Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD30 is a transmembrane receptor of the nerve growth factor/tumor necrosis factor receptor superfamily. Its expression associated with Hodgkin's lymphoma and a subset of non-Hodgkin's lymphoma. Recently, its ligand (CD30L) has been cloned. CD30L enhances the proliferation of peripheral T cells and the Hodgkin's cell line HDLM-2 but seems to exert antiproliferative effects on large cell anaplastic lymphoma cell lines. Since tyrosine kinases are critical regulators of cell growth, we investigated whether CD30L induced changes in cellular tyrosine phosphorylation in CD30-positive lymphoma cell lines. Stimulation with CD30L or with an agonistic mAb against CD30, M44, induced a rapid, transient, and concentration-dependent tyrosine phosphorylation of a cytosolic protein of M(r) 42,000 (p42) in the Hodgkin's lymphomas cell line HDLM-2 but not in other CD30-positive lymphomas. In HDLM-2 cells, the phrobol ester phorbol 12-myristate 13-acetate also stimulated tyrosine phosphorylation of p42, and this effect was enhanced by M44. In marked contrast, agents stimulating the protein kinase A pathway, like forskolin or dibutyryl cAMP, did not affect tyrosine phosphorylation of P42. By immunoprecipitation with mAbs against mitogen-activated protein kinase (MAPK; p42ERKII), a M(r) 42,000 protein was identified which comigrated with p42 on SDS gels and which was phosphorylated on tyrosine residues in response to stimulation of CD30. Immune complex kinase assays showed that M44 mAb induced the activation of MAPK (p42ERKII) and the phosphorylation of a MAPK substrate, myelin basic protein. Taken together, the results suggest that CD30L induces the tyrosine phosphorylation and activation of the MAPK p42ERKII isoform in HDLM-2 cells. These findings may have implications for the understanding of the pathogenesis of Hodgkin's disease.
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PMID:CD30 ligand signal transduction involves activation of a tyrosine kinase and of mitogen-activated protein kinase in a Hodgkin's lymphoma cell line. 754 87

To dissect tumor necrosis factor receptor (Tnfr)-1 (CD120a) and Tnfr2 (CD120b)-dependent signal transduction pathways, primary fibroblasts isolated from inguinal adipose tissue of wild type (wt), tnfr1(o), tnfr2(o), and tnfr1(o)/tnfr2(o) mice were studied. The mitogen-activated protein kinases Erk1 and Erk2 were found to be tyrosine-phosphorylated and activated by Tnf treatment in all wt, tnfr1(o), and tnfr2(o) fibroblasts; the activation was down-regulated 60 min after the start of steady state Tnf treatment. Distinct kinetics of Erk1 and Erk2 activation were detected; the Tnfr1-mediated activation of Erk1 and Erk2 started more slowly and persisted for more prolonged times as compared with Tnfr2 activation. Raf-1, Raf-B, Mek-1, Mek kinase, and p90(rsk) kinases were also shown to be activated independently in a distinct time-dependent pattern through the two Tnf receptors. In addition, both Tnfr1 and Tnfr2 mediated independently the activation of the transcription factor Ap-1 albeit with parallel activation kinetics. In contrast, Tnfr1 exclusively mediated activation of NF-kappaB and fibroblast proliferation; however, Tnfr2 enhanced proliferation triggered through Tnfr1. These findings indicate distinct but also overlapping roles of Tnfr1 and Tnfr2 in primary mouse fibroblasts and suggest different regulation mechanisms of signal transduction pathways under the control of both Tnf receptors.
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PMID:Tumor necrosis factor receptors (Tnfr) in mouse fibroblasts deficient in Tnfr1 or Tnfr2 are signaling competent and activate the mitogen-activated protein kinase pathway with differential kinetics. 891 Apr 23

