Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Raf-1 plays important roles in cell proliferation, differentiation, and survival. However, the unique and essential function of Raf-1 is anti-apoptotic. The molecules that mediate Raf-1's anti-apoptotic function are not known. In the course of identifying new substrates of Raf-1, we found that the Raf-1 kinase domain interacted with apoptosis-linked gene-2 (ALG-2) in yeast two-hybrid system. Our further studies showed that Raf-1 phosphorylated ALG-2 in an in vitro kinase assay. We also found that apoptosis signal-regulating kinase 1 (ASK1) strongly phosphorylated ALG-2. Importantly, Raf-1 blocks the ASK1-dependent ALG-2 phosphorylation. Since ALG-2 associates with ASK1, and both ASK1 and ALG-2 are involved in apoptosis, our observations indicate that Raf-1 may mediate its anti-apoptotic function by interrupting ASK1-dependent phosphorylation of ALG-2.
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PMID:Apoptosis-linked gene-2 connects the Raf-1 and ASK1 signalings. 1592 22

13-Deoxytedanolide is a structurally unique macrolide with strong antitumor activity isolated from a marine sponge. Recently, we showed that 13-deoxytedanolide bound to the large subunit of the yeast ribosome and inhibited polypeptide elongation in vitro, but the mechanism by which it exerts antitumor activity is still unknown. Here we show that 13-deoxytedanolide strongly induces plasminogen activator inhibitor 1 (PAI-1) promoter-derived gene expression. 13-Deoxytedanolide, unlike TGF-beta, did not cause apparent nuclear translocation of Smad2/3, but it relocalized the temperature-sensitive mutant of mouse p53 (p53Val153) from the cytoplasm to the nucleus at a nonpermissive temperature, suggesting that 13-deoxytedanolide inhibits protein synthesis. Indeed, the drug inhibited in vivo protein synthesis at low nanomolar concentrations and strongly activated stress-activated protein kinases such as p38 mitogen-activated protein kinase and Jun NH2-terminal protein kinase (JNK). Anisomycin, a well-known inducer of ribotoxic stress that activates both p38 and JNK, also activated PAI-1 gene expression, while other protein synthesis inhibitors that do not activate the kinases failed to do so. PAI-1 gene expression by 13-deoxytedanolide and anisomycin was blocked by SB202190, a specific inhibitor of p38, and SP600125, an inhibitor of both p38 and JNK. 13-Deoxytedanolide and anisomycin caused activation of apoptosis signal-regulating kinase 1, MKK3/MKK6, and SEK1/MKK4, the regulatory kinases upstream of p38 and JNK. These results suggest that 13-deoxytedanolide, like anisomycin, triggers a ribotoxic stress response that activates stress-activated protein kinase cascades, thereby inducing PAI-1 gene expression and apoptosis.
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PMID:Induction of a ribotoxic stress response that stimulates stress-activated protein kinases by 13-deoxytedanolide, an antitumor marine macrolide. 1642 34

Apoptosis signal-regulating kinase 1 (ASK1), a serine/threonine protein kinase, is a reactive oxygen species-sensitive mitogen-activated protein kinase kinase kinase and activates both p38 and c-Jun N-terminal kinase pathways. Two isoforms of thioredoxin (Trx), cytosolic and mitochondrial Trx (Trx1 and Trx2, respectively), have been identified in mammalian cells. Trx1 was initially identified as an ASK1-binding protein. Trx1 and Trx2 bind directly to the N-terminal regulatory domain of ASK1 and inhibit ASK1-dependent apoptosis. Numerous other proteins interact with ASK1 and regulate its activity. In cardiomyocytes, ASK1 is involved not only in cardiac apoptosis, leading to cardiac remodeling, but also in cardiac hypertrophy as well as nonapoptotic cardiomyocyte death.
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PMID:The role of apoptosis signal-regulating kinase 1 in cardiomyocyte apoptosis. 1698 25

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogenactivated protein kinase (MAPK) kinase kinase that activates JNK and p38 kinases. ASK1 is activated by various stresses, such as reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, lipopolysaccharide (LPS) and calcium influx which are thought to be responsible for the pathogenesis or exacerbations of various human diseases. Recent studies revealed the involvement of ASK1 in ROS- or ER stressrelated diseases, suggesting that ASK1 may be a potential therapeutic target of various human diseases. In this review, we focus on the current findings for the relationship between pathogenesis and ASK1-MAPK pathways.
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PMID:Pathophysiological roles of ASK1-MAP kinase signaling pathways. 1724 75

