p(FPLX:JNK)

Entity

Name

JNK

Namespace

FPLX

Namespace Version

20180917

Namespace URL

https://raw.githubusercontent.com/sorgerlab/famplex/e8ae9926ff95266032cb74f77973c84939bffbeb/export/famplex.belns

In neuroblastoma cells, as well as cultured hippocampal neurons, Abeta activates JNK and ERK, and blocking these prevents Abeta hyperphosphorylating tau protein, as does alpha7 antisense oligonucleotides or alpha7 antagonists, suggesting that Abeta may trigger tau protein phosphorylation through ERK and JNK via alpha7 receptors (Wang et al., 2003b). Abeta leads to phosphorylation of AKT in cultured mouse neurons through a mechanism that requires alpha7 nAChRs (Abbott et al., 2008), AKT phosphorylation levels returning to baseline upon prolonged application of Abeta. PubMed:19293145

Which pathway is activated by Abeta depends upon the time of exposure to the amyloid peptide: chronic applications of oligomeric Abeta to hippocampal slice cultures activate the JNK/MAPK pathway but inhibit the ERK/MAPK pathway, whereas short-term applications of Abeta oligomers do not activate JNK (Bell et al., 2004). This may be one of the routes whereby Abeta impairs memory, because ERK-1 and ERK-2 play key roles in the signaling events central to memory (Satoh et al., 2007). PubMed:19293145

Nicotine may regulate the neuroprotective secretion of TNFalpha by microglia through enhancement of lowlevel TNF secretion and suppression of lipopolysaccharide- induced TNFalpha secretion (Suzuki et al., 2006; Park et al., 2007) via alpha7-dependent activation of JNK and MAPK pathways. PubMed:19293145

Utilizing Western blot, electrophoretic mobility shift assay, supershift and reverse transcriptase-polymerase chain reaction techniques, it has been demonstrated that micromolar S100B concentrations stimulate c-Jun N-terminal kinase (JNK) phosphorylation through the receptor for advanced glycation ending products, and subsequently activate nuclear AP-1/cJun transcription, in cultured human neural stem cells. In addition, as revealed by Western blot, small interfering RNA and immunofluorescence analysis, S100B-induced JNK activation increased expression of Dickopff-1 that, in turn, promoted glycogen synthase kinase 3β phosphorylation and β-catenin degradation, causing canonical Wnt pathway disruption and tau protein hyperphosphorylation. These findings propose a previously unrecognized link between S100B and tau hyperphosphorylation, suggesting S100B can contribute to NFT formation in AD and in all other conditions in which neuroinflammation may have a crucial role. PubMed:18494933

Utilizing Western blot, electrophoretic mobility shift assay, supershift and reverse transcriptase-polymerase chain reaction techniques, it has been demonstrated that micromolar S100B concentrations stimulate c-Jun N-terminal kinase (JNK) phosphorylation through the receptor for advanced glycation ending products, and subsequently activate nuclear AP-1/cJun transcription, in cultured human neural stem cells. In addition, as revealed by Western blot, small interfering RNA and immunofluorescence analysis, S100B-induced JNK activation increased expression of Dickopff-1 that, in turn, promoted glycogen synthase kinase 3β phosphorylation and β-catenin degradation, causing canonical Wnt pathway disruption and tau protein hyperphosphorylation. These findings propose a previously unrecognized link between S100B and tau hyperphosphorylation, suggesting S100B can contribute to NFT formation in AD and in all other conditions in which neuroinflammation may have a crucial role. PubMed:18494933

In the present study we injected bilaterally 3-morpholino-sydnonimine (SIN-1), a recognized and widely used peroxynitrite donor (25–30), into rat hippocampus, and investigated whether or not peroxynitrite could induce simultaneously nitration and hyperphosphorylation of tau and the underlying mechanisms in vivo. The level of nitrated and hyperphosphorylated tau was markedly increased in rat hippocampus 24 h, and prevented by preinjection of uric acid, a natural scavenger of peroxynitrite. GSK-3beta and p38 MAPKs, including p38alpha, p38beta, and p38delta activity was increased, but no change in the activity of p38gamma, ERK, and c-Jun amino-terminal kinase (JNK). Both nitrated tau and hyperphosphorylated tau were aggregated in the hippocampus, with activity of 20S proteasome significantly arrested in SIN-1-injected rats. Hyperphosphorylated tau was degraded as efficiently as normal tau by 20S proteasome, but the nitrated tau with an unorderly secondary structure became more resistant to the proteolysis, providing evidence that peroxynitrite simultaneously induces tau hyperphosphorylation, nitration, and accumulation, and that activation of GSK-3beta, p38alpha, p38beta, p38delta isoforms and the inhibition of proteasome activity are respectively responsible for the peroxynitrite-induced tau hyperphosphorylation and accumulation. PubMed:16816118

Only middle-aged Tet-mev-1 mice showed JNK/MARK activation and Ca2+ overload, particularly in astrocytes with decreased hippocampal GFAP and S100ß, but without pathological features such as apoptosis, amyloidosis, and lactic acidosis in neurons and astrocytes. This led to decreasing levels of glial fibrillary acidic protein and S100β in the hippocampal area. PubMed:27623715

Overexpression of wild-type UNC5C causes low-grade death, intensified by an AD-linked mutation T835M inhibited by a AD-linked survival factor, calmodulin-like skin protein (CLSP), and a natural ligand of UNC5C, netrin1. T835M-UNC5C-induced neuronal cell death is mediated by an intracellular death-signaling cascade, consisting of DAPK1/protein kinase D/apoptosis signal-regulating kinase 1 (ASK1)/JNK/NADPH oxidase/caspases, which merges at ASK1 with a death-signaling cascade, mediated by amyloid ß precursor protein (APP). PubMed:27068745