The dsRNA-dependent protein kinase (PKR) is considered to play a key role in interferon-mediated host defense against viral infection and conceivably malignant transformation. To investigate further the mechanisms of PKR-induced growth inhibition, we have developed tetracycline-inducible murine cell lines that express wild-type PKR or a catalytically inactive PKR variant, PKRdelta6. Following induction, the growth of the wild-type PKR-expressing cells was similar to that of cells transfected with vector alone, while cells expressing PKRdelta6 became malignantly transformed. Significantly, treatment with dsRNA caused the wild-type PKR-overexpressing cells to undergo programed cell death while, conversely, cells expressing PKRdelta6 were completely resistant. Our studies demonstrated that activation of PKR induces the expression of members of the tumor necrosis factor receptor (TNFR) family, including Fas (CD95/Apo-1) and pro-apopotic Bax. In contrast, transcripts representing Fas, TNFR-1, FADD (Fas-associated death domain), FLICE, Bad and Bax were ablated in cells expressing PKRdelta6. The involvement of the death receptors in PKR-induced apoptosis was underscored by demonstrating that murine fibroblasts lacking FADD were almost completely resistant to dsRNA-mediated cell death. Thus, PKR, a key cellular target for viral repression, is a receptor/inducer for the induction of pro-apoptotic genes by dsRNA and probably functions in interferon-mediated host defense to trigger cell death in response to virus infection and perhaps tumorigenesis.
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PMID:Activation of the dsRNA-dependent protein kinase, PKR, induces apoptosis through FADD-mediated death signaling. 984 95

Reactive oxygen intermediates (ROIs) are among the important mediators in the pathogenesis of lung diseases in which tumor necrosis factor (TNF) plays a pivotal role. However, the effects of ROIs on the TNF- TNF receptor system remain unclear. Effects of hydrogen peroxide on the shedding of soluble tumor necrosis factor receptor (sTNF-R) were investigated in a pulmonary epithelial cell line (A549) using enzyme-linked immunoassay. A549 cells spontaneously released type I sTNF-R (sTNF-RI) into the culture medium. Hydrogen peroxide accelerated the release of sTNF-RI from the A549 cells time- and dose- dependently. Stimulated release of sTNF-RI by hydrogen peroxide or phorbol myristate acetate (PMA) was inhibited by pretreatment with the intracellular hydroxyl radical scavengers dimethyl sulfoxide and dimethyl thiourea. A synthetic metalloproteinase inhibitor (KB-R8301) inhibited not only spontaneous release of sTNF-RI but also shedding enhanced by hydrogen peroxide and PMA. Preincubation with a protein kinase C inhibitor, calphostin C, downregulated the hydrogen peroxide- or PMA-induced shedding of sTNF-RI. Neither genistein, a tyrosine kinase inhibitor, nor H-89, a protein kinase A inhibitor, inhibited shedding of sTNF-RI by hydrogen peroxide and PMA. Although the surface expression of TNF-R assessed by 125I-TNF specific binding was decreased in the presence of hydrogen peroxide or PMA, TNF-RI mRNA transcript levels remained unchanged. These results show that hydrogen peroxide is involved in the activation of metalloproteinase and protein kinase C responsible for the shedding of sTNF-RI. Accordingly, ROIs may alter TNF action by enhanced shedding of sTNF-RI and reducing its surface receptor expression.
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PMID:Hydrogen peroxide enhances shedding of type I soluble tumor necrosis factor receptor from pulmonary epithelial cells. 987 Sep 25

