Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many cells (e.g., epithelial cells) require attachment to the extracellular matrix (ECM) to survive, a phenomenon known as anchorage-dependent cell survival. Disruption of the cell-ECM interactions mediated by the integrin receptors results in apoptosis. Focal adhesion kinase (FAK), a 125-kD protein tyrosine kinase activated by integrin engagement, appears to be involved in mediating cell attachment and survival. Proline-rich tyrosine kinase 2 (PYK2), also known as cellular adhesion kinase beta (CAKbeta) and related adhesion focal tyrosine kinase, is a second member of the FAK subfamily and is activated by an increase in intracellular calcium levels, or treatment with TNFalpha and UV light. However, the function of PYK2 remains largely unknown. In this study, we show that over-expression of PYK2, but not FAK, in rat and mouse fibroblasts leads to apoptotic cell death. Using a series of deletion mutants and chimeric fusion proteins of PYK2/FAK, we determined that the NH2-terminal domain and tyrosine kinase activity of PYK2 were required for the efficient induction of apoptosis. Furthermore, the apoptosis mediated by PYK2 could be suppressed by over-expressing catalytically active v-Src, c-Src, phosphatidylinositol-3-kinase, or Akt/protein kinase B. In addition, it could also be suppressed by overexpressing an ICE or ICE-like proteinase inhibitor, crmA, but not Bcl2. Collectively, our results suggest that PYK2 and FAK, albeit highly homologous in primary structure, appear to have different functions; FAK is required for cell survival, whereas PYK2 induces apoptosis in fibroblasts.
 ...
PMID:Induction of apoptosis after expression of PYK2, a tyrosine kinase structurally related to focal adhesion kinase. 933 54

Fas ligand/Fas receptor molecular interactions have been implicated as having an important function for the regulation of eosinophil apoptosis. The purpose of the present study was to investigate biochemical events triggered by the engagement of the Fas receptor in freshly isolated human and mouse eosinophils. Activation of the Fas receptor on eosinophils with the agonistic anti-Fas monoclonal antibody (MoAb) resulted in increased tyrosine phosphorylation of several intracellular proteins. The tyrosine kinase inhibitors lavendustin A and genistein inhibited Fas receptor-induced cell death in both human and mouse eosinophils in vitro and prevented, at least partially, Fas receptor-mediated resolution of eosinophilic inflammation in a mouse in vivo model of lung eosinophilia. In addition, in freshly purified human eosinophils, lavendustin A prevented anti-Fas MoAb-induced proteolytic cleavage of lamin B, suggesting that tyrosine kinases may amplify the proteolytic signaling cascade within interleukin-1beta converting enzyme (ICE) family proteases. Moreover, the tyrosine kinase Lyn was identified as being involved in Fas receptor-mediated cell death. Collectively, these results demonstrate that tyrosine phosphorylation is an important step in the generation of the Fas receptor-linked transmembrane death signal in eosinophils and that Lyn participates in this pathway.
 ...
PMID:Role for tyrosine phosphorylation and Lyn tyrosine kinase in fas receptor-mediated apoptosis in eosinophils. 965 55

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.
 ...
PMID:Disruption of cell adhesion and caspase-mediated proteolysis of beta- and gamma-catenins and APC protein in paclitaxel-induced apoptosis. 1117 55

In addition to direct activation of caspase-1 and induction of apoptosis by SipB, invasive Salmonella stimulates multiple signaling pathways that are key regulators of host cell survival. Nevertheless, little is known about the relative contributions of these pathways to Salmonella-mediated death of macrophages. We studied human monocytic U937 cells and found that apoptosis was induced by invading wild-type Salmonella typhimurium but not by phagocytosed, serum-opsonized, noninvasive Salmonella mutants. Pretreating U937 cells with inhibitors of tyrosine kinases or phosphatidylinositol-3 kinase (PI-3K) completely blocked phagocytosis of opsonized Salmonella mutants but did not affect invasion by wild-type Salmonella or the apoptosis caused by invasion. However, pretreatment with GGTI-298, a geranylgeranyltransferase-1 inhibitor that prevents prenylation of Cdc42 and Rac1, suppressed Salmonella-induced apoptosis by approximately 70%. Transduction of Tat fusion constructs containing dominant-negative Cdc42 or Rac1 significantly inhibited Salmonella-induced cell death, indicating that the cytotoxicity of Salmonella requires activation of Cdc42 and Rac. In contrast to phagocytosis of opsonized bacteria, invasion by S. typhimurium stimulated Cdc42 and Rac1, regardless of the activities of tyrosine- or PI-3K. Moreover, Salmonella infection activated Akt protein in a tyrosine-kinase or PI-3K-dependent manner, and a reduced expression of Akt by antisense transfection rendered the cells more sensitive to apoptosis induced by opsonized Salmonella. These results indicate that direct activation of Cdc42 and Rac1 by invasive Salmonella is a prerequisite of Salmonella-mediated death of U937 cells, whereas the simultaneous activation of Akt by tyrosine kinase and PI-3K during receptor-mediated phagocytosis protects cells from apoptosis.
 ...
PMID:Differential effects of invasion by and phagocytosis of Salmonella typhimurium on apoptosis in human macrophages: potential role of Rho-GTPases and Akt. 1296 Feb 45

