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

We have previously demonstrated that the secreted form of the beta-amyloid precursor protein (beta-APP) activates mitogen-activated protein (MAP) kinases in PC-12 pheochromocytoma cells. beta-APP as well as other treatments that activate MAP kinase also enhance phosphorylation of the microtubule-associated protein tau in these cells. In this study, we extended this analysis to neurons. Using dissociated cultures of cortical neurons, we found that exposure to beta-APP activated MAP kinase 4 and 7 days but not 1 day after plating. Phosphorylation of tau in neurons was measured by immunoreactivity with the AT8 antibody, which recognizes a phosphorylated epitope present in tau from paired helical filaments. We found that activation of MAP kinase in neurons was associated with increased amounts of AT8-reactive tau. These results support a role for MAP kinase in transducing the biological effects of secreted beta-APP on neurons and suggest possible mechanisms by which beta-APP might be involved in the pathogenesis of Alzheimer's disease.
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PMID:Secreted beta-APP stimulates MAP kinase and phosphorylation of tau in neurons. 756 49

Microtubule-associated protein tau from Alzheimer brain has been shown to be phosphorylated at several ser/thr-pro and ser/thr-X sites (Hasegawa, M. et al., J. Biol. Chem. 267, 17047-17054, 1992). Several proline-dependent protein kinases (PDPKs) (MAP kinase, cdc2 kinase, glycogen synthase kinase-3, tubulin-activated protein kinase, and 40 kDa neurofilament kinase) are implicated in the phosphorylation of the ser-thr-pro sites. The identity of the kinase(s) that phosphorylate the ser/thr-X sites are unknown. To identify the latter kinase(s) we have compared the phosphorylation of bovine tau by several brain protein kinases. Stoichiometric phosphorylation of tau was achieved by casein kinase-1, calmodulin-dependent protein kinase II, Gr kinase, protein kinase C and cyclic AMP-dependent protein kinase, but not with casein kinase-2 or phosphorylase kinase. Casein kinase-1 and calmodulin-dependent protein kinase II were the best tau kinases, with greater than 4 mol and 3 mol 32P incorporated, respectively, into each mol of tau. With the sequential addition of these two kinases, 32P incorporation approached 6 mol. Peptide mapping revealed that the different kinases largely phosphorylate different sites on tau. After phosphorylation by casein kinase-1, calmodulin-dependent protein kinase II, Gr kinase, cyclic AMP-dependent protein kinase and casein kinase-2, the mobility of tau isoforms as detected by SDS-PAGE was decreased. Protein kinase C phosphorylation did not produce such a mobility shift. Our results suggest that one or more of the kinases studied here may participate in the hyperphosphorylation of tau in Alzheimer disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of the phosphorylation of microtubule-associated protein tau by non-proline dependent protein kinases. 803 84

Biological effects related to cell growth, as well as a role in the pathogenesis of Alzheimer disease, have been ascribed to the beta-amyloid precursor protein (beta-APP). Little is known, however, about the intracellular cascades that mediate these effects. We report that the secreted form of beta-APP potently stimulates mitogen-activated protein kinases (MAPKs). Brief exposure of PC-12 pheochromocytoma cells to beta-APP secreted by transfected Chinese hamster ovary cells stimulated the 43-kDa form of MAPK by > 10-fold. Induction of a dominant inhibitory form of ras in a PC12-derived cell line prevented the stimulation of MAPK by secreted beta-APP, demonstrating the dependence of the effect upon p21ras. Because the microtubule-associated protein tau is hyperphosphorylated in Alzheimer disease, we sought and found a 2-fold enhancement in tau phosphorylation associated with the beta-APP-induced MAPK stimulation. In the ras dominant inhibitory cell line, beta-APP failed to enhance phosphorylation of tau. The data presented here provide a link between secreted beta-APP and the phosphorylation state of tau.
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PMID:Secreted beta-amyloid precursor protein stimulates mitogen-activated protein kinase and enhances tau phosphorylation. 804 53