The Hsp90 family of proteins in mammalian cells consists of Hsp90 alpha and beta, Grp94, and Trap-1 (Hsp75). Radicicol, an antifungal antibiotic that inhibits various signal transduction proteins such as v-src, ras, Raf-1, and mos, was found to bind to Hsp90, thus making it the prototype of a second class of Hsp90 inhibitors, distinct from the chemically unrelated benzoquinone ansamycins. We have used two novel methods to immobilize radicicol, allowing for detailed analyses of drug-protein interactions. Using these two approaches, we have studied binding of the drug to N-terminal Hsp90 point mutants expressed by in vitro translation. The results point to important drug contacts with amino acids inside the N-terminal ATP/ADP-binding pocket region and show subtle differences when compared with geldanamycin binding. Radicicol binds more strongly to Hsp90 than to Grp94, the Hsp90 homolog that resides in the endoplasmic reticulum. In contrast to Hsp90, binding of radicicol to Grp94 requires both the N-terminal ATP/ADP-binding domain as well as the adjacent negatively charged region. Radicicol also specifically binds to yeast Hsp90, Escherichia coli HtpG, and a newly described tumor necrosis factor receptor-interacting protein, Trap-1, with greater homology to bacterial HtpG than to Hsp90. Thus, the radicicol-binding site appears to be specific to and is conserved in all members of the Hsp90 family of molecular chaperones from bacteria to mammals, but is not present in other molecular chaperones with nucleotide-binding domains.
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PMID:Interaction of radicicol with members of the heat shock protein 90 family of molecular chaperones. 1047 36

MYC affects normal and neoplastic cell proliferation by altering gene expression, but the precise pathways remain unclear. We used oligonucleotide microarray analysis of 6,416 genes and expressed sequence tags to determine changes in gene expression caused by activation of c-MYC in primary human fibroblasts. In these experiments, 27 genes were consistently induced, and 9 genes were repressed. The identity of the genes revealed that MYC may affect many aspects of cell physiology altered in transformed cells: cell growth, cell cycle, adhesion, and cytoskeletal organization. Identified targets possibly linked to MYC's effects on cell growth include the nucleolar proteins nucleolin and fibrillarin, as well as the eukaryotic initiation factor 5A. Among the cell cycle genes identified as targets, the G1 cyclin D2 and the cyclin-dependent kinase binding protein CksHs2 were induced whereas the cyclin-dependent kinase inhibitor p21(Cip1) was repressed. A role for MYC in regulating cell adhesion and structure is suggested by repression of genes encoding the extracellular matrix proteins fibronectin and collagen, and the cytoskeletal protein tropomyosin. A possible mechanism for MYC-mediated apoptosis was revealed by identification of the tumor necrosis factor receptor associated protein TRAP1 as a MYC target. Finally, two immunophilins, peptidyl-prolyl cis-trans isomerase F and FKBP52, the latter of which plays a role in cell division in Arabidopsis, were up-regulated by MYC. We also explored pattern-matching methods as an alternative approach for identifying MYC target genes. The genes that displayed an expression profile most similar to endogenous Myc in microarray-based expression profiling of myeloid differentiation models were highly enriched for MYC target genes.
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PMID:Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. 1073 92

Hepatitis C virus (HCV) core protein has been shown to interact with the death domain (DD) of tumor necrosis factor receptor-1 (TNFR1). In this study, we further examined the interaction of the core protein with the signaling molecules of TNFR1, including FADD, TRADD, and TRAF2, in a human embryonic kidney cell line, HEK-293, that overexpresses the HCV core protein. This core protein-expressing cell line exhibited enhanced sensitivity to TNF-induced apoptosis. By in vitro binding and in vivo coimmunoprecipitation assays, we showed that the HCV core protein interacted with the DD of FADD and enhanced apoptosis induced by FADD overexpression. This enhancement could be blocked by a dominant-negative mutant of FADD. In contrast, the core protein did not directly interact with the DD of TRADD, but could disrupt the binding of TRADD to TNFR1. TRAF2 recruitment to the TNFR1 signaling complex was also disrupted by the core protein. Correspondingly, TRAF2-dependent activation of the protein kinase JNK was suppressed in the core protein-expressing cells. However, NF kappa B activation by TNF was not significantly altered by the HCV core protein, suggesting the existence of TRAF2-independent pathways for NF kappa B activation. These results combined indicate that the HCV core protein sensitizes cells to TNF-induced apoptosis primarily by facilitating FADD recruitment to TNFR1. The inhibition of JNK activation by the HCV core protein may also contribute to the increased propensity of cells for apoptosis. These results, in comparison with other published studies, suggest that the effects of the HCV core protein and their underlying mechanisms vary significantly among cells of different origins.
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PMID:Hepatitis C virus core protein enhances FADD-mediated apoptosis and suppresses TRADD signaling of tumor necrosis factor receptor. 1133 43

