Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The amino acid sequence of the Alzheimer disease amyloid precursor (ADAP) has been deduced from the corresponding cDNA, and hydropathy analysis of the sequence suggests a receptor-like structure with a single transmembrane domain. The putative cytoplasmic domain of ADAP contains potential sites for serine and threonine phosphorylation. In the present study, synthetic peptides derived from this domain were used as model substrates for various purified protein kinases. Protein kinase C rapidly catalyzed the phosphorylation of a peptide corresponding to amino acid residues 645-661 of ADAP [ADAP peptide(645-661)] on Ser-655. Ca2+/calmodulin-dependent protein kinase II phosphorylated ADAP peptide (645-661) on Thr-654 and Ser-655. This peptide was virtually ineffective as a substrate for cAMP-dependent protein kinase, cGMP-dependent protein kinase, casein kinase II, or insulin receptor protein-tyrosine kinase. When a homogenate of rat cerebral cortex was used as the source of protein kinase, phosphorylation of ADAP peptide(645-661) was stimulated by calcium/phosphatidylserine/diolein to a level 4.6-fold above the basal level of phosphorylation, consistent with a prominent stimulation by protein kinase C. Using rat cerebral cortex synaptosomes prelabeled with 32Pi, a 32P-labeled phosphoprotein of approximately equal to 135 kDa was immunoprecipitated by using antisera prepared against ADAP peptide(597-624), consistent with the possibility that the holoform of ADAP in rat brain is a phosphoprotein. Based on analogy with the effect of phosphorylation by protein kinase C of juxtamembrane residues in the cytoplasmic domain of the epidermal growth factor receptor and the interleukin 2 receptor, phosphorylation of ADAP may target it for internalization.
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PMID:Phosphorylation of Alzheimer disease amyloid precursor peptide by protein kinase C and Ca2+/calmodulin-dependent protein kinase II. 313 67

Picomolar concentrations of purified amyloid precursor protein (APP) potentiate the neurotrophic activity of suboptimal concentrations of NGF on PC12 cells. To understand the molecular basis for this potentiation, we have characterized the signal transduction pathway used by APP for its neurotrophic activity. APP stimulated the tyrosine phosphorylation of a number of proteins including insulin receptor substrate-1 (IRS-1). Incubation of naive cells with antisense oligonucleotides to IRS-1 mRNA resulted in a dramatic reduction of IRS-1 levels and inhibition of APP stimulated neurite outgrowth. Phosphotidylinositol 3-kinase became associated with IRS-1 and activated upon APP stimulation. Extracellular signal-regulated kinase (ERK 1 and ERK 2) phosphorylation was detected by both immunoblot analysis and immunocytochemistry using antibodies directed to their phosphorylated (and hence, activated) form. There was also an elevation of ERK kinase activity. The potentiation of NGF activity was reflected in a correspondingly synergistic elevation of tyrosine phosphorylated ERK. The pattern of signal transduction targets indicates that APP potentiated the neurotrophic effects of NGF via the activation of the IRS-1 signaling pathway.
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PMID:Amyloid precursor protein requires the insulin signaling pathway for neurotrophic activity. 949 42

Angiogenesis, the formation of new capillary blood vessels, is essential not only for the growth and metastasis of solid tumors, but also for wound and ulcer healing, because without the restoration of blood flow, oxygen and nutrients cannot be delivered to the healing site. Nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin and ibuprofen are the most widely used drugs for pain, arthritis, cardiovascular diseases and, more recently, the prevention of colon cancer and Alzheimer disease. However, NSAIDs produce gastroduodenal ulcers in about 25% of users (often with bleeding and/or perforations) and delay ulcer healing, presumably by blocking prostaglandin synthesis from cyclooxygenase (COX)-1 and COX-2 (ref. 10). The hypothesis that the gastrointestinal side effects of NSAIDs result from inhibition of COX-1, but not COX-2 (ref. 11), prompted the development of NSAIDs that selectively inhibit only COX-2 (such as celecoxib and rofecoxib). Our study demonstrates that both selective and nonselective NSAIDs inhibit angiogenesis through direct effects on endothelial cells. We also show that this action involves inhibition of mitogen-activated protein (MAP) kinase (ERK2) activity, interference with ERK nuclear translocation, is independent of protein kinase C and has prostaglandin-dependent and prostaglandin-independent components. Finally, we show that both COX-1 and COX-2 are important for the regulation of angiogenesis. These findings challenge the premise that selective COX-2 inhibitors will not affect the gastrointestinal tract and ulcer/wound healing.
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PMID:Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing. 1058 Oct 68

