Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.25 (MEKK1)
 1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteolytic modification of certain key regulatory molecules involved in apoptotic and prosurvival pathways may be a feature of the control of programmed cell death. Four molecules of the Bd-2 family (BID, Bcl-2, Bax, Bcl-X(L)) have been reported to be deaved during apoptosis, as has a cellular inhibitor of apoptosis (XIAP). Two proteins involved in NF-kappaB activation, RIP and TRAF1, are cleaved during apoptosis induced by agents that activate both pathways. MEKK1, a molecule involved in a protein kinase stress signaling cascade that contributes to apoptosis and NF-kappaB activation, also undergoes cleavage. In each case, the cleavage products may result in the inactivation of a former function or the gaining of a new function, thus contributing to the delicately balanced regulation of apoptosis.
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PMID:Proteolytic cleavage of molecules involved in cell death or survival pathways: a role in the control of apoptosis? 1206 67

Signal transduction induced by tumor necrosis factor (TNF) family members and their receptors has been an intensive area of research for several years. The major impact of these studies has been the delineation of apoptotic and cell survival signaling pathways. These discoveries, coupled with major advances in the study of mammalian apoptotic machinery, constitute a promising blueprint of the molecular network governing the fate of all living cells. In this review, we concentrate on the fate of cells in the immune system, where regulation of cell death and cell survival is a frequent and important exercise. A small imbalance in favor of either fate can result in disastrous pathological outcomes, such as cancer, autoimmunity or immune deficiency. It is an insurmountable task to discuss all molecules reported in the literature that are implicated in lymphocyte death or survival. We have therefore focused on discoveries made by mouse gene targeting, as these studies provide the most physiologically relevant information on each molecule. We begin with a description of signaling channels initiated by TNF receptor type 1 engagement, which can lead to either cell survival or to cell death. The point of bifurcation of this pathway and the decision-making molecules FADD, TRAF2 and RIP are discussed. We then follow apoptotic and survival pathways from upstream to downstream, describing many important players involved in signal transduction. Molecules important for NF-kappaB and JNK/stress-activated protein kinase activation such as IKKbeta, NEMO, MAP3K and TRAF6 are discussed, as is the impact of BAFF and its receptors on B-cell survival. Mouse mutants that have helped to define the mammalian apoptosis execution machinery, including animals lacking Apaf-1, caspase-3 and caspase-9, are also described. We conclude with a brief analysis of the potential therapeutic options arising from this body of work.
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PMID:Signaling for survival and apoptosis in the immune system. 1211 Jan 44

Previously we have shown that TGF-beta1 protects murine L929 fibroblasts from TNF/ActD-mediated cell death by inducing the expression of an extracellular matrix TNF-resistance triggering (TRT) protein. TRT promotes TNF-resistance via activation of tyrosine and serine/threonine kinases in L929 cells. To examine the presence of TRT activity in serum (designated STRT), human sera were diluted, treated with or without PMSF and subjected to sequential ammonium sulfate precipitation (ASP). Aliquots of the ASP protein fractions were coated onto 96-well plates, followed by thorough washing. When L929 cells were seeded and cultured on the wells coated with STRT proteins, these cells resisted killing by TNF, TNF/ActD, doxorubicin and serum deprivation, but not by anti-Fas/ActD, staurosporine and ActD. STRT activity was found at the 15% ASP fraction of untreated sera, but shifted to the 20% ASP fraction of PMSF-treated sera. Two likely STRT proteins of approximately 226 and 265 kDa were found in these fractions, compared to the corresponding nonfunctional ASP fractions. Functionally, STRT was inactivated by trypsin, but not by 5 M salt, various serine and/or cysteine protease inhibitors, and antibodies against fibronectin, vitronectin, C1q, histidine-rich glycoprotein, CD44, chondroitin sulfate and hyaluronic acid. STRT failed to alter the expression of proteins involved in apoptosis such as RIP, ICH-1L, BCL-X, TIAR and IkappaBalpha, and could not induce IkappaBalpha degradation. The induced TNF-resistance could be reversed by treatment of STRT-stimulated cells with testicular hyaluronidase, as well as with tyrosine kinase inhibitors tyrophostin, lavendustin A and AG-490 (a selective inhibitor of JAK2 kinase). However, the STRT function could not be blocked by the MEK kinase inhibitor PD98059 and the NF-kappaB inhibitors curcumin and a synthetic inhibitor peptide for NF-kappaB translocation. Together, our data suggest that tyrosine kinase activation is involved in the STRT-mediated resistance to TNF and TNF/ActD in L929 cells.
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PMID:Characterization of serum adhesive proteins that block tumor necrosis factor-mediated cell death. 1646 90

Tumor Necrosis Factor alpha (TNFalpha) is a pro-inflammatory cytokine that plays important roles in different biological processes, including the induction of other cytokines. One of the most important downstream signaling targets activated by TNFalpha is the NF-kappaB transcription factor, which has been identified to be involved in inflammatory, anti-apoptotic, and immune responses. Stimulation of cells with TNFalpha triggers activation of NF-kappaB through various signaling molecules, including TRAF2, RIP, MAP3K, and the IKK complex. Recently, numerous studies have been performed to explore the detailed mechanism by which NF-kappaB is activated upon TNFalpha stimulation. Current understanding of this pathway has been focused on the identification of signaling components, the role of post-translational modification and the sub-cellular translocation of those components. Additionally, more negative regulators in the TNF-IKK pathway are emerging.
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PMID:Positive and negative signaling components involved in TNFalpha-induced NF-kappaB activation. 1806 98

p38 mitogen-activated protein kinases (MAPKs) play important roles in various cellular stress responses, including cell death, which is roughly categorized into apoptosis and necrosis. Although p38 signaling has been extensively studied, the molecular mechanisms of p38-mediated cell death are unclear. ASK1 is a stress-responsive MAP3K that acts as an upstream kinase of p38 and is activated by various stresses, such as oxidative stress. Here, we show that NR4A2, a member of the NR4A nuclear receptor family, acts as a necrosis promoter downstream of ASK1-p38 pathway during oxidative stress. Although NR4A2 is well known as a nucleus-localized transcription factor, we found that it is translocated into the cytosol after phosphorylation by p38. Because the phosphorylation site mutants of NR4A2 cannot rescue the cell death-promoting activity, ASK1-p38 pathway-dependent phosphorylation and subsequent cytoplasmic translocation of NR4A2 may be required for oxidative stress-induced cell death. In addition, NR4A2-mediated cell death does not depend on caspases and receptor-interacting protein 1 (RIP1)-RIP3 complex, suggesting that NR4A2 promotes an RIP kinase-independent necrotic type of cell death. Our findings may enable a more precise understanding of molecular mechanisms that regulate oxidative stress-induced and p38-mediated necrosis.
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PMID:Apoptosis Signal-regulating Kinase 1 (ASK1)-p38 Pathway-dependent Cytoplasmic Translocation of the Orphan Nuclear Receptor NR4A2 Is Required for Oxidative Stress-induced Necrosis. 2575 9