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)

The Akt family of serine/threonine-directed kinases promotes cellular survival in part by phosphorylating and inhibiting death-inducing proteins. Here we describe a novel functional interaction between Akt and apoptosis signal-regulating kinase 1 (ASK1), a mitogen-activated protein kinase kinase kinase. Akt decreased ASK1 kinase activity stimulated by both oxidative stress and overexpression in 293 cells by phosphorylating a consensus Akt site at serine 83 of ASK1. Activation of the phosphoinositide 3-kinase (PI3-K)/Akt pathway also inhibited the serum deprivation-induced activity of endogenous ASK1 in L929 cells. An association between Akt and ASK1 was detected in cells by coimmunoprecipitation. Phosphorylation by Akt inhibited ASK1-mediated c-Jun N-terminal kinase and activating transcription factor 2 activities in intact cells. Finally, activation of the PI3-K/Akt pathway reduced apoptosis induced by ASK1 in a manner dependent on phosphorylation of serine 83 of ASK1. These results provide the first direct link between Akt and the family of stress-activated kinases.
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PMID:Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. 1115 76

Peptide growth factors can promote the cell migration and proliferation that is needed to repair epithelia after mechanical or chemical injury. We report here that scrape-wounding rat intestinal epithelial (RIE-1) cell monolayers caused a rapid increase in levels of heparin-binding epidermal-growth-factor-like growth factor (HB-EGF) mRNA, with a maximal response at approx. 1 h. Hybridization in situ showed that transcript induction occurred primarily in cells at or near wound borders. The increase in HB-EGF mRNA was preceded by activation of the p42 mitogen-activated protein kinase (MAPK) in the wounded cell cultures. Moreover, the induction of HB-EGF mRNA was blocked by PD098059 and U0126, inhibitors that prevent the activation of p42/p44 MAPKs and extracellular signal-regulated protein kinase 5 (ERK5). Both p42 MAPK activation and HB-EGF mRNA induction were inhibited by genistein, indicating a requirement for an upstream tyrosine kinase activity. In contrast, neither response was affected by inhibition of phosphoinositide 3-kinase activity, down-regulation of protein kinase C, or disruption of the actin cytoskeleton with cytochalasin B. We conclude that scrape-wounding epithelial cell monolayers induces HB-EGF mRNA expression by a mechanism that most probably requires p42/p44 MAPK activation, although we cannot exclude a role for ERK5. Our results suggest a physiological role for locally synthesized HB-EGF in promoting epithelial repair after injury.
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PMID:Heparin-binding epidermal-growth-factor-like growth factor gene expression is induced by scrape-wounding epithelial cell monolayers: involvement of mitogen-activated protein kinase cascades. 1117 Oct 84

We have previously shown that cAMP protects against hydrophobic bile acid-induced apoptosis in cultured rat hepatocytes through pathways dependent on activation of phosphoinositide 3-kinase and inhibition of mitogen activated protein kinase. Hepatocyte growth factor protects epithelial cells against apoptosis and activates both of these kinases in hepatocytes. We studied the effect of hepatocyte growth factor on glycochenodeoxycholate-induced apoptosis to determine whether hepatocyte growth factor protects hepatocytes against bile acid-induced apoptosis and whether the protective effect is mediated via phosphoinositide 3-kinase and/or mitogen-activated protein kinase pathways. Two-hour exposure of cultured rat hepatocytes to glycochenodeoxycholate resulted in apoptosis in 12.5 +/- 0.49% of the cells. Pretreatment with hepatocyte growth factor (50 ng/mL) decreased apoptosis by 50% to 70%. Hepatocyte growth factor cytoprotection was prevented by pretreatment with the phosphoinositide 3-kinase inhibitors, wortmannin (50 nmol/L) or Ly 294002 (40 micromol/L). Hepatocyte growth factor activated phosphoinositide 3-kinase dependent protein kinase B and mitogen-activated protein kinase. Pretreatment of hepatocytes with a mitogen-activated protein kinase inhibitor, U0126 (40 micromol/L) or an inhibitor of pp70(s6) kinase, rapamycin (100 nmol/L), had no effect on the growth factor's anti-apopotic effect. Treatment with hepatocyte growth factor resulted in mitogen-activated protein kinase-dependent phosphorylation of BAD on serine(112). In summary, hepatocyte growth factor protection against bile acid-induced apoptosis occurs via a phosphoinositide 3-kinase pathway and is not dependent on the mitogen-activated protein kinase pathway, phosphorylation of BAD on serine(112), or activation of p70(S6) kinase.
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PMID:Phosphoinositide 3-kinase, but not mitogen-activated protein kinase, pathway is involved in hepatocyte growth factor-mediated protection against bile acid-induced apoptosis in cultured rat hepatocytes. 1123 Jul 41

