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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptotic cells undergo specific morphological changes that include loss of cell-cell interactions. Cellular adhesiveness is dependent on members of the cadherin family of adhesion receptors and on the cytoplasmic adaptor proteins alpha-catenin, beta-catenin and gamma-catenin/plakoglobin. The caspase family of cystein proteases play a key role during the execution phase of the apoptotic program. These proteolytic enzymes, once activated, cleave cellular proteins which are important for the maintenance of cell integrity. Here we report that gamma-catenin is cleaved at different sites during apoptosis in various cell lines. The major apoptotic product of gamma-catenin still retains the ability to bind alpha-catenin but loses the carboxy-terminal region. We also show that gamma-catenin is cleaved by caspase-3 in vitro although with lower affinity when compared to PARP or beta-catenin. These findings indicate that multiple proteolytic events regulate the dismantling of the cell-cell junctional complexes during apoptosis.
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PMID:Proteolytic processing of the adherens junctions components beta-catenin and gamma-catenin/plakoglobin during apoptosis. 989 11

Cleavage of structural proteins by caspases has been associated with the severe morphological changes occurring during the apoptotic process. One of the proteins regulating the connection of the actin filament with cadherins in a cell-cell adhesion complex is beta-catenin. During apoptosis, both an N-terminal and a small C-terminal part are removed from beta-catenin. Removal of the N-terminal part may result in a disconnection of the actin filament from a cadherin cell-cell adhesion complex. We demonstrate that caspase-8, -3 and -6 directly proteolyse beta-catenin in vitro. However, the beta-catenin cleavage products generated by caspase-8 were different from those generated by caspase-3 or caspase-6. Caspase-1, -2, -4/11 and -7 did not or only very inefficiently cleave beta-catenin. These data suggest that activation of procaspase-3, -6 or -8 by different stimuli in the cell might result in a differential proteolysis of beta-catenin.
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PMID:Proteolytic cleavage of beta-catenin by caspases: an in vitro analysis. 1048 Oct 58

Apoptotic cell death induces dramatic molecular changes in cells, becoming apparent on the structural level as membrane blebbing, condensation of the cytoplasm and nucleus, and loss of cell-cell contacts. The activation of caspases is one of the fundamental steps during programmed cell death. Here we report a detailed analysis of the fate of the Ca(2+)-dependent cell adhesion molecule E-cadherin in apoptotic epithelial cells and show that during apoptosis fragments of E-cadherin with apparent molecular masses of 24, 29, and 84 kDa are generated by two distinct proteolytic activities. In addition to a caspase-3-mediated cleavage releasing the cytoplasmic domain of E-cadherin, a metalloproteinase sheds the extracellular domain from the cell surface during apoptosis. Immunofluorescence analysis confirmed that concomitant with the disappearance of E-cadherin staining at the cell surface, the E-cadherin cytoplasmic domain accumulates in the cytosol. In the presence of inhibitors of caspase-3 and/or metalloproteinases, cleavage of E-cadherin was almost completely blocked. The simultaneous cleavage of the intracellular and extracellular domains of E-cadherin may provide a highly efficient mechanism to disrupt cadherin-mediated cell-cell contacts in apoptotic cells, a prerequisite for cell rounding and exit from the epithelium.
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PMID:Cleavage and shedding of E-cadherin after induction of apoptosis. 1107 37

Cell adhesion is important in the regulation of cell proliferation, migration, survival, and apoptosis. The major components of cell adhesion are the cadherin family of proteins, alpha-, beta- and gamma-catenins, and cytoskeletons. In addition, beta-catenin, when associated with adenomatous polyposis coli (APC) protein, an oncosuppressor, is implicated in the regulation of beta-catenin/APC-related signaling pathways. To examine the correlation between impairment of cell adhesion events and apoptosis, we used human non-small-cell lung cancer H460 and H520 cell lines as models to determine whether paclitaxel-induced apoptosis is associated with disruption of the components of cell adhesion and their functions. Paclitaxel treatment resulted in cells rounding up and losing contact with their neighboring cells, suggesting that the drug does indeed affect cell adhesion and related events. Western blot analysis revealed that paclitaxel caused a time- and concentration-dependent cleavage of beta-catenin, gamma-catenin, and APC protein, but not alpha-catenin or E-cadherin. These cleavages of beta-catenin and gamma-catenin were apoptosis-dependent, not mitosis-dependent. Paclitaxel treatment led to the proteolysis and activation of caspase-3 and -7, but not caspase-1. Furthermore, paclitaxel-induced apoptosis and cleavage of beta-catenin and gamma-catenin were inhibited by the pan-caspase inhibitor Z-VAD-FMK and partially inhibited by the caspase-3 inhibitor Z-DEVD-FMK but were not affected by the caspase-1 inhibitor AC-YVAD-CMK. Although the pan-caspase inhibitor blocked the cleavage of beta-catenin as well as DNA fragmentation, it did not affect paclitaxel-induced M-phase arrest and only partially prevented cell-growth inhibition. Biochemical studies revealed that cleaved beta-catenin was detected only in the Triton X-100 insoluble fraction, suggesting that it might localize in nuclear and/or membrane structures. Interestingly, the paclitaxel-induced beta-catenin fragment lost its ability to bind to E-cadherin, alpha-catenin, or APC protein and to serve as a substrate for tyrosine kinase. All our data demonstrate that the caspase-mediated cleavage of beta-catenin, gamma-catenin, and APC protein might contribute to paclitaxel-induced apoptosis.
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PMID:Disruption of cell adhesion and caspase-mediated proteolysis of beta- and gamma-catenins and APC protein in paclitaxel-induced apoptosis. 1117 55