The hematopoietic cell kinase Hck is a Src family tyrosine kinase expressed in cells of myelomonocytic lineage, B lymphocytes, and embryonic stem cells. To study its role in signaling pathways we used the Hck-SH3 domain in protein interaction cloning and identified C3G, the guanine nucleotide exchange factor for Rap1 and R-Ras, as a protein that associated with Hck. This interaction was direct and was mediated partly through the proline-rich region of C3G. C3G could be co-immunoprecipitated with Hck from Cos-1 cells transfected with Hck and C3G. C3G was phosphorylated on tyrosine 504 in cells when coexpressed with Hck but not with a catalytically inactive mutant of Hck. Phosphorylation of endogenous C3G at Tyr-504 was increased by treatment of human myelomonocytic THP-1 cells with mercuric chloride, which is known to activate Hck tyrosine kinase specifically. Coexpression of Hck with C3G induced a high level of apoptosis in many cell lines by 30-42 h of transfection. Induction of apoptosis was not dependent on Tyr-504 phosphorylation or the catalytic domain of C3G but required the catalytic activity of Hck. Using dominant negative constructs of caspases we found that caspase-1, -8, and -9 are involved in this apoptotic pathway. These results suggest that C3G and Hck interact physically and functionally in vivo to activate kinase-dependent and caspase-mediated apoptosis, which is independent of catalytic domain of C3G.
 ...
PMID:Physical and functional interaction between Hck tyrosine kinase and guanine nucleotide exchange factor C3G results in apoptosis, which is independent of C3G catalytic domain. 1455 Nov 97

Helicobacter pylori (Hp) can induce apoptosis of gastric cancer cells. The mechanism of the process still needs further elucidating. This study was aimed to analyse the mechanism through which Hp induce apoptosis in human gastric cancer cell line BGC-823. The extract from VacA(+) and CagA(+) Helicobacter pylori strain NCTC11637 was applied to induce apoptosis. The expression, breakdown, and phosphorylation of proteins were probed by Western blotting with specific antibodies. Apoptosis of the cells was detected by flow cytometry. The results showed that incubating the cells with Hp extract caused the breakdown of both caspase-3 and -1. The breakdown was dose-dependent and correlated with the occurrence of the Hp extract-induced apoptosis. Among the substrates of caspase-3, DNA fragment factor (DFF) was degraded during incubation with Hp extract and a small fragment was released. However, poly(ADP-ribose) polymerase (PARP) did not break down during the incubation. Tyrosine kinase inhibitor Genistein prevented both the break down of caspase-3 and the apoptosis induced by Hp extract. MAPK/ERK inhibitor PD98059 did not prevent the apoptosis induced by Hp extract. The expression and activity of JNK, and the expression of Bcl-2 and Fas proteins did not change during the incubation with Hp extract. The results suggested that Hp extract initiated apoptosis in BGC-823 cells through activating tyrosine kinase, caspase-1, -3, and DFF.
 ...
PMID:Analysis on the mechanism of Helicobacter pylori-induced apoptosis in gastric cancer cell line BGC-823. 1614 14

Macrophages are unique innate immune cells that play an integral role in the defense of the host by virtue of their ability to recognize, engulf, and kill pathogens while sending out danger signals via cytokines to recruit and activate inflammatory cells. It is becoming increasingly clear that purinergic signaling events are essential components of the macrophage response to pathogen challenges and disorders such as sepsis may be, at least in part, regulated by these important sensors. The activation of the P2X(7) receptor is a powerful event in the regulation of the caspase-1 inflammasome. We provide evidence that the inflammasome activation requires "priming" of macrophages prior to ATP activation of the P2X(7)R. Inhibition of the inflammasome activation by the tyrosine kinase inhibitor, AG126, suggests regulation by phosphorylation. Finally, the P2X(7)R may also be activated by other elements of the host response such as the antimicrobial peptide LL-37, which adds a new, physiologically relevant agonist to the P2X(7)R pathway. Therapeutic approaches to inflammation and sepsis will certainly be enhanced by an increased understanding of how purinergic receptors modulate the inflammasomes.
 ...
PMID:P2X(7) receptor and macrophage function. 1921 78