Scatter factor/hepatocyte growth factor (SF/HGF) and its tyrosine kinase receptor c-met are developmentally expressed, neuroprotective, and tumorigenic within the CNS. In the present study SF/HGF is shown to induce the expression of c-met in two human glioblastoma cell lines, U-373 MG and T98G, and the signaling pathways involved in this induction are dissected. SF/HGF activated mitogen-activated protein kinase (MAPK) and inhibition of either Ras or MAPK-kinase completely inhibited SF/HGF-mediated c-met induction. Inhibition of phospholipase-C (PLC) did not affect c-met induction in either cell line. Inhibition of phosphoinositide 3-kinase (PI3-kinase) substantially reduced c-met induction by SF/HGF in T98G cells but had no effect in U-373 MG cells. Protein kinase C (PKC) inhibition reduced c-met induction in T98G cells but not in U-373 MG cells. SF/HGF induced the expression of c-fos and c-jun mRNA and increased the levels of AP-1 transcription factor in both cells lines as determined by AP-1-luciferase reporter expression. Transfection of either cell line with TAM-67, a dominant negative for the jun transactivation domain, completely inhibited AP-1 and c-met induction by SF/HGF. These results support a model of c-met induction by SF/HGF in human glioma cells that uniformly involves Ras, MAPK, and AP-1 and additionally involves PI3-kinase and PKC in some cell lines.
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PMID:Signaling pathways in the induction of c-met receptor expression by its ligand scatter factor/hepatocyte growth factor in human glioblastoma. 1123 34

It has been demonstrated that proinsulin C-peptide possesses several biological activities and that its specific binding sites are present on the surface of cell membranes. However, the molecular and cellular mechanisms of C-peptide actions are poorly known. In the present study we examined the possible involvement of the mitogen-activated protein kinase (MAPK) pathway in C-peptide effects. C-peptide induced the phosphorylation of MAPK [p44 extracellular signal-regulated kinase 1 (ERK1) and p42 ERK2] in Swiss 3T3 and 3T3-F442A fibroblasts but not in 3T3-L1 fibroblasts and some other cell lines such as L(6)E(9) muscle cells. In Swiss 3T3 cells, C-peptide-induced phosphorylation of MAPK was dependent on time and concentration, being maximal at 1 min and at 1 nM C-peptide and was accompanied by an increase in MAPK activity and MAPK kinase (MEK) phosphorylation. The MAPK phosphorylation by C-peptide was abolished by treatment with pertussis toxin (PTX) and also with a MEK inhibitor, PD 98059. In addition, MAPK phosphorylation was attenuated by treatment with a phosphoinositide 3-kinase (PI-3K) inhibitor, wortmannin, and with a protein kinase C (PKC) inhibitor, GF109203X, and by down-regulation of PKC by prolonged treatment with PMA. Similar effects of the inhibitors and PTX were found on the MAPK phosphorylation induced by neuropeptide Y. These results suggest that C-peptide activates MAPK through a putative G(i)/G(o)-linked receptor for C-peptide and through PI-3K-dependent and PKC-dependent pathways.
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PMID:Proinsulin C-peptide rapidly stimulates mitogen-activated protein kinases in Swiss 3T3 fibroblasts: requirement of protein kinase C, phosphoinositide 3-kinase and pertussis toxin-sensitive G-protein. 1125 56