As transmembrane, Ca2+-dependent cell-cell adhesion molecules, cadherins play a central role in tissue morphogenesis and homeostasis. Stable adhesion is dependent on interactions of the cytoplasmic domain of the cadherins with a group of intracellular proteins, the catenins. In the present study, we have detected the expression of alpha-, beta-, and gamma-catenins in human osteoblasts, which assemble with cadherins to form two distinct complexes containing cadherin and alpha-catenin, with either beta- or gamma-catenin. In osteoblasts undergoing apoptosis, proteolytic cleavage of N-cadherin and beta- and gamma- catenins but not alpha-catenin was associated with the activation of caspase-3 and prevented by the caspase inhibitor Z-VAD-fmk. The pattern of cadherin/catenin cleavage detected in apoptotic osteoblasts was reproduced in vitro by recombinant caspase-3. The presence of a 90-kDa extracellular domain fragment of N-cadherin in conditioned medium from apoptotic cells indicates that additional extracellular or membrane-associated proteases also are activated. Disruption of N-cadherin-mediated cell-cell adhesion with function-blocking antibodies induced osteoblast apoptosis, activation of caspases, and cleavage of beta-catenin. These findings provide compelling evidence that N-cadherin-mediated cell-cell adhesion promotes osteoblast survival and suggest that the underlying mechanism may involve activation of beta-catenin signaling.
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PMID:Caspase-dependent cleavage of cadherins and catenins during osteoblast apoptosis. 1127 64

Alpha-catenin, an intracellular protein, associates with the COOH-terminal region of cadherin cell adhesion molecules through interactions with either beta-catenin or gamma-catenin (plakoglobin). The full activity of cadherins requires a linkage to the actin cytoskeleton mediated by catenins. We transfected alpha-catenin-deficient colon carcinoma cells with a series of alpha-catenin constructs to determine that alpha-catenin expression increases the resistance to apoptosis induced by sphingosine. Two groups of constructs, containing deletions in either the middle segment of the molecule or the COOH terminus, induced morphological changes, cell compaction, and decreases in cell death. In alpha-catenin-expressing cells, inhibition of cadherin cell adhesion by treatment with anti-E-cadherin antibodies did not decrease the cells viability. alpha-Catenin expression partially suppressed the downregulation of Bcl-xL and the activation of caspase 3. Expression of p27kip1 protein, an inhibitor of cyclin-dependent kinases, was increased by alpha-catenin expression in low density cell cultures. The increased levels of p27kip1 correlated with both increased resistance to cell death and morphological changes in transfectants containing deletion mutants. Transfection-mediated upregulation of p27kip1 decreases sphingosine-induced cell death in alpha-catenin-deficient cells. We postulate that alpha-catenin mediates transduction of signals from the cadherin-catenin complex to regulate the apoptotic cascade via p27kip1.
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PMID:Expression of alpha-catenin in alpha-catenin-deficient cells increases resistance to sphingosine-induced apoptosis. 1148 17

Activation of caspases results in the disruption of structural and signaling networks in apoptotic cells. Recent biochemical and cell biological studies have shown that components of the cadherin-catenin adhesion complex in epithelial adherens junctions are targeted by caspases during apoptosis. In epithelial cells, desmosomes represent a second type of anchoring junctions mediating strong cell-cell contacts. Using antibodies directed against a set of desmosomal proteins, we show that desmosomes are proteolytically targeted during apoptosis. Desmogleins and desmocollins, representing desmosome-specific members of the cadherin superfamily of cell adhesion molecules, are specifically cleaved after onset of apoptosis. Similar to E-cadherin, the desmoglein-3 cytoplasmic tail is cleaved by caspases. In addition the extracellular domains of desmoglein-3 and desmocollin-3 are released from the cell surface by a metalloproteinase activity. In the presence of caspase and/or metalloproteinase inhibitors, both cleavage reactions are almost completely inhibited. As reported previously, the desmosomal plaque protein plakoglobin is cleaved by caspase-3 during apoptosis. Our studies now show that plakophilin-1 and two other major plaque proteins, desmoplakin-1 and -2, are also cleaved by caspases. Immunofluorescence analysis confirmed that this cleavage results in the disruption of the desmosome structure and thus contributes to cell rounding and disintegration of the intermediate filament system.
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PMID:The fate of desmosomal proteins in apoptotic cells. 1150 May 11

