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

CD11a/CD18 (beta2)-integrins are expressed on leukocytes and are involved in cell adhesion and signaling. Despite extensive studies the signaling pathways and molecular mechanisms involved in integrin regulation in T cells remain not completely understood. We have now studied the involvement of the tyrosine kinase Lck in the regulation of CD11a/CD18 function in Jurkat T cells. Using the Src-family kinase inhibitor PP2, we found that CD3 ligation-induced adhesion to ICAM-1 was inhibited by PP2 at the same concentration required for complete inhibition of the MAP kinase pathway, implicating a role for Lck in integrin activation. We therefore used the Lck-deficient Jurkat cell line JCaM1.6 to further examine the involvement of Lck in integrin regulation. Interestingly, JCaM1.6 cells showed dramatically reduced levels of both CD3- and phorbol ester-induced adhesion to coated ICAM-1 as compared to normal Jurkat cells. By using flow cytometry and cell surface labeling, it was found that the surface expression of the CD11a/CD18-integrins was significantly lower in Lck-deficient T cells as compared to normal Jurkat cells. CD18 was expressed as a mature and an immaturely glycosylated form in Jurkat T cell lines, and predominantly the immature form, not associated with CD11a, was found in Lck-deficient cells. Retransfection of human Lck in JCaM1.6 cells restored adhesion. Thus, Lck is involved in regulating CD11a/CD18-integrins in T cells.
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PMID:Lck tyrosine kinase is important for activation of the CD11a/CD18-integrins in human T lymphocytes. 1211 50

The aim of this study was to explore the intracellular signaling pathways involved in the stimulatory effects of estrogens on cholangiocyte proliferation. We investigated the tyrosine kinase-receptor pathway by evaluating the protein expression of total and phosphorylated mitogen-activated protein kinase (MAPK) isoform p44/p42 (e.g., extracellular signal-regulated kinase [ERK]1/2), the steroid-receptor coactivator Src and Shc (Src-homology/collagen protein). The study was performed in 3-week-old bile duct-ligated (BDL) rats, BDL rats treated with the antiestrogens, tamoxifen or Ici 182,780, and normal control rats. Proliferation was also evaluated in normal purified cholangiocytes treated with 17 beta estradiol in the presence or absence of tamoxifen, Ici 182,780, ERK, or Src inhibitors. After bile duct ligation, cholangiocyte proliferation was associated with a marked immunohistochemical nuclear positivity for phosphorylated (p)-ERK1/2, which was inhibited by in vivo treatment with tamoxifen or Ici 182,780. Protein expression of total and p-ERK1/2, and Shc in cholangiocytes isolated from BDL rats was markedly increased compared with controls and was inhibited by in vivo treatment with antiestrogens. In vitro, 17 beta estradiol-induced proliferation of isolated normal cholangiocyte was associated with increased (P <.01) protein expression of p-ERK1/2, Src, and Shc. Specific inhibitors of ER (Ici 182,780), ERK (U0125), and Src (PP2) inhibited in vitro 17 beta estradiol-induced cholangiocyte proliferation. In conclusion, this study showed that estrogens induced cholangiocyte proliferation by activating the Src/Shc/ERK pathway. This might suggest that pharmacologic modulation of ER, ERK, and/or Src could be proposed for the treatment of human pathology characterized by dysregulation of cholangiocyte proliferation.
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PMID:Intracellular pathways mediating estrogen-induced cholangiocyte proliferation in the rat. 1214 37