Recognition of pathogens is mediated by a set of germline-encoded receptors that are referred to as pattern-recognition receptors (PRRs). These receptors recognize conserved molecular patterns (pathogen-associated molecular patterns), which are shared by large groups of microorganisms. Toll-like receptors (TLRs) function as the PRRs in mammals and play an essential role in the recognition of microbial components. The TLRs may also recognize endogenous ligands induced during the inflammatory response. Similar cytoplasmic domains allow TLRs to use the same signaling molecules used by the interleukin 1 receptors (IL-1Rs): these include MyD88, IL-1R--associated protein kinase and tumor necrosis factor receptor--activated factor 6. However, evidence is accumulating that the signaling pathways associated with each TLR are not identical and may, therefore, result in different biological responses.
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PMID:Toll-like receptors: critical proteins linking innate and acquired immunity. 1147 2

Receptor-interacting protein (RIP) is a serine/threonine protein kinase that is critically involved in tumor necrosis factor receptor-1 (TNF-R1)-induced NF-kappa B activation. In a yeast two-hybrid screening for potential RIP-interacting proteins, we identified ZIN (zinc finger protein inhibiting NF-kappa B), a novel protein that specifically interacts with RIP. ZIN contains four RING-like zinc finger domains at the middle and a proline-rich domain at the C terminus. Overexpression of ZIN inhibits RIP-, IKK beta-, TNF-, and IL1-induced NF-kappa B activation in a dose-dependent manner in 293 cells. Domain mapping experiments indicate that the RING-like zinc finger domains of ZIN are required for its interaction with RIP and inhibition of RIP-mediated NF-kappa B activation. Overexpression of ZIN also potentiates RIP- and TNF-induced apoptosis. Moreover, immunofluorescent staining indicates that ZIN is a cytoplasmic protein and that it colocalizes with RIP. Our findings suggest that ZIN is an inhibitor of TNF- and IL1-induced NF-kappa B activation pathways.
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PMID:A novel zinc finger protein interacts with receptor-interacting protein (RIP) and inhibits tumor necrosis factor (TNF)- and IL1-induced NF-kappa B activation. 1185 71

We reported previously that bone marrow granulocytes respond to small amounts of enterobacterial lipopolysaccharide (LPS) via a CD14-independent and TLR4-mediated mechanism by de novo expression of an inducible receptor (CD14) and by down-modulation of a constitutive receptor (L-selectin). In this report we address another effect of LPS: the down-regulation of receptors for tumor necrosis factor-alpha. In mouse bone marrow cells (BMC), this down-regulation is detectable soon (20 min) after exposure of the cells to low levels (0.5 ng/ml) of LPS. This temperature-dependent effect is rather selective for LPS and requires the presence of a conventional lipid A structure in the LPS molecule and a functional TLR4 molecule in the cells. The down-modulation, due to a shedding of the receptors, is blocked by p38 MAPK inhibitors, by a furin inhibitor, and by three metalloproteinase inhibitors (BB-3103, TIMP-2, and TIMP-3). In contrast, inhibitors of MEK, protein kinase C, cAMP-dependent protein kinase, and kinases of the Src family do not block the shedding. Analysis of BMC from mice lacking tumor necrosis factor receptor-1 (CD120a-/-) or tumor necrosis factor receptor-2 (CD120b-/-) indicates that the LPS-induced shedding is specific for CD120b. Thus, exposure of BMC to LPS triggers a rapid shedding of CD120b via a protein kinase C- and Src-independent pathway mediated by p38 MAPK, furin, and metalloproteinase. The additive effects of furin and metalloproteinase inhibitors suggest that these enzymes are involved in parallel shedding pathways.
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PMID:TLR4-dependent lipopolysaccharide-induced shedding of tumor necrosis factor receptors in mouse bone marrow granulocytes. 1266 67


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