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)

Aldosterone plays an important role in the pathogenesis of hypertension. We previously demonstrated that nongenomic signaling by aldosterone in vascular smooth muscle cells occurs through c-Src-dependent pathways. Here we tested the hypothesis that upregulation of c-Src by aldosterone plays a role in increased mitogen-activated protein (MAP) kinase activation, [3H]-proline incorporation, and NADPH-driven generation of reactive oxygen species, thereby inducing cell growth, collagen production, and inflammation, respectively, in vascular smooth muscle cells from spontaneously hypertensive rats. The time course of c-Src phosphorylation by aldosterone was shifted to the left in vascular myocytes from hypertensive animals. Aldosterone rapidly increased phosphorylation of p38 MAP kinase and extracellular signal-regulated kinase with significantly greater effects in cells from spontaneously hypertensive rats versus control cells (P<0.05). Aldosterone increased NADPH oxidase activity with significantly greater responses in vascular smooth muscle cells from hypertensive animals (P<0.05). These events were associated with enhanced [3H]proline incorporation (index of collagen synthesis) in cells from spontaneously hypertensive rats (P<0.05). The NADPH oxidase activity increase, collagen synthesis, c-Src, and MAP kinase phosphorylation induced by aldosterone were significantly reduced by eplerenone (selective mineralocorticoid receptor blocker) and PP2 (selective c-Src inhibitor). In conclusion, nongenomic signaling by exogenous aldosterone, mediated through c-Src, is increased in vascular smooth muscle cells from spontaneously hypertensive rats. Upregulation of c-Src signaling may be important in the profibrotic and proinflammatory actions of aldosterone in this genetic model of hypertension.
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PMID:c-Src-dependent nongenomic signaling responses to aldosterone are increased in vascular myocytes from spontaneously hypertensive rats. 1615 90

Hyperglycemia aggravates ischemic brain injury, possibly due to the activation of signaling pathways involving reactive oxygen species, Src and mitogen-activated protein kinases. The aim of this study was to investigate the effects of the spin trap agent alpha-phenyl-N-tert-butyl nitrone (PBN), the Src family kinase inhibitor PP2 and the MEK1-inhibitor U0126 on focal hyperglycemic ischemic brain injury. Temporary middle cerebral artery occlusion (90 min) was induced in four groups of rats (PBN, PP2, and U0126 vs. control). Neurological testing and tetrazolium red staining were performed after 1 day. PBN decreased the infarct volume by 70% compared with the control (P<0.05) and a tendency towards reduced infarcts was seen in the PP2 or U0126 groups. Furthermore, neurological testing was consistent with the volumetric analysis. In conclusion, PBN appears to be a potential neuroprotective agent in hyperglycemic, focal ischemic brain injury, while the efficacy of PP2 and U0126 could not be confirmed by the present data.
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PMID:Experimental treatment for focal hyperglycemic ischemic brain injury in the rat. 1626 39

Matrix metalloproteinase-9 (MMP-9) is present in the tertiary granules of neutrophils and is rapidly released following stimulation. We examined the pathways that regulate tumor necrosis factor (TNF)-mediated MMP-9 release and found this to be dependent on the TNF receptor I. TNF rapidly activated extracellular signal-regulated kinase and p38 mitogen-activated protein kinases, but neither of these pathways was critical for MMP-9 release. Many neutrophil responses to TNF require beta2-integrin-dependent signaling and subsequent Src family kinase activation. In contrast, we found that MMP-9 release from tertiary granules was only partially affected by blocking beta2-integrin-mediated adhesion. Similarly, blocking Src family kinases with the inhibitor PP2 only attenuated TNF-induced MMP-9 release. Blocking beta2-integrin-mediated adhesion and Src family kinases did not result in additive inhibition of MMP-9 release. In contrast, inhibiting protein kinase C (PKC) with a pan-specific inhibitor blocked greater than 85% of MMP-9 release. Inhibitors against specific PKC isoforms suggested a role for PKC alpha and PKC delta in maximal MMP-9 release. These data suggest that MMP-9 release from tertiary granules uses beta2-integrin-independent signaling pathways. Furthermore, PKC isoforms play a critical role in regulating tertiary granule release.
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PMID:Regulation of matrix metalloproteinase-9 (MMP-9) in TNF-stimulated neutrophils: novel pathways for tertiary granule release. 1627 91