Fc receptors of avian heterophils play a primary role in the elimination of bacterial pathogens in poultry. The cross-linking of Fc receptors with IgG-bacteria complexes results in the secretion of toxic oxygen metabolites and anti-bacterial granules. We have been investigating the upstream signaling events that precede degranulation following crosslinkage of Fc receptors on heterophils. Previously when using the non-selective pharmacological inhibitors genistein, chelerythrine, verapamil, and pertussis toxin, we found no significant inhibitory effects on Fc-mediated heterophil degranulation. In the present studies, we used more selective pharmacological inhibitors to investigate the roles of protein tyrosine kinases, phospholipase C (PLC), phosphatidylinositol 3'-kinase, and the family of mitogen-activated protein kinases (MAPK) on Fc-mediated heterophil degranulation. Inhibitors of the receptor-linked tyrosine kinases (the tryphostins AG 1478 and AG 1296) had no attenuating effects on the Fc receptor-mediated degranulation of chicken heterophils. Likewise, PP2, a selective inhibitor of the Src family of protein tyrosine kinases, had no inhibitory effects on degranulation. However, piceatannol, a selective inhibitor of Syk tyrosine kinase, significantly attenuated the effect of Fc receptor-mediated degranulation. Additionally, Fc-mediated degranulation was significantly attenuated by SB 203580, an inhibitor of p38 MAPK, but not by PD98059, an inhibitor of the extracellular signal-regulated kinase (ERK). An inhibitor of phospholipase C, U73122 and LY294002, an inhibitor of phosphoinositol-3 kinase significantly decreased heterophil degranulation. These results suggest that the Fc receptors on chicken heterophils, like their counterparts on mammalian neutrophils, have no intrinsic tyrosine kinase activity, but probably mediate downstream events through activation of tyrosine-based activation motifs (ITAM). Activation of the Syk tyrosine kinase stimulates downstream phosphorylation of p38 MAPK, phospholipase C, and phosphatidylinositol-3 kinase as signaling pathways that regulate Fc-receptor-mediated degranulation of chicken heterophils. Engaging Fc receptors on chicken heterophils activates a Syk-->PLC-->PI3-K-->p38 MAPK signal transduction pathway that induces degranulation.
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PMID:Selective pharmacological inhibitors reveal the role of Syk tyrosine kinase, phospholipase C, phosphatidylinositol-3'-kinase, and p38 mitogen-activated protein kinase in Fc receptor-mediated signaling of chicken heterophil degranulation. 1218 37

Hyaluronan (HA) is a large nonsulfated glycosaminoglycan and an important regulator of angiogenesis, in particular, the growth and migration of vascular endothelial cells. We have identified some of the key intermediates responsible for induction of mitogenesis and wound recovery. Treatment of bovine aortic endothelial cells with oligosaccharides of hyaluronan (o-HA) resulted in rapid tyrosine phosphorylation and plasma membrane translocation of phospholipase Cgamma1 (PLCgamma1). Cytoplasmic loading with inhibitory antibodies to PLCgamma1, Gbeta, and Galpha(i/o/t/z) inhibited activation of extracellular-regulated kinase 1/2 (ERK1/2). Treatment with the Galpha(i/o) inhibitor, pertussis toxin, reduced o-HA-induced PLCgamma1 tyrosine phosphorylation, protein kinase C (PKC) alpha and beta1/2 membrane translocation, ERK1/2 activation, mitogenesis, and wound recovery, suggesting a mechanism for o-HA-induced angiogenesis through G-proteins, PLCgamma1, and PKC. In particular, we demonstrated a possible role for PKCalpha in mitogenesis and PKCbeta1/2 in wound recovery. Using antisense oligonucleotides and the Ras farnesylation inhibitor FTI-277, we showed that o-HA-induced bovine aortic endothelial cell proliferation, wound recovery, and ERK1/2 activation were also partially dependent on Ras activation, and that o-HA-stimulated tyrosine phosphorylation of the adapter protein Shc, as well as its association with Sos1. Binding of Src to Shc was required for its activation and for Ras-dependent activation of ERK1/2, cell proliferation, and wound recovery. Neither Src nor Ras activation was inhibited by pertussis toxin, suggesting that their activation was independent of heterotrimeric G-proteins. However, the specific Src kinase inhibitor PP2 inhibited Gbeta subunit co-precipitation with PLCgamma1, suggesting a possible role for Src in activation of PLCgamma1 and interaction between two distinct o-HA-induced signaling pathways.
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PMID:Angiogenic oligosaccharides of hyaluronan induce multiple signaling pathways affecting vascular endothelial cell mitogenic and wound healing responses. 1219 65

We have shown previously that the muscarinic agonist, carbachol (CCh), transactivates the epidermal growth factor receptor (EGFr) via calmodulin, Pyk-2, and Src kinase activation. EGFr phosphorylation causes extracellular signal-regulated kinase (ERK) activation and inhibits CCh-stimulated chloride secretion across intestinal epithelial cells. Here we investigated whether CCh-stimulated EGFr transactivation involves EGFr ligand release. Pre-incubation of T(84) cell monolayers with a neutralizing antibody to the EGFr ligand binding domain decreased CCh-induced phosphorylation of EGFr and ERK. CCh-stimulated efflux of (86)Rb+ from T(84) cell monolayers, which parallels changes in chloride secretion, was potentiated by anti-EGFr pre-incubation. Anti-EGFr did not reduce CCh-stimulated Pyk-2 phosphorylation. Co-incubation with the Src kinase inhibitor PP2 and anti-EGFr had an additive inhibitory effect on CCh-induced ERK phosphorylation greater than either inhibitor alone. CCh caused the basolateral release of transforming growth factor alpha (TGF-alpha) into T(84) cell bathing media. A metalloproteinase inhibitor, WAY171318, reduced CCh-induced phosphorylation of ERK and completely blocked EGFr phosphorylation and TGF-alpha release. We conclude that CCh-stimulated EGFr transactivation and subsequent ERK activation, a pathway that limits CCh-induced chloride secretion, is mediated by metalloproteinase-dependent extracellular release of TGF-alpha and intracellular Src activation. These findings have important implications for our understanding of the role of growth factors in regulating epithelial ion secretion.
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PMID:Transactivation of the epidermal growth factor receptor in colonic epithelial cells by carbachol requires extracellular release of transforming growth factor-alpha. 1220 86