The cyclin-dependent kinase inhibitor p21(Cip1) regulates multiple cellular functions and protects cells from genotoxic and other cellular stresses. Activation of apoptosis signal-regulating kinase 1 (ASK1) induced by inhibition of mTOR signaling leads to sustained phospho-c-Jun that is suppressed in cells with functional p53 or by forced expression of p21(Cip1). Here we show that small deletions of p21(Cip1) around S98 abrogate its association with ASK1 but do not affect binding to Cdk1, hence distinguishing between the cell cycle-regulating functions of p21(Cip1) and its ability to suppress activation of the ASK1/Jun N-terminal protein kinase (JNK) pathway. p21(Cip1) is phosphorylated in vitro by both ASK1 and JNK1 at S98. In vivo phosphorylation of p21(Cip1), predominantly carried out by ASK1, is associated with binding to ASK1 and inactivation of ASK1 kinase function. Binding of p21(Cip1) to ASK1 requires ASK1 kinase function and may involve phosphorylation of S98.
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PMID:Negative regulation of ASK1 by p21Cip1 involves a small domain that includes Serine 98 that is phosphorylated by ASK1 in vivo. 1732 29

Genotoxic stress induced by anticancer drugs can lead to apoptosis of both angiogenic endothelial cells (ECs) and proliferating tumor cells. However, growth factors such as basic fibroblast growth factor (bFGF) and vascular endothelial cell growth factor (VEGF) present within the tumor microenvironment can promote chemoresistance by suppressing apoptotic mechanisms in these cells. Here, we have identified apoptosis signal-regulating kinase 1 (ASK1), a proapoptotic member of the MAP3K family, as a target of bFGF-mediated survival signaling in ECs. Evidence is provided that ASK1 is required for EC apoptosis in response to the genotoxic chemotherapeutic agent doxorubicin, and that bFGF, but not VEGF, neutralizes the death-promoting activity of ASK1. Specifically, bFGF stimulation promotes the formation of a Raf-1/ASK1 complex at the mitochondria, inhibits ASK1 kinase activity, and protects ECs from genotoxic stress. Mutation of the Raf-1 activation domain (SS338/9AA) not only prevents Raf-1/ASK1 complex formation but abolishes bFGF-mediated EC protection from genotoxic stress. In line with these observations, bFGF, but not VEGF, neutralizes the antiangiogenic effects of doxorubicin in vivo. These findings reveal a new pathway of EC survival signaling and define a molecular mechanism for chemoresistance induced by bFGF.
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PMID:Chemoresistance of endothelial cells induced by basic fibroblast growth factor depends on Raf-1-mediated inhibition of the proapoptotic kinase, ASK1. 1736 98

The current study aimed to understand the anti-apoptotic effect of overexpressed gap junction forming protein connexin (Cx) 43 in C6 glioma cells. C6 cells exposed to hydrogen peroxide (H2O2) or staurosporine demonstrated morphological and biochemical changes consistent with apoptosis, whereas C6 cells expressing Cx43 demonstrated relative resistance to H2O2, but not to staurosporine. This selective protection against H2O2 was due to inhibition of caspase-3 activation in Cx43 expressing cells. siRNA knockdown experiments in rat primary astrocytes confirmed the presence of endogenous Cx43-mediated anti-apoptotic effect. Cx43 interacts with the upstream apoptosis signal-regulating kinase 1 known to mediate H2O2-induced apoptosis providing a possible mechanism for protection. These findings provided new evidence for regulation of the mitogen activated protein kinase pathway and apoptosis by Cx43 implicating this protein in intracellular signaling beyond its role as a gap junction forming protein on the plasma membrane.
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PMID:Connexin 43 confers resistance to hydrogen peroxide-mediated apoptosis. 1776 Nov 41

Osteosarcoma is the most common primary bone tumor associated with childhood and adolescence. In the present study, we investigated the anticancer effect of a new isoflavone derivative, 3',4'-dichloro-3-(3,4-dichlorophenylacetyl)-2,4,6-trihydroxydeoxybenzoin (DDTD) in human osteosarcoma cells. DDTD induced cell apoptosis in human osteosarcoma cell lines (including: U2OS, MG-63, Saos2 and ROS 17/2.8). We found that the accumulation of reactive oxygen species is a critical mediator in DDTD-induced cell death. DDTD induced apoptosis signal-regulating kinase 1 (ASK1) dephosphorylation and its dissociation from 14-3-3. Treatment of osteosarcoma cells with DDTD induced p38 and p53 phosphorylation. Transfection with ASK1, mitogen activated protein kinase (MAPK) kinase (MKK)3/6, and p38 small interfering RNA (siRNA) antagonized the DDTD-induced cell apoptosis. DDTD also triggered the mitochondrial apoptotic pathway, as indicated by a change in Bax/Bcl2 ratio and Caspase-9 activation. Bax knockdown using a Bax siRNA strategy reduced Bax expression and subsequent cell death. In addition, transfection of cells with ASK1, MKK3/6, and p38 siRNA reduced DDTD-induced p38 activation, p53 phosphorylation and Bax expression. These results suggest that DDTD generates reactive oxygen species and activates the ASK1-MKK3/6-p38-p53-Bax pathway to cause osteosarcoma cell death.
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PMID:DDTD, an isoflavone derivative, induces cell apoptosis through the reactive oxygen species/apoptosis signal-regulating kinase 1 pathway in human osteosarcoma cells. 1882 83

