Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aggregated beta-amyloid (Abeta) binds to the neurotrophin receptor p75 and induces signaling. We examined this signaling process in different cell lines which express p75 either naturally (Schwannoma RN22 cells) or which are stably transfected with wild-type p75 (MDCKwt and PCNA cells) or with a truncated form of p75 comprising only extracellular and transmembrane domains (MDCKtm cells). While Abeta in higher concentrations (10-100 microM) is known to cause apoptosis via p75, our experiments focused on the effects of low concentrations of Abeta (25 nM) which may occur in early stages of Alzheimer disease. Application of Abeta caused tyrosine phosphorylation of wild-type p75 and induced the Ras-ERK pathway as has been reported for nerve growth factor (NGF). Since Ras activation and ERK phosphorylation (via MEK) could not be observed in MDCKtm cells and since they were clearly reduced in cells transfected with a p75 antisense construct, these effects should have been mediated by p75. Abeta also induced Ras and ERK activation in cerebellar neurons of 2-day-old rats which express p75 at that developmental stage but not TrkA; other Trk receptors were inhibited by K252a. In these neurons, Abeta led to quick formation, branching and elongation of processes. But while NGF distinctly promoted neurite branching and elongation, Abeta was less effective in neurite elongation and counts of small processes and of growth cones remained clearly elevated after 24-h stimulation; these peculiarities might be linked to aberrant neuronal connections reported for an animal model of Alzheimer disease. Essentially, the observed effects were mediated by interaction of Abeta and p75.
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PMID:Low concentrations of aggregated beta-amyloid induce neurite formation via the neurotrophin receptor p75. 1600 Dec 31

The Alzheimer's disease-linked genes, PS1 and PS2, are required for intramembrane proteolysis of multiple type I proteins, including Notch and amyloid precursor protein. In addition, it has been documented that PS1 positively regulates, whereas PS1 familial Alzheimer disease mutations suppress, phosphatidylinositol 3-kinase (PI3K)/Akt activation, a pathway known to inactivate glycogen synthase kinase-3 and reduce tau phosphorylation. In this study, we show that the loss of presenilins not only inhibits PI3K/Akt signaling and increases tau phosphorylation but also suppresses the MEK/ERK pathway. The deficits in Akt and ERK activation in cells deficient in both PS1 and PS2 (PS-/-) are evident after serum withdrawal and stimulation with fetal bovine serum or ligands of select receptor tyrosine kinases, platelet-derived growth factor receptor beta (PDGFR beta) and PDGFR alpha, but not insulin-like growth factor-1R and epidermal growth factor receptor. The defects in PDGF signaling in PS-/- cells are due to reduced expression of PDGF receptors. Whereas fetal bovine serum-induced Akt activation is reconstituted by both PS1 and PS2 in PS-/- cells, PDGF signaling is selectively restored by PS2 but not PS1 and is dependent on the N-terminal fragment of PS2 but not gamma-secretase activity or the hydrophilic loop of PS2. The rescue of PDGF receptor expression and activation by PS2 is facilitated by FHL2, a PS2-interacting transcriptional co-activator. Finally, we present evidence that PS1 mutations interfere with this PS2-mediated activity by reducing PS2 fragments. These findings highlight important roles of both presenilins in Akt and ERK signaling via select signaling receptors.
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PMID:Presenilins mediate phosphatidylinositol 3-kinase/AKT and ERK activation via select signaling receptors. Selectivity of PS2 in platelet-derived growth factor signaling. 1601 29

Extracellular-regulated kinases play a fundamental role in several neuroplasticity processes. In order to test whether endogenous beta-amyloid peptides play a role in the activation of extracellular-regulated kinase, we investigated the Rap1-extracellular-regulated kinase pathway in PC12 cells expressing human beta-amyloid precursor protein containing familial Alzheimer's disease mutations. In PC12 cells transfected with mutant human beta-amyloid precursor proteins that lead to higher levels of endogenous beta-amyloid, we observed an up-regulation of phospho-extracellular-regulated kinase and higher levels of activity-induced cAMP response element-directed gene expression. These results suggest that moderate levels of endogenous beta-amyloid peptides stimulate cAMP response element-directed gene expression. This stimulation was via a Rap1/MEK/extracellular-regulated kinase signaling pathway, as it was blocked by inhibition of Rap1 and MEK activities, and it requires beta-amyloid precursor protein cleavage at the gamma-site as it was abolished by a gamma-secretase inhibitor. Interestingly, in agreement with the previous observations, micromolar levels of extracellular fibrillar beta-amyloid blocked the cAMP response element-regulated gene expression stimulated by potassium and forskolin. This indicates that beta-amyloid can provoke different responses on cAMP response element-directed gene expression, such that low beta-amyloid levels may play a physiological role favoring synaptic plasticity under normal conditions while it would inhibit this mechanism under pathological conditions.
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PMID:Endogenous beta-amyloid peptide synthesis modulates cAMP response element-regulated gene expression in PC12 cells. 1618 36