Collectively, these studies demonstrate that the soluble, astroglial-derived S100B protein interacts with RAGE leading to the JNK phosphorylation and the pJNK-dependent up-regulation of c-Jun, a component of the AP-1 complex. PubMed:18494933

Overexpression of wild-type UNC5C causes low-grade death, intensified by an AD-linked mutation T835M inhibited by a AD-linked survival factor, calmodulin-like skin protein (CLSP), and a natural ligand of UNC5C, netrin1. T835M-UNC5C-induced neuronal cell death is mediated by an intracellular death-signaling cascade, consisting of DAPK1/protein kinase D/apoptosis signal-regulating kinase 1 (ASK1)/JNK/NADPH oxidase/caspases, which merges at ASK1 with a death-signaling cascade, mediated by amyloid ß precursor protein (APP). PubMed:27068745

Overexpression of wild-type UNC5C causes low-grade death, intensified by an AD-linked mutation T835M inhibited by a AD-linked survival factor, calmodulin-like skin protein (CLSP), and a natural ligand of UNC5C, netrin1. T835M-UNC5C-induced neuronal cell death is mediated by an intracellular death-signaling cascade, consisting of DAPK1/protein kinase D/apoptosis signal-regulating kinase 1 (ASK1)/JNK/NADPH oxidase/caspases, which merges at ASK1 with a death-signaling cascade, mediated by amyloid ß precursor protein (APP). PubMed:27068745

Specific PP2A inhibition has been proven to lead to in vivo deregulation of many major brain Ser/Thr kinases implicated in AD, including GSK3β (Wang et al., 2010; Louis et al., 2011), cdk5 (Louis et al., 2011; Kimura et al., 2013), extracellular signal- regulated kinase (ERK) and JNK (Kins et al., 2003). PubMed:24653673

In contrast, SP600125 treatment, a JNK inhibitor, increases the p38 MAPK depen- dent phosphorylation of p65 NF-κB subunit in the nucleus [47]. PubMed:27288790

Utilizing Western blot, electrophoretic mobility shift assay, supershift and reverse transcriptase-polymerase chain reaction techniques, it has been demonstrated that micromolar S100B concentrations stimulate c-Jun N-terminal kinase (JNK) phosphorylation through the receptor for advanced glycation ending products, and subsequently activate nuclear AP-1/cJun transcription, in cultured human neural stem cells. In addition, as revealed by Western blot, small interfering RNA and immunofluorescence analysis, S100B-induced JNK activation increased expression of Dickopff-1 that, in turn, promoted glycogen synthase kinase 3β phosphorylation and β-catenin degradation, causing canonical Wnt pathway disruption and tau protein hyperphosphorylation. These findings propose a previously unrecognized link between S100B and tau hyperphosphorylation, suggesting S100B can contribute to NFT formation in AD and in all other conditions in which neuroinflammation may have a crucial role. PubMed:18494933

Utilizing Western blot, electrophoretic mobility shift assay, supershift and reverse transcriptase-polymerase chain reaction techniques, it has been demonstrated that micromolar S100B concentrations stimulate c-Jun N-terminal kinase (JNK) phosphorylation through the receptor for advanced glycation ending products, and subsequently activate nuclear AP-1/cJun transcription, in cultured human neural stem cells. In addition, as revealed by Western blot, small interfering RNA and immunofluorescence analysis, S100B-induced JNK activation increased expression of Dickopff-1 that, in turn, promoted glycogen synthase kinase 3β phosphorylation and β-catenin degradation, causing canonical Wnt pathway disruption and tau protein hyperphosphorylation. These findings propose a previously unrecognized link between S100B and tau hyperphosphorylation, suggesting S100B can contribute to NFT formation in AD and in all other conditions in which neuroinflammation may have a crucial role. PubMed:18494933

Collectively, these studies demonstrate that the soluble, astroglial-derived S100B protein interacts with RAGE leading to the JNK phosphorylation and the pJNK-dependent up-regulation of c-Jun, a component of the AP-1 complex. PubMed:18494933

In addition, as revealed by Western blot, small interfering RNA and immunofluorescence analysis, S100B-induced JNK activation increased expression of Dickopff-1 that, in turn, promoted glycogen synthase kinase 3-beta phosphorylation and beta-catenin degradation, causing canonical Wnt pathway disruption and tau protein hyperphosphorylation. PubMed:18494933

Overexpression of wild-type UNC5C causes low-grade death, intensified by an AD-linked mutation T835M inhibited by a AD-linked survival factor, calmodulin-like skin protein (CLSP), and a natural ligand of UNC5C, netrin1. T835M-UNC5C-induced neuronal cell death is mediated by an intracellular death-signaling cascade, consisting of DAPK1/protein kinase D/apoptosis signal-regulating kinase 1 (ASK1)/JNK/NADPH oxidase/caspases, which merges at ASK1 with a death-signaling cascade, mediated by amyloid ß precursor protein (APP). PubMed:27068745

Overexpression of wild-type UNC5C causes low-grade death, intensified by an AD-linked mutation T835M inhibited by a AD-linked survival factor, calmodulin-like skin protein (CLSP), and a natural ligand of UNC5C, netrin1. T835M-UNC5C-induced neuronal cell death is mediated by an intracellular death-signaling cascade, consisting of DAPK1/protein kinase D/apoptosis signal-regulating kinase 1 (ASK1)/JNK/NADPH oxidase/caspases, which merges at ASK1 with a death-signaling cascade, mediated by amyloid ß precursor protein (APP). PubMed:27068745