Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of extracellular-regulated kinases 1/2 (ERK) is involved in lipopolysaccharide (LPS)-induced cellular responses such as the increased production of proinflammatory cytokines. However, mitogen-activated protein kinases (MAPKs) such as p38 are also activated by LPS and have been postulated to be important in the control of these end points. Therefore, establishing the relative contribution of MAPKs in each cell type is important, as is elucidating the molecular mechanisms by which these MAPKs are activated in LPS-induced signaling cascades. We demonstrated in DC2.4 dendritic cells that ERK regulates tyrosine phosphorylation of phosphatidyl-inositol-3-kinase (PI3-K) and the production of TNF-alpha. We also demonstrated that Raf1 is phosphorylated and involved in the production of TNF-alpha and tyrosine phosphorylation of PI3-K via ERK. Raf1 also regulates the activation of NF-kappaB. We propose that Raf1 plays a pivotal role in LPS-induced activation of the dendritic cells.
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PMID:Raf1 plays a pivotal role in lipopolysaccharide-induced activation of dendritic cells. 1290 76

Cell motility and invasion are crucial events for the spread of cancer and, consequently, the metastatic process. Platelet-derived growth factor (PDGF) is not only capable of stimulating the proliferation of SH-SY5Y human neuroblastoma cells, but also their migration and invasion through an extracellular matrix barrier. Experiments using wortmannin and PD98059, specific inhibitors of the phosphatidylinositol 3-kinase (PI3-K) and of the mitogen-activated protein kinases (ERK 1 and 2) signaling, respectively, show that the activation of both pathways is required for the PDGF-induced cell motility responses. We have previously shown that somatostatin inhibits cell division and ERK 1/2 and Ras activity in SH-SY5Y cells. We report here that it is also capable of potently and effectively inhibiting their PDGF-stimulated migration and invasion. The inhibitory effect of somatostatin is sensitive to pertussis toxin. Although somatostatin does not affect PI3-K, it inhibits ERK 1/2 and the small G-protein Rac activation and ruffle formation induced by PDGF. These results indicate that somatostatin can be considered an anti-migratory and anti-invasive agent that acts by inhibiting ERK 1/2 signaling and the PI3-K pathway via the inhibition of Rac in SHSY5Y cells.
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PMID:Anti-migratory and anti-invasive effect of somatostatin in human neuroblastoma cells: involvement of Rac and MAP kinase activity. 1290 25

High-density lipoprotein (HDL), apolipoprotein A-I (apoA-I), and the principal high-affinity HDL receptor, scavenger receptor class B type I (SR-BI), are antiatherogenic and beneficial to the response to vascular injury. However, the fundamental mechanisms underlying these properties remain complex and not well understood. Recent work in both cell culture and in mice indicates that HDL causes robust activation of endothelial nitric oxide synthase (eNOS), and that this effect is mediated in endothelial cell caveolae by SR-BI through a process that requires apoA-I binding. Further studies have revealed that HDL stimulates eNOS through src- and PI3 kinase-mediated signaling, which leads to parallel activation of Akt and mitogen-activated protein kinases and their resultant independent modulation of the enzyme. As such, signaling initiated by HDL increases the production of the potent atheroprotective molecule nitric oxide, and this novel mechanism of action may be critically involved in the impact of the lipoprotein on vascular health and disease.
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PMID:HDL stimulation of endothelial nitric oxide synthase: a novel mechanism of HDL action. 1292 18

Although evidence suggests that insulin-like growth factor (IGF) plays an important role in the development and growth of the nervous system, the effect of IGF-1 in the regulation of neurotransmitter release in the peripheral nervous system remains unknown. Here we show that acute application of IGF-1, a factor widely expressed in developing myocytes, dose-dependently enhances the spontaneous acetylcholine (ACh) secretion at developing neuromuscular synapses in Xenopus cell culture using whole-cell patch clamp recording. We studied the role of endogenously released IGF-1 by examining the effect of IGF-1 antibody on the frequency of spontaneous synaptic currents (SSCs) at high-activity synapses, and found SSC frequency was markedly reduced at these high-activity synapses. The IGF-1-induced synaptic potentiation was not abolished when Ca2+ was eliminated from the culture medium or there was bath-application of the pharmacological Ca2+ channel inhibitor Cd2+, indicating that Ca2+ influxes through voltage-activated Ca2+ channels are not required. Application of membrane-permeable inhibitors of inositol 1,4,5-trisphosphate (IP3) or ryanodine receptors effectively occluded the increase of SSC frequency elicited by IGF-I. Treating cells with the phosphoinositide-3 kinase (PI3-K) inhibitors wortmannin or LY294002, and with phospholipase Cgamma (PLCgamma) inhibitor U73122, but not the inhibitor of mitogen-activated protein (MAP) kinase PD98059, abolished IGF-1-induced synaptic potentiation. Taken collectively, these results suggest that endogenously released IGF-1 from myocytes elicits Ca2+ release from IP3- and/or ryanodine-sensitive intracellular Ca2+ stores of the presynaptic nerve terminal. This is done via PI3-K and PLCgamma signalling cascades, leading to an enhancement of spontaneous transmitter release.
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PMID:Potentiation of quantal secretion by insulin-like growth factor-1 at developing motoneurons in Xenopus cell culture. 1451 75