To explore the direct role of beta-amyloid (Abeta) and carboxyl-terminal fragments of amyloid precursor protein in the inflammatory processes possibly linked to neurodegeneration associated with Alzheimer's disease, the effects of the 105-amino acid carboxyl-terminal fragment (CT(105)) of amyloid precursor protein on the production of tumor necrosis factor-alpha (TNF-alpha) and matrix metalloproteinase-9 (MMP-9) were examined in a human monocytic THP-1 cell line and compared with that of Abeta. CT(105) elicited a marked increase in TNF-alpha and MMP-9 production in the presence of interferon-gamma in a dose- and time-dependent manner. Similar patterns were obtained with Abeta despite its low magnitude of induction. Autocrine TNF-alpha is likely to be a main mediator of the induction of MMP-9 because the neutralizing antibody to TNF-alpha inhibits MMP-9 production. Genistein, a specific inhibitor of tyrosine kinase, dramatically diminished both TNF-alpha secretion and subsequent MMP-9 release in response to CT(105) or Abeta. Furthermore, PD98059 and SB202190, specific inhibitors of ERK or p38 MAPK respectively, efficiently suppressed CT(105)-induced effects whereas only PD98059 was effective at reducing Abeta-induced effects. Our results suggest that CT(105) in combination with interferon-gamma might serve as a more potent activator than Abeta in triggering inflammatory processes and that both tyrosine kinase and MAPK signaling pathways may represent potential therapeutic targets for the control of Alzheimer's disease progression.
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PMID:Effects of the beta-amyloid and carboxyl-terminal fragment of Alzheimer's amyloid precursor protein on the production of the tumor necrosis factor-alpha and matrix metalloproteinase-9 by human monocytic THP-1. 1130 64

There are multiple lines of evidence showing that oxidative stress and aberrant mitogenic signaling play an important role in the pathogenesis of Alzheimer disease. However, the chronological relationship between these and other events associated with disease pathogenesis is not known. Given the important role that mitogen-activated protein kinase (MAPK) pathways play in both mitogenic signaling (ERK) and cellular stress signaling (JNK/SAPK and p38), we investigated the chronological and spatial relationship between activated ERK, JNK/SAPK and p38 during disease progression. While all three kinases are activated in the same susceptible neurons in mild and severe cases (Braak stages III-VI), in non-demented cases with limited pathology (Braak stages I and II), both ERK and JNK/SAPK are activated but p38 is not. However, in non-demented cases lacking any sign of pathology (Braak stage 0), either ERK alone or JNK/SAPK alone can be activated. Taken together, these findings indicate that MAPK pathways are differentially activated during the course of Alzheimer disease and, by inference, suggest that both oxidative stress and abnormalities in mitotic signaling can independently serve to initiate, but both are necessary to propagate, disease pathogenesis. Therefore, we propose that both 'hits', oxidative stress and mitotic alterations, are necessary for the progression of Alzheimer disease.
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PMID:Differential activation of neuronal ERK, JNK/SAPK and p38 in Alzheimer disease: the 'two hit' hypothesis. 1164 Sep 50

The cytoplasmic tail of the beta-amyloid precursor protein (APP) contains a Y(682)ENPTY(687) sequence through which APP associates with phosphotyrosine binding (PTB) domain containing proteins in a tyrosine phosphorylation-independent manner. We have recently found that tyrosine phosphorylation of APP-Y(682) promotes docking of Shc proteins that modulate growth factor signaling to the ERK and PI3K/Akt pathways. We have also shown that APP is phosphorylated on Y(682) in cells that overexpress a constitutively active form of the tyrosine kinase abl. Here we present evidence that the nerve growth factor receptor TrkA may also promote phosphorylation of APP. Overexpression of TrkA, but not of mutated, kinase inactive TrkA resulted in tyrosine phosphorylation of APP. Site-directed mutagenesis studies showed that TrkA overexpression was associated with phosphorylation of APP-Y(682). Moreover, overexpression of TrkA also affected APP processing reducing the generation of the APP intracellular domain (AID). Thus, tyrosine phosphorylation of APP may functionally link APP processing and neurotrophic signaling to intracellular pathways associated with cellular differentiation and survival.
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PMID:Evidence for a role of the nerve growth factor receptor TrkA in tyrosine phosphorylation and processing of beta-APP. 1215 Sep 51