The intraerythrocytic parasite Plasmodium -- the causative agent of malaria -- produces an inorganic crystal called hemozoin (Hz) during the heme detoxification process, which is released into the circulation during erythrocyte lysis. Hz is rapidly ingested by phagocytes and induces the production of several pro-inflammatory mediators such as interleukin-1beta (IL-1beta). However, the mechanism regulating Hz recognition and IL-1beta maturation has not been identified. Here, we show that Hz induces IL-1beta production. Using knockout mice, we showed that Hz-induced IL-1beta and inflammation are dependent on NOD-like receptor containing pyrin domain 3 (NLRP3), ASC and caspase-1, but not NLRC4 (NLR containing CARD domain). Furthermore, the absence of NLRP3 or IL-1beta augmented survival to malaria caused by P. chabaudi adami DS. Although much has been discovered regarding the NLRP3 inflammasome induction, the mechanism whereby this intracellular multimolecular complex is activated remains unclear. We further demonstrate, using pharmacological and genetic intervention, that the tyrosine kinases Syk and Lyn play a critical role in activation of this inflammasome. These findings not only identify one way by which the immune system is alerted to malarial infection but also are one of the first to suggest a role for tyrosine kinase signaling pathways in regulation of the NLRP3 inflammasome.
 ...
PMID:Malarial hemozoin activates the NLRP3 inflammasome through Lyn and Syk kinases. 1969 95

Francisella tularensis is a highly infectious intracellular bacterium that causes the fulminating disease tularemia, which can be transmitted between mammals by arthropod vectors. Genomic studies have shown that the F. tularensis has been undergoing genomic decay with the most virulent strains having the lowest number of functional genes. Entry of F. tularensis into macrophages is mediated by looping phagocytosis and is associated with signalling through Syk tyrosine kinase. Within macrophages and arthropod-derived cells, the Francisella-containing phagosome matures transiently into an acidified late endosome-like phagosome with limited fusion to lysosomes followed by rapid bacterial escape into the cytosol within 30-60 min, and bacterial proliferation within the cytosol. The Francisella pathogenicity island, which potentially encodes a putative type VI secretion system, is essential for phagosome biogenesis and bacterial escape into the cytosol within macrophages and arthropod-derived cells. Initial sensing of F. tularensis in the cytosol triggers IRF-3-dependent IFN-beta secretion, type I IFNR-dependent signalling, activation of the inflammasome mediated by caspase-1, and a pro-inflammatory response, which is suppressed by triggering of SHIP. The past few years have witnessed a quantum leap in our understanding of various aspects of this organism and this review will discuss these remarkable advances.
 ...
PMID:Cell biology and molecular ecology of Francisella tularensis. 1986 54

Invasive aspergillosis (IA) is a life-threatening disease that occurs in immunodepressed patients when infected with Aspergillus fumigatus. This fungus is the second most-common causative agent of fungal disease after Candida albicans. Nevertheless, much remains to be learned about the mechanisms by which A. fulmigatus activates the innate immune system. We investigated the inflammatory response to conidia and hyphae of A. fumigatus and specifically, their capacity to trigger activation of an inflammasome. Our results show that in contrast to conidia, hyphal fragments induce NLRP3 inflammasome assembly, caspase-1 activation and IL-1beta release from a human monocyte cell line. The ability of Aspergillus hyphae to activate the NLRP3 inflammasome in the monocytes requires K(+) efflux and ROS production. In addition, our data show that NLRP3 inflammasome activation as well as pro-IL-1beta expression relies on the Syk tyrosine kinase, which is downstream from the pathogen recognition receptor Dectin-1, reinforcing the importance of Dectin-1 in the innate immune response against fungal infection. Furthermore, we show that treatment of monocytes with corticosteroids inhibits transcription of the gene encoding IL-1beta. Thus, our data demonstrate that the innate immune response against A. fumigatus infection involves a two step activation process, with a first signal promoting expression and synthesis of pro-IL-1beta; and a second signal, involving Syk-induced activation of the NLRP3 inflammasome and caspase-1, allowing processing and secretion of the mature cytokine.
 ...
PMID:Aspergillus fumigatus stimulates the NLRP3 inflammasome through a pathway requiring ROS production and the Syk tyrosine kinase. 2036


1 2 3 Next >>