During neuronal differentiation, an exquisitely controlled program of signal transduction events takes place, leading to the temporally and spatially regulated expression of genes associated with the differentiated phenotype. A critical class of genes involved in this phenomenon is that made up of genes encoding neurotransmitter-gated ion channels that play a central role in signal generation and propagation within the nervous system. We used the well established PC12 cell line to investigate the molecular details underlying the expression of the neuronal nicotinic acetylcholine receptor class of ion channels. Neuronal differentiation of PC12 cells can be induced by nerve growth factor, leading to an increase in neuronal nicotinic acetylcholine receptor gene expression. Nerve growth factor initiates several signal transduction cascades. Here, we show that the Ras-dependent mitogen-activated protein kinase and phosphoinositide 3-kinase pathways are critical for the nerve growth factor-mediated increase in the transcriptional activity of a neuronal nicotinic acetylcholine receptor gene promoter. In addition, we show that a component of the Ras-dependent mitogen-activated protein kinase pathway, nerve growth factor-inducible c-Jun, exerts its effects on receptor gene promoter activity most likely through protein-protein interactions with Sp1. Finally, we demonstrate that the target for nerve growth factor signaling is an Sp1-binding site within the neuronal nicotinic acetylcholine receptor gene promoter.
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PMID:The signal transduction pathway underlying ion channel gene regulation by SP1-C-Jun interactions. 1126 97

Neurite outgrowth of PC12 cells is induced by nerve growth factor (NGF) but not by epidermal growth factor (EGF). This differential response has been explained by the duration of mitogen-activated protein kinase (MAPK) activation; NGF induces sustained MAPK activation but EGF leads short-lived activation. However, precise mechanisms have not yet been understood. Here we demonstrate the difference between NGF and EGF in regulation of Rac1, a small GTPase involved in neurite outgrowth, in PC12 cells. NGF phosphoinositide 3-kinase dependently induces transient activation of Rac1 and accumulation of active Rac1 at protrusion sites on the cell surface, inducing filamentous actin-rich protrusions and subsequent neurite formation in a Rac1-dependent manner. On the other hand, EGF phosphoinositide 3-kinase independently induces more transient Rac1 activation but neither accumulates active Rac1 nor forms Rac1- and filamentous actin-rich protrusions. Difference in the Rac1 localization between NGF and EGF was also observed with the localization of exogenously expressed green fluorescent protein-tagged Rac1. The Rac1-mediated protrusion by NGF is independent of MAPK cascade, but the subsequent neurite extension requires the cascade. Thus, the differential activation of Rac1 and localization of active Rac1 contribute to the difference in the ability of NGF and EGF to induce neurite outgrowth, and we propose that the MAPK cascade-independent prompt activation of Rac1 and recruitment of active Rac1 at the protrusion sites trigger the initiation of neurite formation.
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PMID:Differential responses to nerve growth factor and epidermal growth factor in neurite outgrowth of PC12 cells are determined by Rac1 activation systems. 1127 19

The anti-tumorigenic and anti-proliferative effects of N-alpha-tosyl-l-phenylalanyl chloromethyl ketone (TPCK) have been known for more than three decades. Yet little is known about the discrete cellular targets of TPCK controlling these effects. Previous work from our laboratory showed TPCK, like the immunosuppressant rapamycin, to be a potent inhibitor of the 70-kilodalton ribosomal S6 kinase 1 (S6K1), which mediates events involved in cell growth and proliferation. We show here that rapamycin and TPCK display distinct inhibitory mechanisms on S6K1 as a rapamycin-resistant form of S6K1 was TPCK-sensitive. Additionally, we show that TPCK inhibited the activation of the related kinase and proto-oncogene Akt. Upstream regulators of S6K1 and Akt include phosphoinositide 3-kinase (PI 3-K) and 3-phosphoinositide-dependent kinase 1 (PDK1). Whereas TPCK had no effect on either mitogen-regulated PI 3-K activity or total cellular PDK1 activity, TPCK prevented phosphorylation of the PDK1 regulatory sites in S6K1 and Akt. Furthermore, whereas both PDK1 and the mitogen-activated protein kinase (MAPK) are required for full activation of the 90-kilodalton ribosomal S6 kinase (RSK), TPCK inhibited RSK activation without inhibiting MAPK activation. Consistent with the capacity of RSK and Akt to mediate a cell survival signal, in part through phosphorylation of the pro-apoptotic protein BAD, TPCK reduced BAD phosphorylation and led to cell death in interleukin-3-dependent 32D cells. Finally, in agreement with results seen in embryonic stem cells lacking PDK1, protein kinase A activation was not inhibited by TPCK showing TPCK specificity for mitogen-regulated PDK1 signaling. TPCK inhibition of PDK1 signaling thus disables central kinase cascades governing diverse cellular processes including proliferation and survival and provides an explanation for its striking biological effects.
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PMID:Disruption of 3-phosphoinositide-dependent kinase 1 (PDK1) signaling by the anti-tumorigenic and anti-proliferative agent n-alpha-tosyl-l-phenylalanyl chloromethyl ketone. 1127 84