The goals of this study were 2-fold: 1) to determine whether stimulation of Eph B4 receptors promotes microvascular endothelial cell migration and/or proliferation, and 2) to elucidate signaling pathways involved in these responses. The human endothelial cells used possessed abundant Eph B4 receptors with no endogenous ephrin B2 expression. Stimulation of these receptors with ephrin B2/Fc chimera resulted in dose- and time-dependent phosphorylation of Akt. These responses were inhibited by LY294002 and ML-9, blockers of phosphatidylinositol 3-kinase (PI3K) and Akt, respectively. Eph B4 receptor activation increased proliferation by 38%, which was prevented by prior blockade with LY294002, ML-9, and inhibitors of protein kinase G (KT5823) and MEK (PD98059). Nitrite levels increased over 170% after Eph B4 stimulation, indicating increased nitric oxide production. Signaling of endothelial cell proliferation appears to be mediated by a PI3K/Akt/endothelial nitric-oxide synthase/protein kinase G/mitogen-activated protein kinase cascade. Stimulation with ephrin B2 also increased migration by 63% versus controls. This effect was inhibited by blockade with PP2 (Src inhibitor), LY294002 or ML-9 but was unaffected by the PKG and MEK blockers. Eph B4 receptor stimulation increased activation of both matrix metalloproteinase-2 and -9. The results from these studies indicate that Eph B4 stimulates migration and proliferation and may play a role in angiogenesis.
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PMID:Eph B4 receptor signaling mediates endothelial cell migration and proliferation via the phosphatidylinositol 3-kinase pathway. 1223 51

Interleukin-17 (IL-17) is a T cell derived pro-inflammatory cytokine exhibiting multiple biological activities in a variety of cells. In our previous study, we found that IL-17 expressed early on borderline change of renal allograft rejection by Banff classification both in rat renal allograft model and human renal specimens. Renal epithelial cells (RECs) are the important targets in renal allograft rejection. The purpose of this study was to explore the signalling pathways by which human interleukin-17 (hIL-17) contributes to renal allograft rejection by inducing IL-6, IL-8 and MCP-1 expression in human renal epithelial cells (hRECs). Using reverse transcriptase-polymerase chain reaction (RT-PCR), immunoprecipitation and western blot analysis, we report that the early signalling events triggered by the hIL-17 involved tyrosyl phosphorylation of proteins and increased the levels of IL-6, IL-8 and MCP-1 in a dose-dependent manner. Tyrosyl phosphorylation of proteins was induced by IL-17 in 1 min and peaked in 5 min. Further, IL-17 induced the phosphorylation of src kinase and mitogen-activated protein (MAP) kinase. Using a specific src kinase inhibitor, PP2, to treat the hRECs before hIL-17 stimulation, we found that PP2 not only inhibited the phosphorylation of src kinase but also inhibited IL-6, IL-8 and MCP-1 mRNA expression, in a dose-dependent manner. These findings provide the first evidence that the mechanism of IL-17 signalling involves src/MAPK cascades activation.
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PMID:Interleukin-17 induces src/MAPK cascades activation in human renal epithelial cells. 1229 9

It has been shown that endogenous production of reactive oxygen species (ROS) during T cell activation regulates signaling events including MAPK activation. Protein tyrosine phosphatases (PTPs) have been regarded as targets of ROS which modify the catalytic cysteine residues of the enzymes. We have analyzed the interplay between the inhibition of PTPs and the activation of MAPK by H(2)O(2). Stimulation of Jurkat T cells with H(2)O(2) induces the phosphorylation of ERK, p38, and JNK members of MAPK family. H(2)O(2) stimulation of T cells was found to inhibit the PTP activity of CD45, SHP-1, and HePTP. Transfection of cells with wtSHP-1 decreased H(2)O(2)-induced ERK and JNK phosphorylation without affecting p38 phosphorylation. Transfection with wtHePTP inhibited H(2)O(2)-induced ERK and p38 phosphorylation without inhibiting JNK phosphorylation. The Src-family kinase inhibitor, PP2, inhibited the H(2)O(2)-induced phosphorylation of ERK, p38, and JNK. The phospholipase C (PLC) inhibitor, U73122, or the protein kinase C (PKC) inhibitor, Ro-31-8425, blocked H(2)O(2)-induced ERK phosphorylation, whereas the same treatment did not inhibit p38 or JNK phosphorylation. Taken together, these results suggest that inhibition of PTPs by H(2)O(2) contributes to the induction of distinct MAPK activation profiles via differential signaling pathways.
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PMID:Inhibition of PTPs by H(2)O(2) regulates the activation of distinct MAPK pathways. 1237 24