Sphingosine 1-phosphate (S1P) is a platelet-derived sphingolipid that activates G protein-coupled S1P receptors and initiates a broad range of responses in vascular endothelial cells. The small GTPase Rac1 is implicated in diverse S1P-modulated cellular responses in endothelial cells, yet the molecular mechanisms involved in S1P-mediated Rac1 activation are incompletely understood. We studied the pathways involved in S1P-mediated Rac1 activation in bovine aortic endothelial cells (BAEC) and found that S1P-induced Rac1 activation is impaired following chelation of G protein betagamma subunits by transfection of betaARKct. Treatment with the Src tyrosine kinase inhibitor PP2 completely attenuated S1P-mediated Rac1 activation; however, pretreatment of BAEC with wortmannin, an inhibitor of phosphoinositide (PI) 3-kinase, had no effect on Rac1 activation while completely blocking S1P-induced Akt phosphorylation. We used Rac1-specific small interfering RNA (siRNA) duplexes to "knock down" endogenous Rac1 expression and found that siRNA-mediated Rac1 knockdown significantly impaired basal as well as S1P-induced phosphorylation of protein kinase Akt, as well as several downstream targets of Akt including endothelial nitric-oxide synthase and glycogen synthase kinase 3beta. By contrast, S1P-induced phosphorylation of the mitogen-activated protein kinases ERK1/2 was unperturbed by siRNA-mediated Rac1 knockdown. We found that overexpression of the Rac1 guanine nucleotide exchange factor (GEF) Tiam1 markedly enhanced Rac1 activity, whereas a dominant negative Tiam1 mutant significantly attenuated S1P-mediated Rac1 activation. Taken together, these studies identify G protein betagamma subunits, Src kinase and the GEF Tiam1 as upstream modulators of S1P-mediated Rac1 activation, and establish a central role for Rac1 in S1P-mediated activation of PI 3-kinase/Akt/endothelial nitric-oxide synthase signaling in vascular endothelial cells.
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PMID:Rac1 modulates sphingosine 1-phosphate-mediated activation of phosphoinositide 3-kinase/Akt signaling pathways in vascular endothelial cells. 1633 42

The receptor for advanced glycation end products (RAGE) and its ligands have been implicated in the activation of oxidant stress and inflammatory pathways in vascular smooth muscle cells (VSMCs) leading to the initiation and augmentation of atherosclerosis. Here we report that non-receptor Src tyrosine kinase and the membrane protein caveolin-1 (Cav-1) play a key role in the activation of RAGE by S100B in VSMCs. S100B increased the activation of Src kinase and tyrosine phosphorylation of caveolin-1 in VSMCs. A RAGE-specific antibody blocked both these effects. An inhibitor of Src kinase, PP2, significantly blocked S100B-induced activation of Src kinase, mitogen-activated protein kinases, transcription factors NF-kappaB and STAT3, superoxide production, tyrosine phosphorylation of Cav-1, VSMC migration, and expression of the pro-inflammatory genes monocyte chemotactic protein-1 and interleukin-6. Cholesterol depletion also inhibited S100B-induced effects indicating the requirement for intact caveolae in RAGE-specific signaling. Nucleofection of either a Src dominant negative mutant, or a Cav-1 mutant lacking the scaffolding domain, or Cav-1 short hairpin RNA significantly reduced S100B-induced inflammatory gene expression in VSMCs. Furthermore, VSMCs derived from insulin-resistant and diabetic db/db mice displayed increased RAGE expression, Src activation, and migration compared with those from control db/+ mice. The RAGE antibody blocked enhanced migration in db/db cells. These studies demonstrate for the first time that, in VSMCs, Src kinase and Cav-1 play important roles in RAGE-mediated inflammatory gene expression and migration, key events associated with diabetic vascular complications.
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PMID:Key role of Src kinase in S100B-induced activation of the receptor for advanced glycation end products in vascular smooth muscle cells. 1655 28