Oxidative stress in the human brain has been strongly implicated as the cause of neuronal cell losses in Alzheimer's disease patients, but the exact mechanism still remains unknown. In this report several oxidative stress parameters and an associated signalling transduction cascade predating neuronal cell death in cultures treated with the oxidative stressors Fe(2+) (5 microm) and the amyloid beta (A beta(1-40)) peptide (5 microm) were studied. Production of reactive oxygen species as detected by dichlorofluorescein staining was apparent within 5 min in the presence of both agents. Lipid peroxide content increased by approximately 10-fold after 2 h, while mitochondrial activity was impaired by 40% after 6 h. Caspase-3 activity was elevated 5-6 fold, all indicative of oxidative cell stress. The combined presence of A beta(1-40) and Fe(2+) resulted in a rapid (5 min) ERK activation followed by a decline by 30 min and a second activation that continued up to 24 h when nuclear translocation was noticed. Neither treatment with Fe(2+) nor that with A beta(1-40) alone caused similar changes. Addition of either deferroxamine (DFe, 25 microm), catalase (0.4 mg/mL) or N-acetyl cysteine (0.5 mm) - the last two known as suppressants of oxidative stress - attenuated ERK activation and nuclear translocation. The mitogen-activated protein/ERK kinase (MEK) inhibitor U0126 blocked ERK and caspase 3 activation, suppressed ERK translocation and reduced the number of apoptotic cells, suggesting a central role for the ERK signalling cascade in A beta(1-40) plus Fe(2+) (A beta(1-40)/Fe(2+)) -induced apoptotic death. The full peptide A beta(1-42) was very effective at 0.5 microm while the inverse peptide A beta(40-1) at 5 microm was ineffective. The acetyl-amyloid-beta protein amide fragment 15-20 (V-pep) known to be an A beta aggregation inhibitor, prevented A beta(1-40)/Fe(2+)-induced toxicity. These findings indicate that metal ions chelators and antioxidants suppress the A beta(1-40)/Fe(2+)-induced oxidative stress cascade and may be beneficial in reducing the severity of Alzheimer's disease.
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PMID:ERK activation and nuclear translocation in amyloid-beta peptide- and iron-stressed neuronal cell cultures. 1215 30

The signalling pathways by which muscarine and epidermal growth factor (EGF) regulate the secretion of the alpha-secretase cleavage product (sAPPalpha) of the amyloid precursor protein (APP) were examined in the human neuroblastoma SH-SY5Y. Using specific inhibitors it was found that over 80% of sAPPalpha secretion, enhanced by muscarine, occurred via the extracellular signal-regulated kinase (ERK1/2) member of the mitogen-activated protein kinase (MAPK) family and was dependent on protein kinase Calpha (PKCalpha) and a member of the Src family of non-receptor tyrosine kinases (Src-TK). In contrast the stimulation of sAPPalpha secretion by EGF was not affected by inhibitors of PKC nor Src-TK but was dependent on ERK1/2. In addition muscarine-enhanced sAPPalpha secretion and ERK1/2 activation were inhibited 60 and 80%, respectively, by micromolar concentrations of the phosphatidylinositol 3 kinase (PI-3K) inhibitor wortmannin. In comparison wortmannin decreased EGF stimulation of sAPPalpha secretion and ERK 1/2 activation by approximately 40%. Unexpectedly, U73122, an inhibitor of phosphoinositide-specific phospholipase C, did not inhibit muscarine enhancement of sAPPalpha secretion. These data are discussed in relation to a pathway for the enhancement of sAPPalpha secretion by muscarine which involves the activation of a Src-TK by G-protein beta/gamma-subunits leading to activation of PKCalpha, and ERK1/2 by a mechanism not involving phospholipase C.
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PMID:Muscarine enhances soluble amyloid precursor protein secretion in human neuroblastoma SH-SY5Y by a pathway dependent on protein kinase C(alpha), src-tyrosine kinase and extracellular signal-regulated kinase but not phospholipase C. 1219 95