We have shown earlier that certain proline-directed kinases such as MAP kinase or GSK-3 can phosphorylate tau protein in an abnormal manner reminiscent of tau from Alzheimer paired helical filaments [Drewes et al. (1992); Mandelkow et al. (1992)]. Both kinases are abundant in brain tissue and associate physically with microtubules through several cycles of assembly and disassembly. In this report we show that cdk2/cyclin A incorporates = 5 Pi into recombinant tau, and that it also induces the MR shift and antibody reactivity typical of Alzheimer tau. However, since there is no cdk2 in brain [Meyerson et al. (1992)] we looked for other members of this family of kinases. Using an antibody against the conserved N-terminus we isolated a cdk-like kinase from brain which was capable of inducing the Alzheimer-like characteristics in tau by phosphorylation. Its size (31 kDa), target specificity (proline-directed), chromatographic behavior, and abundance in brain suggest that this kinase is similar or identical to the neuronal cdc2-like kinase nclk alias PSSARLE or cdk5 [Hellmich et al. (1992); Meyerson et al. (1992); Xiong et al. (1992); Tsai et al. (1993)]. This was confirmed by an antibody specific for cdk5. Like MAP kinase and GSK-3, this kinase is physically associated with microtubules and can be enriched by cycles of microtubule assembly and disassembly. Thus, cdk5 should be regarded as another kinase that could be held responsible for the changes in tau protein during Alzheimer disease progression.
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PMID:Abnormal Alzheimer-like phosphorylation of tau-protein by cyclin-dependent kinases cdk2 and cdk5. 828 4

The secreted form of the beta-amyloid precursor protein (beta-APP) has previously been shown to stimulate mitogen-activated protein (MAP) kinases in PC-12 pheochromocytoma cells. The amino-terminal half of secreted beta-APP contains a region rich in cysteine residues reminiscent of cysteine-rich binding regions in other families of extracellular proteins. We found that reductive alkylation of disulfide linkages eliminated the ability of secreted beta-APP to activate MAP kinase. To confirm the role of the cysteine-rich amino-terminal region, fragments representing the amino- and carboxyl-terminal halves of secreted beta-APP were expressed in bacteria as fusion proteins and purified. Ten-minute treatment with the amino-terminal segment of beta-APP activated MAP kinase approximately 15-fold, while the carboxyl segment had no effect. The amino-terminal fragment, like intact secreted beta-APP, was substantially inactivated by reduction of sulfhydryl groups. These results suggest that the amino-terminal region of beta-APP is responsible for activation of MAP kinase and that it requires structural loops created by disulfide linkages for activity.
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PMID:Amino-terminal region of the beta-amyloid precursor protein activates mitogen-activated protein kinase. 857 96

The two pathological lesions found in the brains of Alzheimer's disease patients, neurofibrillary tangles and neuritic plaques, are likely to be formed through a common pathway. Neurofibrillary tangles are intracellular aggregates of paired helical filaments, the main component of which is hyperphosphorylated forms of the microtubule-associated protein tau. Extracellular neuritic plaques and diffuse and vascular amyloid deposits are aggregates of beta-amyloid protein, a 4-kDa protein derived from the amyloid precursor protein (APP). Using conditions in vitro under which two proline-directed protein kinases, glycogen synthase kinase-3beta (GSK-3beta) and mitogen-activated protein kinase (MAPK), were able to hyperphosphorylate tau, GSK-3beta but not MAPK phosphorylated recombinant APPcyt. The sole site of phosphorylation in APPcyt by GSK-3beta was determined by phosphoamino acid analysis and phosphorylation of APPcyt mutant peptides to be Thr743 (numbering as for APP770). This site was confirmed by endoproteinase Glu-C digestion of APPcyt and peptide sequencing. The ability of GSK-3beta to phosphorylate APPcyt and tau provides a putative link between the two lesions and indicates a critical role of GSK-3beta in the pathogenesis of Alzheimer's disease.
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PMID:In vitro phosphorylation of the cytoplasmic domain of the amyloid precursor protein by glycogen synthase kinase-3beta. 876 98