Cytokines like interleukin-6 (IL-6) play an important role in triggering the acute phase response of the body to injury or inflammation. Signaling by IL-6 involves two pathways: Janus-associated kinases (JAK) and signal transducers and activators of transcription (STAT 3) are activated in the first pathway while the second pathway involves the activation of mitogen-activated protein kinases (MAPK). While it is recognized that both pathways play a major role in IL-6 signal transduction, a majority of studies have focused on signaling through either one of the pathways. However, simultaneous signaling through both JAK/STAT and MAPK pathways is still poorly understood. In this work, a mathematical model has been developed that integrates signaling through both the JAK/STAT and the MAPK pathway. The presented model is used to analyze the effect of three molecules that are involved in the regulation of IL-6 signaling-SHP-2 (domain containing tyrosine phosphatase 2), SOCS3 (suppressor of cytokine signaling 3), and a STAT3 nuclear phosphatase (PP2)-on the dynamics of IL-6 signal transduction in hepatocytes. The obtained results suggest that interactions between SHP-2 and SOCS3 influence signaling through the JAK/STAT and the MAPK pathways. It is shown that SHP-2 and SOCS3 do not just regulate the pathway that they are known to be associated with, (SHP-2 with MAPK and SOCS3 with JAK/STAT), but also have a strong effect on the other pathway. Several simulations with SOCS3, SHP-2, and PP2 knockout cells, that is, where the signaling pathway is unable to produce these proteins, have been performed to characterize the effect of these regulatory proteins on IL-6 signal transduction in hepatocytes.
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PMID:Modeling regulatory mechanisms in IL-6 signal transduction in hepatocytes. 1675 69

Antimicrobial peptides, human beta-defensin (hBD), and the 18-kDa cationic antimicrobial protein (CAP18) are components of innate immunity. These peptides have antimicrobial activity against bacteria, fungi, and viruses. Actinobacillus actinomycetemcomitans is a gram-negative facultative anaerobe implicated in the initiation of periodontitis. The innate immunity peptides have antibacterial activity against A. actinomycetemcomitans. We investigated the molecular mechanism of human gingival epithelial cells (HGEC) responding to exposure to A. actinomycetemcomitans. HGEC constitutively express hBD1 and inducibly express hBD2, hBD3, and CAP18 on exposure to A. actinomycetemcomitans. The level of expression varies among clinical isolates. In the signaling pathway for hBD2 induction by the bacterial contact, we demonstrate that the mitogen-activated protein (MAP) kinase and not the NF-kappaB transcription factor pathway is used. We found the outer membrane protein 100 (Omp100; identified by molecular mass) is the component inducing the hBD2 response. Omp100 binds to fibronectin, an extracellular matrix inducing hBD2 via the MAP kinase pathway. Anti-integrin alpha(5)beta(1), antifibronectin, genistein, and PP2 suppress the Omp100-induced expression of hBD2, suggesting that Src kinase is involved through integrin alpha(5)beta(1). The inflammatory cytokines, tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6 and IL-8, produced by HGEC on contact with A. actinomycetemcomitans also stimulate expression of hBD2. Further, neutralizing antibody against TNF-alpha or IL-8 partially inhibits the induction of hBD2 on bacterial contact. Therefore, we found that the induction of the antimicrobial peptides is mediated by a direct response principally through an Omp100-fibronectin interaction, and using secondary stimulation by inflammatory cytokines induced by the bacterial exposure.
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PMID:Actinobacillus actinomycetemcomitans outer membrane protein 100 triggers innate immunity and production of beta-defensin and the 18-kilodalton cationic antimicrobial protein through the fibronectin-integrin pathway in human gingival epithelial cells. 1692 14