The early 4 region (E4) of the adenoviral vectors (AdE4(+)) prolongs human endothelial cell (EC) survival and alters the angiogenic response, although the mechanisms for the EC-specific, AdE4(+)-mediated effects remain unknown. We hypothesized that AdE4(+) modulates EC survival through activation of the vascular endothelial (VE)-cadherin/Akt pathway. Here, we showed that AdE4(+), but not AdE4(-) vectors, selectively stimulated phosphorylation of both Akt at Ser(473) and Src kinase in ECs. The phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 and wortmannin abrogated AdE4(+) induction of both phospho-Akt expression and prolonged EC survival. Regulation of phospho-Akt was found to be under the control of various factors, namely VE-cadherin activation, Src kinase, tyrosine kinase, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). Downstream targets of Akt signaling resulted in glycogen synthase kinase-3alpha/beta phosphorylation, beta-catenin up-regulation, and caspase-3 suppression, all of which led to AdE4(+)-mediated EC survival. Furthermore, infection with AdE4(+) vectors increased the angiogenic potential of ECs by promoting EC migration and capillary tube formation in Matrigel plugs. This selective AdE4(+)-mediated enhanced motility of ECs was also blocked by PI3K inhibitors. Taken together, these results suggest that activation of the VE-cadherin/Akt pathway is critical for AdE4(+)-mediated survival of ECs and angiogenic potential.
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PMID:Adenovirus E4 gene promotes selective endothelial cell survival and angiogenesis via activation of the vascular endothelial-cadherin/Akt signaling pathway. 1466 May 86

The ability of keratinocyte growth factor 1 to modulate apoptosis in the absence of proliferation was studied in vitro. A HaCaT scrape wound model was developed in which dense monolayers prior to wounding were cultured to quiescence in defined media with hydroxyurea at concentrations that blocked proliferation without loss of cell viability. Scrape wounding was then found to induce apoptosis, originating at the wound edge, but subsequently radiating away over a 24 h period to encompass areas not originally damaged. Keratinocyte growth factor 1 inhibited this radial progression of apoptosis in a concentration-dependent manner up to 20 ng per mL with induced migration present at the wound edge. The extent of this rescue was modulated by the concentration of Ca2+ prior to wounding. In control wound cultures apoptotic bodies were found in cells adjacent to the wound interface but were greatly reduced in keratinocyte-growth-factor-1-treated groups. Keratinocyte growth factor 1 receptor expression was significantly induced within two to three cell widths of the scraped wound edge, at levels far exceeding those found at the leading edge of a nonwounded epithelial sheet. Tumor necrosis factor alpha (1-5 ng per mL) or Escherichia coli lipopolysaccharide (10-50 ng per mL) exacerbated scrape-induced early apoptosis (1-4 h), but was largely ameliorated by coculture with keratinocyte growth factor 1. Keratinocyte growth factor 1 protection was associated with a reduction in both caspase-3 activation and cytokeratin-19 loss. Protected wound edges were also associated with the maintenance of e-cadherin expression and induction of beta1 integrin and actin stress fiber organization. These results suggest that keratinocyte growth factor 1 may play a role in limiting mechanically induced apoptotic processes at the epithelial wound edge in a manner that is distinct from its proliferative function.
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PMID:Keratinocyte growth factor 1 inhibits wound edge epithelial cell apoptosis in vitro. 1496 12

Although ischemia has been shown to disrupt cell adhesion, the underlying molecular mechanism is unknown. In these studies, we adapted a model of ischemia-reperfusion to normal rat kidney (NRK) cells, examined disruption of the cadherin/catenin complex, and identified a role for matrix metalloproteinases (MMPs) in ischemia-induced cleavage of cadherins. In NRK cells, ischemia was induced by applying a thin layer of PBS solution supplemented with calcium and magnesium and a layer of mineral oil, which restricts exposure to oxygen. NRK cells exhibited extracellular 80-kDa and intracellular 40-kDa E-cadherin fragments after 4 h of ischemia, and at 6 h the expression of full-length E-cadherin decreased. While no fragments of N-cadherin, alpha-catenin, and gamma-catenin were observed at any time point, the detectable levels of these proteins decreased during ischemia. Ischemia was detected by an increase in pimonidazole adducts, as well as an increase in glucose transporter-1 protein expression. Ischemia did not decrease cell number, but there was a decrease in ATP levels. In addition, there was no evidence of cleaved caspase 3 or 9 during 6 h of ischemia. The MMP inhibitors GM-6001 and TAPI-O inhibited cleavage and/or loss of E- and N-cadherin protein expression. Tissue inhibitors of metalloproteinases (TIMP)-3 and to a lesser extent TIMP-2, but not TIMP-1, inhibit ischemic cleavage and/or loss of E- and N-cadherin. These results demonstrate that ischemia induces a selective metalloproteinase-dependent cleavage of E-cadherin and decrease in N-cadherin that are associated with a disruption of junctional contacts.
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PMID:Ischemia-induced cleavage of cadherins in NRK cells: evidence for a role of metalloproteinases. 1576 36


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