This study examines the molecular mechanisms by which hypoxia regulates phosphorylated endothelial nitric oxide synthase (eNOS) activity and NO production in porcine coronary artery endothelial cells (PCAEC). Exposure to hypoxia (pO(2)=10 mmHg) for periods up to 3 h resulted in a time-dependent increase in eNOS protein expression and an early (15 min) and sustained increase in eNOS phosphorylation at Ser-1177. Exposure to hypoxia for 30 min led to a doubling in eNOS activity (control=6.2+/-4.4 vs hypoxia=14.1+/-5.0 fmol cGMP/microg protein, P<0.05) and NO release (control=5.9+/-0.8 vs hypoxia=11.8+/-1.2 nM/microg protein, P<0.05). Hypoxia also led to a significant increase in Akt phosphorylation and upregulation of Hsp90 binding to eNOS. Pretreatment of cells with either 1 microg/ml geldanamycin (a specific inhibitor of Hsp90) or 500 nM wortmannin (a specific PI3 kinase inhibitor) suppressed hypoxia-stimulated Akt and eNOS phosphorylation and significantly attenuated hypoxia-stimulated Hsp90 binding to eNOS. Both eNOS activity and NO production were inhibited by geldanamycin and wortmannin. Although hypoxia led to early activation of p42/44 mitogen-activated protein kinases (MAPK), inhibition of their pathway by PD98059 did not suppress hypoxia-stimulated eNOS phosphorylation and eNOS activity. These data demonstrate that hypoxia leads to increased eNOS phosphorylation via stimulated Hsp90 binding to eNOS and activation of the PI3-Akt pathway. We conclude that a coordinated interaction between Hsp90 and PI3-Akt may be an important mechanism by which eNOS activity and NO production is upregulated in hypoxic heart.
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PMID:Hypoxia increases Hsp90 binding to eNOS via PI3K-Akt in porcine coronary artery endothelium. 1466 Oct 33

In vivo, ischemia is known to damage the blood-brain barrier (BBB) leading to the development of vasogenic brain edema. Hypoxia-induced vascular endothelial growth factor (VEGF) has been shown to be a key regulator of these permeability changes. However, the signaling pathways that underlie VEGF-induced hyperpermeability are incompletely understood. In this study, we demonstrate that hypoxia- and VEGF-induced permeability changes depend on activation of phospholipase Cgamma (PLCgamma), phosphatidylinositol 3-kinase/Akt (PI3-K/Akt), and protein kinase G (PKG). Inhibition of mitogen-activated protein kinases (MAPK) and of the protein kinase C (PKC) did not affect permeability at all. Paralleling hypoxia- and VEGF-induced permeability changes, localization of the tight junction proteins occludin, zonula occludens-1 (ZO-1), and ZO-2 along the cell membrane changed from a continuous to a more discontinuous expression pattern during hypoxia. In particular, localization of ZO-1 and ZO-2 expression moved from the cell membrane to the cytoplasm and nucleus whereas occludin expression remained at the cell membrane. Inhibition of PLCgamma, PI3-kinase, and PKG abolished these hypoxia-induced changes. These findings demonstrate that hypoxia and VEGF induce permeability through rearrangement of endothelial junctional proteins which involves activation of the PLCgamma and PI3-K/AKT pathway leading to the activation of PKG.
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PMID:Simultaneous activation of several second messengers in hypoxia-induced hyperpermeability of brain derived endothelial cells. 1475 41

Brain-derived neurotrophic factor (BDNF) is a potent trophic factor for striatal cells that promotes survival and/or differentiation of GABAergic neurons in vitro. In the present study, we show that the stimulation of cultured striatal cells with BDNF increased the phosphorylation of Akt and p42/p44. This effect was specifically blocked by inhibitors of phosphatidylinositol 3-kinase (PI3-K) pathways (LY294002 and wortmannin) or p42/p44 mitogen-activated protein (MAP) kinase (PD98059 and U0126). BDNF treatment induced an increase in the number of calbindin-positive neurons but not in the number of GABAergic or total cells. Furthermore, BDNF increased the degree of dendritic arborization, soma area and axon length of striatal neurons. However, PD98059 was more effective blocking BDNF effects on calbindin- than on GABA-positive neurons, whereas LY294002 inhibited morphological differentiation in both neuronal populations. Moreover, BDNF induced neuronal survival only through the activation of the PI3-K pathway.
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PMID:Differential involvement of phosphatidylinositol 3-kinase and p42/p44 mitogen activated protein kinase pathways in brain-derived neurotrophic factor-induced trophic effects on cultured striatal neurons. 1503 74