The phenotypic properties of the endothelium are subject to modulation by oxidative stress, and the c-Jun N-terminal kinase (JNK) pathway is important in mediating cellular responses to stress, although activation of this pathway in endothelial cells has not been fully characterized. Therefore, we exposed endothelial cells to hydrogen peroxide (H(2)O(2)) and observed rapid activation of JNK within 15 min that involved phosphorylation of JNK and c-Jun and induction of AP-1 DNA binding activity. Inhibition of protein kinase C and phosphoinositide 3-kinase did not effect JNK activation. In contrast, the tyrosine kinase inhibitors, genistein, herbimycin A, and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) significantly attenuated H(2)O(2)-induced JNK activation as did endothelial cell adenoviral transfection with a dominant-negative form of Src, implicating Src as an upstream activator of JNK. Activation of JNK by H(2)O(2) was also inhibited by AG1478 and antisense oligonucleotides directed against the epidermal growth factor receptor (EGFR), implicating the EGFR in this process. Consistent with this observation, H(2)O(2) stimulated EGFR tyrosine phosphorylation and complex formation with Shc-Grb2 that was abolished by PP2, implicating Src in H(2)O(2)-induced EGFR activation. Tyrosine phosphorylation of the EGFR by H(2)O(2) did not involve receptor autophosphorylation at Tyr(1173) as assessed by an autophosphorylation-specific antibody. These data indicate that H(2)O(2)-induced JNK activation in endothelial cells involves the EGFR through an Src-dependent pathway that is distinct from EGFR ligand activation. These data represent one potential pathway for mediating oxidative stress-induced phenotypic changes in the endothelium.
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PMID:c-Jun N-terminal kinase activation by hydrogen peroxide in endothelial cells involves SRC-dependent epidermal growth factor receptor transactivation. 1127 82

Zn(2+), one of the most abundant trace metal ions in mammalian cells, modulates the functions of many regulatory proteins associated with a variety of cellular activities. In the central nervous system, Zn(2+) is highly localized in the cerebral cortex and hippocampus. It has been proposed to play a role in normal brain function as well as in the pathophysiology of certain neurodegenerative disorders. We here report that Zn(2+) induced stimulation of the c-Jun N-terminal kinase (JNK) pathway in mouse primary cortical cells and in various cell lines. Exposure of cells to Zn(2+) resulted in the stimulation of JNK and its upstream kinases including stress-activated protein kinase kinase and mitogen-activated protein kinase kinase kinase. Zn(2+) also induced stimulation of phosphoinositide 3-kinase (PI3K) The Zn(2+)-induced JNK stimulation was blocked by LY294002, a PI3K inhibitor, or by a dominant-negative mutant of PI3Kgamma. Furthermore, overexpression of Rac1N17, a dominant negative mutant of Rac1, suppressed the Zn(2+)- and PI3Kgamma-induced JNK stimulation. The stimulatory effect of Zn(2+) on both PI3K and JNK was repressed by the free-radical scavenging agent N-acetylcysteine. Taken together, our data suggest that Zn(2+) induces stimulation of the JNK signaling pathway through PI3K-Rac1 signals and that the free-radical generation may be an important step in the Zn(2+) induction of the JNK stimulation.
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PMID:Zn(2+) induces stimulation of the c-Jun N-terminal kinase signaling pathway through phosphoinositide 3-Kinase. 1130 79


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