of such stimuli, it is obvious that cells also sense direct physical contact, both with the substrate and with neighboring cells. For instance, it is well established that cell-substrate adhesion, mediated by membrane receptors of the integrin family, is at the same time both a source and recipient of intracellular signals (Schwartz et al., 1995). The integration of cell-cell adhesion events and intracellular signals is less well understood. However, cellcell adhesion also appears to be both regulatable (Brieher