Corticosterone (CORT) is well known to induce neuronal damage in various brain regions including the hippocampus, but the precise mechanism(s) of action underlying these effects has yet to be fully established. Insulin-like growth factor-1 (IGF-1) is a trophic factor promoting cell survival by the activation of the phosphatidylinositide 3-kinase (PI3K)/Akt kinase pathway. We report that IGF-1 prevents neuronal cell death induced by CORT, likely via the stimulation of the PI3K/Akt pathway in primary hippocampal cultured neurons. CORT induced neuronal cell death at a minimal concentration of 50 nM. IGF-1 (10 nM) prevented cell death induced by CORT under serum-free conditions. The neuroprotective effect of IGF-1 was accompanied by reversal of the Akt pathway inhibition induced by CORT. The PI3 kinase inhibitor, LY29004, inhibited the neuroprotective effect of IGF-1 whereas the MEK (MAPK kinase) inhibitor PD98059, an upstream blocker of mitogen-activated protein (MAP) kinase, had no effect. These results suggest that IGF-1 can prevent neuronal cell death induced by CORT in hippocampal neurons by modulating the activity of the PI3K/Akt pathway.
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PMID:Insulin-like growth factor 1 prevents neuronal cell death induced by corticosterone through activation of the PI3k/Akt pathway. 1504 33

Estradiol (E2) and other steroids have recently been shown to initiate various intracellular signaling cascades from the plasma membrane, including those stimulating mitogen-activated protein kinases (MAPKs), and particularly extracellular-regulated kinases (ERKs). In this study we demonstrated the ability of E2 to activate ERKs in the GH3/B6/F10 pituitary tumor cell line, originally selected for its enhanced expression of membrane estrogen receptor-alpha (mERalpha). We compared E2 to its cell-impermeable analog (E2 conjugated to peroxidase, E2-P), and to the synthetic estrogen diethylstilbestrol (DES). Time-dependent ERK activation was quantified with a novel fixed cell-based immunoassay developed to efficiently determine activation by multiple compounds over multiple parameters. Both E2 and DES produced bimodal responses, but with distinctly different time courses of enzyme phosphorylation (activation) and inactivation; E2-P induced a monophasic ERK activation. E2 also phosphorylated ERKs in concentration-dependent manner with two concentration optima (10(-14) and 10(-8)M). Inhibitors were employed to determine pathway (ER, EGFR, membrane organization, PI3 kinase, Src kinase, Ca2+) involvement and timing of pathway activations; all affected ERK activation as early as 3-6 min, suggesting simultaneous, not sequential, activation. Therefore, E2 and other estrogenic compounds can produce rapid ERK phosphorylations via nongenomic pathways, using more than one pathway for signal generation.
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PMID:Quantitative measurement of estrogen-induced ERK 1 and 2 activation via multiple membrane-initiated signaling pathways. 1507 20

1. Signaling networks involving different receptor systems allow extracellular signals to be integrated and transformed into various biological activities. In this report, we studied the activity of the c-Jun N-terminal kinase (JNK) subgroup of mitogen-activated protein kinases (MAPKs), in response to stimulation by G protein-coupled receptors (GPCRs) and co-activation with epithermal growth factor receptor (EGFR). 2. Stimulation of exogenous GPCRs in Cos-7 cells induced JNK activation of different magnitudes depending on their G-protein coupling specificities (G(q)>G(i)>G(s)), and a moderate JNK activation was linked to stimulation of endogenous EGFR by EGF. 3. Co-stimulation with GPCR agonists and EGF resulted in differential augmentation of JNK activities, with G(i)-coupled receptors associated with a synergistic JNK activation upon co-stimulation with EGF, while G(q)- and G(s)-coupled receptors were incapable of triggering this effect. 4. This G(i)/EGF-induced synergistic JNK activation was inhibited by pertussis toxin and AG1478, and may involve Src family tyrosine kinases, PI3 K, Ca(2+)/calmodulin and small GTPases as important intermediates, while Ca(2+) mobilization was triggered by the stimulation of G(q)-coupled receptor or EGF treatment, but not by the G(i)- or G(s)-coupled receptors. 5. Transient expression of Gbetagamma subunits with EGF treatment, or co-activation of exogenous G(i)-coupled receptor with thapsigargin also resulted in a synergistic JNK activation. Activation of G(i)-coupled receptor accompanied with EGF treatment enhanced the expression level and activity of MAPK phosphatase type I, which occurred after the maximal synergistic JNK activation. 6. Our results support a mechanistic model where EGF signaling may differentially regulate the JNK activities triggered by GPCRs of different coupling specificities.
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PMID:Epidermal growth factor differentially augments G(i)-mediated stimulation of c-Jun N-terminal kinase activity. 1517 63


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