Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epstein-Barr Virus (EBV) Latent Infection Membrane Protein 1 (LMP1) is expressed in all the EBV related malignancies. LMP1 expression is critical for transformation of human B-cells by EBV. LMP1 expression in human B cells induces activation and adhesion molecule expression and cell dumping, which are characteristic of CD40 activated B lymphocytes. In immortalized fibroblasts, LMP1 mimics aspects of activated ras in enabling serum, contact, and anchorage independent growth. Reverse genetic analyses implicate six transmembrane domains (TM), TM1-6, and two C-terminal cytosolic domains, transformation effector sites 1 and 2 (TES1 and 2) or C-terminal activation regions 1 and 2 (CTAR1 and 2) as the essential domains for LMP1 effects. The 6 transmembrane domains cause intermolecular interaction, whereas the C-terminal domains signal through tumor necrosis factor receptor (TNFR) associated factors (TRAFs) or TNFR associated death domain proteins (TRADD) and activate NF-kappaB, JNK, and p38. LMP1 TES1/CTAR1 directly recruits TRAFs 1, 2, 3 and 5 whereas LMP1 TES2/CTAR2 indirectly recruits TRAF6 via BS69. LMP1 TES1/CTAR1 activates TRAF2, NIK, IKKalpha and p52 mediated noncanonical NF-KB pathway and LMP1 TES2/CTAR2 activates TRAF6, TAB1, TAK1, IKKalpha/ IKKbeta/ IKKgamma mediated canonical NF-KB pathway. Interestingly, TRAF3 is a negative regulator of noncanonical NF-kappaB activation, although a positive role in LMP1 signaling has also been described. LMP1 mediated JNK activation is predominantly TES2/CTAR2 dependent and requires TRAF6. LMP1 specifically increases TRAF3 partitioning into lipid rafts and interestingly does not induce degradation of any of the TRAFs upon NF-kappaB activation. Studies of the chemistry and biology of LMP1-TRAF interaction mediated activation of signaling pathways are important for controlling EBV infected cell survival and growth.
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PMID:LMP1 TRAFficking activates growth and survival pathways. 1763 26

Our previous studies and those of others have strongly suggested that c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in 6-hydroxydopamine (6-OHDA)-induced dopaminergic neuron injury in the substantia nigra. However, the downstream mechanism that accounts for the proapoptotic actions of JNK in 6-OHDA lesion remains to be investigated in detail. Fas, a member of the tumor necrosis factor receptor family with proapoptotic functions, was reported to be elevated within the striatum and substantia nigra pars compacta (SNc) of Parkinson's disease (PD) patients. In the present study, we examined the changes in the protein level of Fas ligand (FasL) and its interaction with Fas in a rat model of PD. We demonstrate that the expression of FasL and not Fas was increased after 6-OHDA lesion; additionally, the interaction of FasL and Fas was increased due to 6-OHDA lesion. This indicates that the 6-OHDA-induced activation of Fas signaling pathway is mediated by JNK and that FasL may be a promising target in the therapeutic approach for PD patients.
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PMID:Expression of FasL and its interaction with Fas are mediated by c-Jun N-terminal kinase (JNK) pathway in 6-OHDA-induced rat model of Parkinson disease. 1795 8

Decoy receptor 3 (DcR3) is a soluble decoy receptor belonging to the tumor necrosis factor receptor (TNFR) superfamily, and its expression is not only up-regulated in cancer cells derived from various cell lineages, but also correlates with overall survival of patients with cancer. It has been shown that DcR3 sensitize cells of hematopoietic origin to TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis; therefore, we asked whether DcR3 down-regulated host immunity by inducing immune cell apoptosis. We demonstrate that DcR3 induces dendritic cell (DC) apoptosis by activating PKC-delta and JNK subsequently to up-regulate DR5 to recruit Fas-associated death domain (FADD) to propagate the apoptotic signals. The association of FADD with DR5 results in the formation of death-inducing signaling complex (DISC) to trigger the downstream apoptotic signaling cascade. PKC-delta is activated via cross-linking of heparan sulfate proteoglycan (HSPG) on DCs, because recombinant protein containing the heparin-binding domain (HBD) of DcR3 and the Fc portion of IgG(1), the HBD.Fc fusion protein, is also able to trigger DC apoptosis. This provides the first evidence that cross-linking of HSPG on DCs can activate PKC-delta to induce DC apoptosis via the formation of DR5 DISC, and elucidates a novel mechanism of DcR3-mediated immunosuppression.
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PMID:Apoptosis of dendritic cells induced by decoy receptor 3 (DcR3). 1865 Apr 68