The biological function of full-length amyloid-beta protein precursor (AbetaPP), the precursor of Abeta, is not fully understood. Multiple laboratories have reported that antibody binding to cell surface AbetaPP causes neuronal cell death. Here we examined whether induced dimerization of the cytoplasmic domain of AbetaPP (AbetaPPCD) triggers neuronal cell death. In neurohybrid cells expressing fusion constructs of the epidermal growth factor (EGF) receptor with AbetaPPCD (EGFR/AbetaPP hybrids), EGF drastically enhanced neuronal cell death in a manner sensitive to acetyl-l-aspartyl-l-glutamyl-l-valyl-l-aspartyl-aldehyde (Ac-DEVD-CHO; DEVD), GSH-ethyl ester (GEE), and pertussis toxin (PTX). Dominant-negative apoptosis signal-regulating kinase 1 (ASK1) blocked this neuronal cell death, but not alpha-synuclein-induced cell death. Constitutively active ASK1 (caASK1) caused DEVD/GEE-sensitive cell death in a manner resistant to PTX and sensitive to Humanin, which also suppressed neuronal cell death by EGFR/AbetaPP hybrid. ASK1 formed a complex with AbetaPPCD via JIP-1b, the c-Jun N-terminal kinase (JNK)-interacting protein. EGFR/AbetaPP hybrid-induced and caASK1-induced neuronal cell deaths were specifically blocked by SP600125 (anthra[1,9-cd]pyrazol-6(2H)-one), a specific JNK inhibitor. Combined with our earlier study, these data indicate that dimerization of AbetaPPCD triggers ASK1/JNK-mediated neuronal cell death. We also noticed a potential role of ASK1/JNK in sustaining the activity of this mechanism after initial activation by AbetaPP, which allows for the achievement of cell death by short-term anti-AbetaPP antibody treatment. Understanding the function of AbetaPPCD and its downstream pathway should lead to effective anti-Alzheimer's disease therapeutics.
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PMID:The cytoplasmic domain of Alzheimer's amyloid-beta protein precursor causes sustained apoptosis signal-regulating kinase 1/c-Jun NH2-terminal kinase-mediated neurotoxic signal via dimerization. 1282 23

The increased intracellular levels and aberrant processing of the amyloid precursor protein (APP) are associated with beta-amyloid peptide (A beta) production, cerebrovascular amyloid deposition, and amyloid plaque formation. Here we report that APP level, soluble APP (sAPP) secretion, and A beta production in HEK293 cells transfected with either wild-type APP(751) or APP(751) carrying the Swedish mutation are all elevated by hepatocyte growth factor (HGF). We investigated the potential molecular mechanisms underlying the HGF effect. Our data show that HGF stimulated extended activation of extracellular signal-regulated protein kinases (ERK1/2). Pretreatment of cells with inhibitors (UO126 or PD98059) for MEK, the upstream kinase of ERK1/2, abolished ERK1/2 activation evoked by HGF, and abrogated HGF-induced increases in APP levels and sAPP secretion. In addition, transient expression of active MEK1 activated ERK1/2 and increased intracellular APP levels and sAPP secretion. Inhibition of ERK1/2 activity, however, failed to block HGF-stimulated A beta production. Consistently, transient expression of active MEK1 did not increase A beta accumulation. Taken together, these results suggest that: (1) HGF regulates the intracellular levels of APP and the secretion of sAPP and A beta; (2) the modulation of APP levels and sAPP secretion induced by HGF is mediated via the MEK1/ERK1/2 signaling pathway; (3) HGF-stimulated A beta production is independent of ERK activity and, therefore, independent of HGF-evoked elevation of intracellular APP levels.
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PMID:Regulation of amyloid precursor protein expression and secretion via activation of ERK1/2 by hepatocyte growth factor in HEK293 cells transfected with APP751. 1283 93


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