The c-Jun N-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases are activated by pleiotropic signals including environmental stresses, growth factors, and hormones. JNK-interacting protein 1 (JIP1) is a scaffold protein that assembles and facilitates the activation of the mixed lineage kinase-dependent JNK module and also establishes an interaction with beta-amyloid precursor protein that has been partially characterized. Here we show that, similarly to other proteins involved in various neurological diseases, JIP1 becomes hyperphosphorylated following activation of stress-activated and MAP kinases. By immobilized metal affinity chromatography and a combined microcapillary LC/MALDI-TOF/ESI-ion trap mass spectrometry approach, we identified 35 sites of mitotic phosphorylation within JIP1, among which eight were present within (Ser/Thr)-Pro sequence. This motif is modified by various kinases in aggregates of the microtubule-associated protein tau, which generates typical intraneuronal lesions occurring in Alzheimer disease. Most of the post-translational modifications found were located within the JNK, MAP kinase kinase, and RAC-alpha Ser/Thr protein kinase binding regions; no modifications occurred in protein Src homology 3 and phosphotyrosine interaction domains, which are essential for binding to kinesin, beta-amyloid precursor protein, and MAP kinase kinase kinase. Protein phosphorylation is known to affect stability and protein-protein interactions. Thus, the findings that JIP1 is extensively phosphorylated after activation of stress-activated and MAP kinases indicate that these signaling pathways might modulate JIP1 signaling by regulating its stability and association with some, but not all, interacting proteins.
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PMID:Hyperphosphorylation of JNK-interacting protein 1, a protein associated with Alzheimer disease. 1619 23

Staurosporine (STS) has been reported as not only a pro-apoptotic agent, but also a terminal differentiation inducer in several neuroblastoma cell lines. Here, we report involvement of amyloid precursor protein (APP) in a STS induced astrocytic differentiation of human neural progenitor cells (NT-2/D1). We found that STS-treated NT-2/D1 cells expressed astrocyte-specific glial fibrillary acidic protein (GFAP), aspartate transporter, and glutamate transporter-1 with a distinctive astrocytic morphology. STS treatment increased GFAP promoter activity and increased expression and secretion of APP in NT-2/D1 cell culture. Overexpressed APP enhanced GFAP promoter activity and expression of GFAP, while gene silencing of APP by RNA interference decreased GFAP expression. These results indicate involvement of APP in STS induced astrocytic differentiation of NT-2/D1 cells. Furthermore, suppression of ERK1/2 phosphorylation, which is known to regulate APP expression by a MEK1 inhibitor, PD098059, reduced both APP and GFAP expression in STS treated NT-2/D1 cells. Thus, STS may induce astrocytic differentiation of NT-2/D1 by increasing APP levels associate with activation of ERK pathway.
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PMID:Amyloid precursor protein is involved in staurosporine induced glial differentiation of neural progenitor cells. 1660 Jan 75

Long-distance organelle transport toward axon terminals, critical for neuron development and function, is driven along microtubules by kinesins [1, 2]. The biophysics of force production by various kinesins is known in detail. However, the mechanisms of in vivo transport processes are poorly understood because little is known about how motor-cargo linkages are controlled. A c-Jun N-terminal kinase (JNK)-interacting protein (JIP1) has been identified previously as a linker between kinesin-1 and certain vesicle membrane proteins, such as Alzheimer's APP protein and a reelin receptor ApoER2 [3, 4]. JIPs are also known to be scaffolding proteins for JNK pathway kinases [5, 6]. Here, we report evidence that a Drosophila ubiquitin-specific hydrolase and a JNK signaling pathway that it modulates can regulate a JIP1-kinesin linkage. The JNK pathway includes a MAPKKK (Wallenda/DLK), a MAPKK (Hemipterous/MKK7), and the Drosophila JNK homolog Basket. Genetic tests indicate that those kinases are required for normal axonal transport. Biochemical tests show that activation of Wallenda (DLK) and Hemipterous (MKK7) disrupts binding between kinesin-1 and APLIP1, which is the Drosophila JIP1 homolog. This suggests a control mechanism in which an activated JNK pathway influences axonal transport by functioning as a kinesin-cargo dissociation factor.
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PMID:Control of a kinesin-cargo linkage mechanism by JNK pathway kinases. 1787 49