At present, the signaling pathways controlling reactive nitrogen species (RNS)-induced non-apoptotic cell death are relatively less understood. In this work, various RNS donors are found to induce caspase-independent non-apoptotic cell death in mouse embryonic fibroblasts (MEF). In search of the molecular mechanisms, we first established the role of c-Jun N-terminal kinase (JNK) in RNS-induced non-apoptotic cell death. RNS readily activate JNK, and the jnk1-/- MEF are resistant to RNS-induced cell death. Moreover, the reconstitution of JNK1 effectively restores the sensitivity to RNS. Next, we identified tumor necrosis factor receptor-associated factor 2 (TRAF2) and apoptosis signal-regulating kinase 1 (ASK1) as the essential upstream molecules for RNS-induced JNK activation and cell death. RNS fail to activate JNK and induce cell death in traf2-/- MEF; and reconstitution of TRAF2 effectively restores the responsiveness of traf2-/- MEF to RNS. Moreover, RNS-induced ASK1 activation is impaired in traf2-/- cells and overexpression of a mutant ASK1 protein suppresses RNS-induced cell death in wild-type MEF cells. Last, we explored the signaling events upstream of TRAF2 and found that translocation of TRAF2 and JNK1 onto membrane lipid rafts is required for RNS-mediated JNK1 activation and cell death. Taken together, data from our study reveal a novel signaling pathway regulating RNS-induced JNK1 activation and non-apoptotic cell death.
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PMID:Signaling pathways from membrane lipid rafts to JNK1 activation in reactive nitrogen species-induced non-apoptotic cell death. 1800 61

Human immunodeficiency virus (HIV)-positive persons are predisposed to pulmonary infections, even after receiving effective highly active antiretroviral therapy. The reasons for this are unclear but may involve changes in innate immune function. HIV type 1 infection of macrophages impairs effector functions, including cytokine production. We observed decreased constitutive tumor necrosis factor alpha (TNF-alpha) concentrations and increased soluble tumor necrosis factor receptor type II (sTNFRII) in bronchoalveolar lavage fluid samples from HIV-positive subjects compared to healthy controls. Moreover, net proinflammatory TNF-alpha activity, as measured by the TNF-alpha/sTNFRII ratio, decreased as HIV-related disease progressed, as manifested by decreasing CD4 cell count and increasing HIV RNA (viral load). Since TNF-alpha is an important component of the innate immune system and is produced upon activation of Toll-like receptor (TLR) pathways, we hypothesized that the mechanism associated with deficient TNF-alpha production in the lung involved altered TLR expression or a deficit in the TLR signaling cascade. We found decreased Toll-like receptor 1 (TLR1) and TLR4 surface expression in HIV-infected U1 monocytic cells compared to the uninfected parental U937 cell line and decreased TLR message in alveolar macrophages (AMs) from HIV-positive subjects. In addition, stimulation with TLR1/2 ligand (Pam(3)Cys) or TLR4 ligand (lipopolysaccharide) resulted in decreased intracellular phosphorylated extracellular signal-regulated kinase and subsequent decreased transcription and expression of TNF-alpha in U1 cells compared to U937 cells. AMs from HIV-positive subjects also showed decreased TNF-alpha production in response to these TLR2 and TLR4 ligands. We postulate that HIV infection alters expression of TLRs with subsequent changes in mitogen-activated protein kinase signaling and cytokine production that ultimately leads to deficiencies of innate immune responses that predispose HIV-positive subjects to infection.
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PMID:Human immunodeficiency virus infection alters tumor necrosis factor alpha production via Toll-like receptor-dependent pathways in alveolar macrophages and U1 cells. 1852 17

In this article we describe the validation of a beta-lactamase reporter assay for high-throughput interrogation of the mitogen-activated protein kinase (MAPK) signaling pathway initiated by multiple receptors. Activation of cell surface receptors, such as epidermal growth factor receptor (EGFR) and cMET, upon ligand binding, leads to the activation of the downstream MAPK signaling pathway and transcription factor, activator protein 1 (AP1), which then induce the expression of genes that are important for cell growth and proliferation. Our MAPK pathway reporter cell line, AP1-bla ME-180, expresses multiple endogenous cell surface receptors. We demonstrate that this reporter assay can be used to monitor the MAPK pathway initiated by cell surface receptors, including EGFR, cMET, and tumor necrosis factor receptor. Our results from Stealth (Invitrogen Corp., Carlsbad, CA) RNA interference and small molecule inhibitor studies suggest that activation of individual kinases of the MAPK pathway is regulated in a ligand-specific manner. The AP1-bla ME-180 reporter cell line can therefore be used to screen for compounds with desired selectivity profiles.
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PMID:HTS assays using a disease-relevant cell model for interrogating the MAP kinase pathway initiated by multiple receptors. 1859 76

Cytokine signaling is thought to require assembly of multicomponent signaling complexes at cytoplasmic segments of membrane-embedded receptors, in which receptor-proximal protein kinases are activated. Indeed, CD40, a tumor necrosis factor receptor (TNFR) family member, forms a complex containing adaptor molecules TRAF2 and TRAF3, ubiquitin-conjugating enzyme Ubc13, cellular inhibitor of apoptosis proteins 1 and 2 (c-IAP1/2), IkappaB kinase regulatory subunit IKKgamma (also called NEMO), and mitogen-activated protein kinase (MAPK) kinase kinase MEKK1 upon ligation. TRAF2, Ubc13, and IKKgamma were required for complex assembly and activation of MEKK1 and MAPK cascades. However, these kinases were not activated unless the multicomponent signaling complex translocated from CD40 to the cytosol upon c-IAP1/2-induced degradation of TRAF3. This two-stage signaling mechanism may apply to other innate immune receptors, accounting for spatial and temporal separation of MAPK and IKK signaling.
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PMID:Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex. 1866 50