Using the whole-cell voltage clamp, we examined the mechanism of activation of the Na(+)/Ca(2+) exchanger (NCX) by hydrogen peroxide (H(2)O(2)) in isolated guinea-pig cardiac ventricular myocytes. Exposure to H(2)O(2) increased the NCX current. The effect was inhibited by cariporide, an inhibitor of the Na(+)/H(+) exchanger (NHE), suggesting that there are NHE-dependent and -independent pathways in the effect of H(2)O(2) on NCX. In addition, both pathways were blocked by edaravone, a hydroxyl radical (*OH) scavenger; pertussis toxin, a Galpha(i/o) protein inhibitor; and U0126, an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK). On the other hand, wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor, inhibited only the NHE-dependent pathway, while PP2, a Src family protein tyrosine kinase inhibitor, inhibited only the NHE-independent pathway. Taken together, our data suggest that H(2)O(2) increases the NCX current via two signal transduction pathways. The common pathway is the conversion of H(2)O(2) to *OH, which activates Galpha(i/o) protein and a mitogen-activated protein (MAP) kinase signaling pathway. Then, one pathway activates NHE with a PI3K-dependent mechanism and indirectly increases the NCX current. Another pathway involves activation of a Src family tyrosine kinase.
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PMID:Mechanism of Na+/Ca2+ exchanger activation by hydrogen peroxide in guinea-pig ventricular myocytes. 1733 93

Substance P (SP) acting through substance P receptor (SPR) increases the proliferation of glioblastoma cells. At the molecular level, stimulation of SPR in human U373 MG glioblastoma cells results in phosphorylation of mitogen-activated protein kinases ERK1/2. Examination of the underlying mechanism reveals that SPR mediates ERK1/2 phosphorylation in a calcium-dependent manner. Surprisingly, blockade of epidermal growth factor receptor (EGFR), which is transactivated by SPR, has a minimal effect on SPR-mediated ERK1/2 phosphorylation. However, SPR-mediated ERK1/2 phosphorylation is significantly reduced by the Src kinase inhibitor PP2. Interestingly, ERK1/2 in U373 MG cells is also activated by several other mitogenic G protein-coupled receptors (GPCRs) including alpha(1B)-adrenergic, M(3)-muscarinic, and H(1)-histaminergic in an Src-dependent manner. We conclude that c-Src is a mediator of SP-stimulated ERK1/2 phosphorylation in human U373 MG glioblastoma cells.
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PMID:Substance P receptor in U373 MG human astrocytoma cells activates mitogen-activated protein kinases ERK1/2 through Src. 1809 97

Differentiation of PC12 cells by nerve growth factor (NGF) requires the activation of various mitogen-activated protein kinases (MAPKs) including p38 MAPK. Accumulating evidence has suggested cross-talk regulation of NGF-induced responses by G protein-coupled receptors, thus we examined whether NGF utilizes G(i/o) proteins to regulate p38 MAPK in PC12 cells. Induction of p38 MAPK phosphorylation by NGF occurred in a time- and dose-dependent manner and was partially inhibited by pertussis toxin (PTX). NGF-dependent p38 MAPK phosphorylation became insensitive to PTX treatment upon transient expressions of Galpha(z) or the PTX-resistant mutants of Galpha(i2) and Galpha(oA). Moreover, Galpha(i2) was co-immunoprecipitated with the TrkA receptor from PC12 cell lysates. To discern the participation of various signaling intermediates, PC12 cells were treated with a panel of specific inhibitors prior to the NGF challenge. NGF-induced p38 MAPK phosphorylation was abolished by inhibitors of Src (PP1, PP2, and SU6656) and MEK1/2 (U0126). Inhibition of the p38 MAPK pathway also suppressed NGF-induced PC12 cell differentiation. In contrast, inhibitors of JAK2, phospholipase C, protein kinase C and Ca(2+)/calmodulin-dependent kinase II did not affect the ability of NGF to activate p38 MAPK. Collectively, these studies indicate that NGF-dependent p38 MAPK activity may be mediated via G(i2) protein, Src, and the MEK/ERK cascade.
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PMID:Nerve growth factor-induced stimulation of p38 mitogen-activated protein kinase in PC12 cells is partially mediated via G(i/o) proteins. 1850 36


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