Mutations in the gene encoding presenilin 1 (PS1) cause the most aggressive form of early-onset familial Alzheimer disease. In addition to its well established role in Abeta production and Notch proteolysis, PS1 has been shown to mediate other physiological activities, such as regulation of the Wnt/beta-catenin signaling pathway, modulation of phosphatidylinositol 3-kinase/Akt and MEK/ERK signaling, and trafficking of select membrane proteins and/or intracellular vesicles. In this study, we present evidence that PS1 is a critical regulator of a key signaling receptor tyrosine kinase, epidermal growth factor receptor (EGFR). Specifically, EGFR levels were robustly increased in fibroblasts deficient in both PS1 and PS2 (PS(-/-)) due to delayed turnover of EGFR protein. Stable transfection of wild-type PS1 but not PS2 corrected EGFR to levels comparable to PS(+/+) cells, while FAD PS1 mutations showed partial loss of activity. The C-terminal fragment of PS1 was sufficient to fully reduce EGFR levels. In addition, the rapid ligand-induced degradation of EGFR was markedly delayed in PS(-/-) cells, resulting in prolonged signal activation. Despite the defective turnover of EGFR, ligand-induced autophosphorylation, ubiquitination, and endocytosis of EGFR were not affected by the lack of PS1. Instead, the trafficking of EGFR from early endosomes to lysosomes was severely delayed by PS1 deficiency. Elevation of EGFR was also seen in brains of adult mice conditionally ablated in PS1 and in skin tumors associated with the loss of PS1. These findings demonstrate a critical role of PS1 in the trafficking and turnover of EGFR and suggest potential pathogenic effects of elevated EGFR as well as perturbed endosomal-lysosomal trafficking in cell cycle control and Alzheimer disease.
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PMID:Presenilin 1 regulates epidermal growth factor receptor turnover and signaling in the endosomal-lysosomal pathway. 1771 70

The amyloid precursor protein (APP) is a type I transmembrane protein translocated to neuronal terminals, whose function is still unknown. The C-terminus of APP mediates its interaction with cellular adaptor and signaling proteins, some of which signal to the stress-activated protein kinase (SAPK) pathway. Here we show that ASK1, a MAPKKK that activates two SAPKs, c-Jun N-terminal-kinase (JNK) and p38, is present in a complex containing APP, phospho-MKK6, JIP1 and JNK1. In primary neurons deprived of growth factors, as well as in brains of (FAD)APP-transgenic mice, ASK1 was upregulated in neuronal projections, where it interacted with APP. In non-transgenic brains, ASK1 and APP associated mainly in the ER. Our results indicate that recruitment of ASK1 to stress-signaling complexes assembled with APP may be triggered and enhanced by cellular stress. Thus, ASK1 may be the apical MAPKKK in a signaling complex assembled with APP as a response to stress.
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PMID:Interaction of ASK1 and the beta-amyloid precursor protein in a stress-signaling complex. 1771 30

Previous studies have demonstrated that the ERK MAPK acts as a negative regulator of gamma-secretase. Here, we demonstrate that the activation of ERK MAPK pathway by sodium selenite can inhibit endogenous gamma-secretase activity. Consistently, the gamma-secretase-mediated production of amyloid-beta (Abeta) was dramatically attenuated by sodium selenite in a temporal manner. To substantiate the functional role of ERK MAPK in the regulation of gamma-secretase, we demonstrate that cells transfected with the wild-type MEK1 and a constitutively active mutant of MEK1 also displayed a significant attenuation of gamma-secretase activity. The active purified ERK1/2 can significantly reduce the gamma-secretase-mediated processing of C99, possibly through inducing alterations in the phosphorylation of both nicastrin and presenilin-1. Together, our data suggest that the selenite-elicited ERK activation could effectively reduce Abeta production, supporting that selenium compounds could represent a novel class of nutrient supplements to slow down the progression of Alzheimer's disease.
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PMID:Sodium selenite inhibits gamma-secretase activity through activation of ERK. 1854 22

The tooth is one of the ectodermal organs that develop from epithelial-mesenchymal interactions during embryonic development. An understanding of the underlying molecular mechanisms would improve our knowledge of the growth factors that regulate cell proliferation and differentiation. One of the related aspects is mitogen-activated protein kinase (MAPK) signaling in tooth differentiation. The extracellular-signal regulated kinase (ERK)/mitogen-activated protein kinase kinase (MEK) cascade plays a pivotal role in many of the essential cellular processes underlying embryonic development, including responses to major developmental changes. However, the role of the ERK pathway in molar development is unclear. This study investigated epithelial patterning and tooth growth in the mouse embryo by monitoring ERK and fibroblast growth factor (FGF) signaling. ERK, MEK, and phosphatase and tensin homolog (PTEN) were activated at different levels and locations in the developing tooth at E13.5 to E16.5 and PN2. ERK was activated in the inner dental epithelium and cervical loop, while PTEN was activated in the outer dental epithelium. In addition, only ERK was activated in secretory ameloblast at PN2. To further define the pathways involving FGF and ERK, tooth germs were cultured in the presence of compounds to inhibit MAPK/ERK-mediated signaling. Western blot analysis indicated that pERK2 was strongly activated in the tooth germ. Moreover, the activation level of pERK1 was dramatically increased by exogenous FGF10 alone and by combined treatment with FGF10 and U0126. The reported results will improve our understanding of the unique developmental processes of the dental epithelium and tooth growth, and will help to elucidate the fundamental mechanisms of ERK signaling underlying tooth development.
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PMID:ERK activation is involved in tooth development via FGF10 signaling. 1955 15


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