Peripheral blood monocytes are plastic cells that migrate to tissues and differentiate into various cell types, including macrophages, dendritic cells, and osteoclasts. We have described the migration of cellular inhibitor of apoptosis protein 1 (cIAP1), a member of the IAP family of proteins, from the nucleus to the Golgi apparatus in monocytes undergoing differentiation into macrophages. Here we show that, once in the cytoplasm, cIAP1 is involved in the degradation of the adaptor protein tumor necrosis factor receptor-associated factor 2 (TRAF2) by the proteosomal machinery. Inhibition of cIAP1 prevents the decrease in TRAF2 expression that characterizes macrophage formation. We demonstrate that TRAF2 is initially required for macrophage differentiation as its silencing prevents Ikappa-Balpha degradation, nuclear factor-kappaB (NF-kappaB) p65 nuclear translocation, and the differentiation process. Then, we show that cIAP1-mediated degradation of TRAF2 allows the differentiation process to progress. This degradation is required for the macrophages to be fully functional as TRAF2 overexpression in differentiated cells decreases the c-Jun N-terminal kinase-mediated synthesis and the secretion of proinflammatory cytokines, such as interleukin-8 and monocyte chemoattractant protein 1 (MCP-1) in response to CD40 ligand. We conclude that TRAF2 expression and subsequent degradation are required for the differentiation of monocytes into fully functional macrophages.
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PMID:cIAP1-dependent TRAF2 degradation regulates the differentiation of monocytes into macrophages and their response to CD40 ligand. 1882 86

Toll-like receptors (TLRs) act to sense the environment for microbial products and submit danger signals to antigen-presenting cells (APCs) resulting in activation of complex immune responses. In this study, we analyzed the function of human monocyte-derived APCs generated in vitro in the presence of interleukin (IL)-10 upon activation by TLR ligands. Exposure of these APCs to IL-10 resulted in a skewed phenotypic maturation in response to stimuli provided by the TLR ligands, a reduced cytokine production, such as IL-12, IL-6 or tumor necrosis factor-alpha, and impaired capacity to stimulate T-cell activation. Furthermore, CCR7 upregulation in APCs exposed to TLR stimulation as well as migration towards CCL19/MIP-3beta were strongly reduced. IL-10 was found to downregulate MyD88, IRAK1 (IL-1 receptor-associated kinase) and tumor necrosis factor receptor-associated factor 6, essential adaptor molecules for TLR signaling, and to decrease TLR-induced nuclear expression of the nuclear factor-kappaB transcription factors c-Rel and Rel-B as well as interferon regulatory factor (IRF)-3 and IRF-8. This was not due to the inhibition of the mitogen-activated protein kinase pathway, but was rather mediated by the blockage of the PI3K signaling cascade. Interestingly, the inhibition of proteins involved in TLR signaling, such as MyD88, IRAK1 and mammalian target of rapamycin, was due to a selective post-transcriptional regulation.
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PMID:Post-transcriptional regulation of adapter molecules by IL-10 inhibits TLR-mediated activation of antigen-presenting cells. 1900 81

Osteoprotegerin (OPG) a soluble tumor necrosis factor receptor family molecule protects endothelial cells from apoptosis in vitro and promotes neovascularization in vivo. In this study, we assessed the role of OPG and its ligands, receptor activator of nuclear factor-kappaB ligand (RANKL) and tumor necrosis factor-related apoptosis inducing ligand (TRAIL), in microvessel formation using the rat aortic ring model of angiogenesis. OPG was found to promote a twofold increase in angiogenic sprouting in the aortic ring model, and this effect was inhibited by pre-incubation with a fivefold molar excess of either RANKL or TRAIL. While TRAIL had no effect upon angiogenesis on its own, RANKL was found to potently inhibit basal and vascular endothelial growth factor-induced angiogenesis. OPG increased the rate of endothelial cell proliferation in sprouting microvessels; in contrast, RANKL inhibited proliferation. RANKL was found to induce endothelial apoptosis at days 6, 7, and 10 in the aortic ring model and after incubation with human umbilical vein endothelial cells (HUVECs). Signaling studies showed that OPG induced ERK1/2 and Akt phosphorylation in HUVECs while RANKL had no effect. Our results indicate that OPG is a positive regulator of microvessel formation, while RANKL is an angiogenic inhibitor due to effects on regulation of endothelial cell proliferation, apoptosis, and signaling.
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PMID:Osteoprotegerin and RANKL differentially regulate angiogenesis and endothelial cell function. 1910 36


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