We have investigated in rat pheochromacytoma PC12 cells the activation of the mitogen-activated protein kinases ERK1 and ERK2 by the mitochondrial uncoupler carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP). This treatment slowly decreases ATP levels to 30% of control, whereas the internal calcium level rises very rapidly to 250% of control, derived from internal stores. Tyrosine phosphorylation of ERK1 and ERK2 increases gradually, starting after 5 min of treatment, to reach a maximum at 30 min; the kinase activity reaches 250% when measured after 1 hr of treatment. The drop in ATP levels is slower still. Comparison of the time courses of the rapid rise in cytosolic calcium with the slower increase in ERK1 and ERK2 activation suggests one or more intermediate stages in this pathway. Chelation of cytosolic calcium with dimethyl bis-(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid abolished the FCCP-stimulated rise in internal calcium, as well as the tyrosine phosphorylation and the activation of the ERKs. Surprisingly, caffeine, which releases calcium from different internal stores, did not increase the tyrosine phosphorylation and did not activate the ERKs. The FCCP effect on calcium storage may be related to mitochondrial dysfunction in Alzheimer disease, which might result in ineffective buffering of cytosolic calcium that leads to mitogen-activated protein kinase activation and subsequent protein phosphorylations.
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PMID:Compromised mitochondrial function leads to increased cytosolic calcium and to activation of MAP kinases. 927 88

Catabolic processing of the amyloid precursor protein (APP) is subject to regulatory control by protein kinases. We hypothesized that this regulation involves sequential activation of the enzymes mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated protein kinase (ERK). In the present investigation, we provide evidence that MEK is critically involved in regulating APP processing by both nerve growth factor and phorbol esters. Western blot analysis of the soluble N-terminal APP derivative APPs demonstrated that the synthetic MEK inhibitor PD 98059 antagonized nerve growth factor stimulation of both APPs production and ERK activation in PC12 cells. Moreover, PD 98059 inhibited phorbol ester stimulation of APPs production and activation of ERK in both human embryonic kidney cells and cortical neurons. Furthermore, overexpression of a kinase-inactive MEK mutant inhibited phorbol ester stimulation of APP secretion and activation of ERK in human embryonic kidney cell lines. Most important, PD 98059 antagonized phorbol ester-mediated inhibition of Abeta secretion from cells overexpressing human APP695 carrying the "Swedish mutation." Taken together, these data indicate that MEK and ERK may be critically involved in protein kinase C and nerve growth factor regulation of APP processing. The mitogen-activated protein kinase cascade may provide a novel target for altering catabolic processing of APP.
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PMID:Regulation of amyloid precursor protein catabolism involves the mitogen-activated protein kinase signal transduction pathway. 939 Sep 97

Activation of protein kinase C (PKC) regulates the processing of Alzheimer amyloid precursor protein (APP) into its soluble form (sAPP) and amyloid beta-peptide (A beta). However, little is known about the intermediate steps between PKC activation and modulation of APP metabolism. Using a specific inhibitor of mitogen-activated protein (MAP) kinase kinase activation (PD 98059), as well as a dominant negative mutant of MAP kinase kinase, we show in various cell lines that stimulation of PKC by phorbol ester rapidly induces sAPP secretion through a mechanism involving activation of the MAP kinase cascade. In PC12-M1 cells, activation of MAP kinase by nerve growth factor was associated with stimulation of sAPP release. Conversely, M1 muscarinic receptor stimulation, which is known to act in part through a PKC-independent pathway, increased sAPP secretion mainly through a MAP kinase-independent pathway. A beta secretion and its regulation by PKC were not affected by PD 98059, supporting the concept of distinct secretory pathways for A beta and sAPP formation.
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PMID:Regulation of secretion of Alzheimer amyloid precursor protein by the mitogen-activated protein kinase cascade. 945 46

In Alzheimer disease brain the microtubule associated protein (MAP) tau is abnormally hyperphosphorylated. The role of protein phosphatases (PP) in the regulation of phosphorylation of tau was studied in undifferentiated SY5Y cells. In cells treated with 10 nM okadaic acid (OA), a PP-2A/PP-1 inhibitor, the PP-1 and -2A activities decreased by 60% and 100% respectively and the activities of MAPKs, cdc2 kinase and cdk5, but not of GSK-3, increased. OA increased the phosphorylation of tau at Thr-231/Ser-235 and Ser-3961404, but not at Ser-262/356 or Ser-199/202. An increase in tyrosinated/detyrosinated tubulin ratio, a decrease in the microtubule binding activities of tau, MAP1b and MAP2, and cell death were observed. Treatment with 1 microm taxol partially inhibited the cell death. These data suggest (1) that OA induced hyperphosphorylation of tau is probably the result of activated MAPK and cdks in addition to decreased PP-2A and PP-1 activities and (2) that in SY5Y cells the OA induced cell death is associated with a decrease in stable microtubules.
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PMID:The regulation of phosphorylation of tau in SY5Y neuroblastoma cells: the role of protein phosphatases. 959 18


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