We have previously shown that Ca(2+)-dependent Cl(-) secretion across intestinal epithelial cells is limited by a signaling pathway involving transactivation of the epidermal growth factor receptor (EGFR) and activation of ERK mitogen-activated protein kinase (MAPK). Here, we have investigated a possible role for p38 MAPK in regulation of Ca(2+)-dependent Cl(-) secretion. Western blot analysis of T(84) colonic epithelial cells revealed that the muscarinic agonist carbachol (CCh; 100 microM) stimulated phosphorylation and activation of p38 MAPK. The p38 inhibitor SB-203580 (10 microM) potentiated and prolonged short-circuit current (I(sc)) responses to CCh across voltage-clamped T(84) cells to 157.4 +/- 6.9% of those in control cells (n = 21; P < 0.001). CCh-induced p38 phosphorylation was attenuated by the EGFR inhibitor tyrphostin AG-1478 (0.1 nM-10 microM) and by the Src family kinase inhibitor PP2 (20 nM-2 microM). The effects of CCh on p38 phosphorylation were mimicked by thapsigargin (TG; 2 microM), which specifically elevates intracellular Ca(2+), and were abolished by the Ca(2+) chelator BAPTA-AM (20 microM), implying a role for intracellular Ca(2+) in mediating p38 activation. SB-203580 (10 microM) potentiated I(sc) responses to TG to 172.4 +/- 18.1% of those in control cells (n = 18; P < 0.001). When cells were pretreated with SB-203580 and PD-98059 to simultaneously inhibit p38 and ERK MAPKs, respectively, I(sc) responses to TG and CCh were significantly greater than those observed with either inhibitor alone. We conclude that Ca(2+)-dependent agonists stimulate p38 MAPK in T(84) cells by a mechanism involving intracellular Ca(2+), Src family kinases, and the EGFR. CCh-stimulated p38 activation constitutes a similar, but distinct and complementary, antisecretory signaling pathway to that of ERK MAPK.
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PMID:p38 mitogen-activated protein kinase inhibits calcium-dependent chloride secretion in T84 colonic epithelial cells. 1238 2

We report that Aplidin, a novel antitumor agent of marine origin presently undergoing Phase II clinical trials, induced growth arrest and apoptosis in human MDA-MB-231 breast cancer cells at nanomolar concentrations. Aplidin induced a specific cellular stress response program, including sustained activation of the epidermal growth factor receptor (EGFR), the non-receptor protein-tyrosine kinase Src, and the serine/threonine kinases JNK and p38 MAPK. Aplidin-induced apoptosis was only partially blocked by the general caspase inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone and was also sensitive to AG1478 (an EGFR inhibitor), PP2 (an Src inhibitor), and SB203580 (an inhibitor of JNK and p38 MAPK) in MDA-MB-231 cells. Supporting a role for EGFR in Aplidin action, EGFR-deficient mouse embryo fibroblasts underwent apoptosis upon treatment more slowly than wild-type EGFR fibroblasts and also showed delayed JNK and reduced p38 MAPK activation. N-Acetylcysteine and ebselen (but not other antioxidants such as diphenyleneiodonium, Tiron, catalase, ascorbic acid, and vitamin E) reduced EGFR activation by Aplidin. N-Acetylcysteine and PP2 also partially inhibited JNK and p38 MAPK activation. The intracellular level of GSH affected Aplidin action; pretreatment of cells with GSH or N-acetylcysteine inhibited, whereas GSH depletion caused, hyperinduction of EGFR, Src, JNK, and p38 MAPK. Remarkably, Aplidin also induced apoptosis and activated EGFR, JNK, and p38 MAPK in two cell lines (A-498 and ACHN) derived from human renal cancer, a neoplasia that is highly refractory to chemotherapy. These data provide a molecular basis for the anticancer activity of Aplidin.
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PMID:Aplidin induces apoptosis in human cancer cells via glutathione depletion and sustained activation of the epidermal growth factor receptor, Src, JNK, and p38 MAPK. 1241 12


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