The trichothecene deoxynivalenol (DON) binds to eukaryotic ribosomes and triggers p38-driven proinflammatory gene expression in the macrophage-a response that is dependent on both double-stranded RNA-activated protein kinase (PKR) and hematopoietic cell kinase (Hck). Here we elucidated critical linkages that exist among the ribosome and these kinases during the course of DON-induced ribotoxic stress in mononuclear phagocytes. Similar to PKR inhibitors, Hck inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyramidine (PP2) suppressed p38 activation and p38-driven interleukin 8 (IL-8) expression in the U937 human monocyte cell line. U937 cells stably transfected with a PKR antisense vector (U9K-A1) displayed marked reduction of DON-induced p38 activation and IL-8 expression as compared to cells transfected with empty vector (U9K-C2), with both responses being completely ablated by PP2. Western analysis of sucrose density gradient fractions revealed that PKR and Hck interacted with the 40S ribosomal subunit in U9K-C2 but not U9K-A1 cells. Subsequent transfection and immunoprecipitation studies with HeLa cells indicated that Hck interacted with ribosomal protein S3. Consistent with U937 cells, DON induced p38 association with the ribosome and phosphorylation in peritoneal macrophages from wild-type but not PKR-deficient mice. DON-induced phosphorylation of ribosome-associated Hck in RAW 264.7 murine macrophages was also suppressed by 2-aminopurine (2-AP). Both 2-AP and PP2 inhibited DON-induced phosphorylation of p38 as well as two kinases, apoptosis signal-regulating kinase 1 and mitogen-activated protein kinase 3/6, known to be upstream of p38. Taken together, PKR and Hck were critical for DON-induced ribosomal recruitment of p38, its subsequent phosphorylation, and, ultimately, p38-driven proinflammatory cytokine expression.
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PMID:Hematopoietic cell kinase associates with the 40S ribosomal subunit and mediates the ribotoxic stress response to deoxynivalenol in mononuclear phagocytes. 2018 60

Apoptosis signal-regulating kinase 1 (ASK1) and ASK2 are both members of mitogen-activated protein kinase kinase kinase (MAP3K) family that are implicated in apoptotic cell death, stress responses, and various diseases. We have determined that NT2RI3007443, TESTI4031745, SGK341, and human MAP3K15 are all transcribed from the same genomic locus, which we designate "ASK3 gene" based on sequence homology to ASK1 and ASK2. NT2RI3007443, TESTI4031745, and SGK341 displayed distinct expression profiles among human tissues. TESTI4031745 was expressed in relatively high levels. The expression of TESTI4031745 was increased in rectum tumor and Alzheimer's disease hippocampus and decreased in kidney tumor and Alzheimer's disease frontal lobe. NT2RI3007443 showed moderate levels of ubiquitous expression in normal adult tissues. They did not drastically change in diseases except for increase in cirrhosis liver. Expression of SGK341 was restricted. It was highly expressed in fetal brain, and moderately expressed in normal hippocampus, pancreas, spleen, lung, and kidney. Further, its expression was dramatically increased in hepatic cirrhosis and decreased in lung tumor. Target proteins encoded by NT2RI3007443 and TESTI4031745 were translated in cell-free protein synthesis system. They exhibited protein kinase activity indicated by ATP consumption and phosphorylation of Syntide 2 as a substrate. We demonstrated that knockdown of ASK3 protected HeLa cells against cytotoxicity induced by anti-Fas monoclonal antibody, TNF-alpha, or oxidative stress. These findings suggest that "ASK3 gene" is a novel member of apoptosis signal-regulating kinases and that it plays a pivotal role in the signal transduction pathway implicated in apoptotic cell death triggered by cellular stresses. It can be a putative therapeutic drug target for multiple human diseases.
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PMID:ASK3, a novel member of the apoptosis signal-regulating kinase family, is essential for stress-induced cell death in HeLa cells. 2036 54


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