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)

Peroxynitrite, generated for example in inflammatory processes, is capable of nitrating and oxidizing biomolecules, implying a considerable impact on the integrity of cellular structures. Cells respond to stressful conditions by the activation of signaling pathways, including receptor tyrosine kinase-dependent pathways such as mitogen-activated protein kinases and the phosphoinositide-3-kinase/Akt pathway. Peroxynitrite affects signaling pathways by nitration as well as by oxidation: while nitration of tyrosine residues by peroxynitrite modulates signaling processes relying on tyrosine phosphorylation and dephosphorylation, oxidation of phosphotyrosine phosphatases may lead to an alteration in the tyrosine phosphorylation/dephosphorylation balance. The flavanol (-)-epicatechin is a potent inhibitor of tyrosine nitration and may be employed as a tool to distinguish signaling effects due to tyrosine nitration from those that are due to oxidation reactions.
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PMID:Peroxynitrite signaling: receptor tyrosine kinases and activation of stress-responsive pathways. 1220 62

Muc4/sialomucin complex (SMC) is a multifunctional glycoprotein complex which can repress apoptosis in transfected tumor cells. Its transmembrane subunit acts as an intramembrane ligand for the receptor tyrosine kinase ErbB2 to induce the phosphorylation of ErbB2 and, by acting synergistically with the ErbB3 ligand neuregulin, can potentiate the phosphorylation of ErbB2 and ErbB3. In the present study we show that Muc4/SMC alone robustly induces the phosphorylation of ErbB2 to enhance the tyrosine phosphate epitope (Tyr1248) recognized by anti-phospho-ErbB2. Although this tyrosine phosphorylation has been implicated in cell transformation, it does not activate any of the three mitogen-activated protein kinases (MAPKs) or protein kinase B/Akt of the phosphatidyl inositol 3-kinase pathway. Instead, Muc4/SMC expression induces up-regulation of the cell cycle inhibitor p27(kip), consistent with the expression of Muc4/SMC in differentiated, rather than proliferative, epithelial cells. Interestingly, a combination of Muc4/SMC and neuregulin down-regulate p27(kip) and activate protein kinase B/Akt. These observations suggest that Muc4/SMC acts as a regulator of differentiation by inducing a limited phosphorylation of ErbB2 and a modulator of proliferation when acting synergistically with neuregulin to induce a more extensive phosphorylation on both ErbB2 and ErbB3.
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PMID:Muc4/sialomucin complex, the intramembrane ErbB2 ligand, induces specific phosphorylation of ErbB2 and enhances expression of p27(kip), but does not activate mitogen-activated kinase or protein kinaseB/Akt pathways. 1238 15

Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase activated by collagen. DDR1 is constitutively expressed in a variety of normal and transformed epithelial cells and plays a role in cell migration and differentiation through as yet unidentified signaling pathways. We previously reported inducible expression of DDR1 in human leukocytes and suggested a role for the DDR1a isoform in leukocyte migration through extracellular matrix. Here, we evaluated the contribution of DDR1 in the differentiation of the human monocytic THP-1 cells overexpressing these isoforms and of primary macrophages. Interestingly, collagen activation of DDR1b, but not DDR1a, further promoted phorbol ester-induced differentiation of THP-1 cells as determined by reduced cell proliferation and up-regulated expression of HLA-DR, CD11c, CD14, and CD40. Collagen activation of DDR1b also induced the recruitment and phosphorylation of Shc and subsequent phosphorylation of p38 mitogen-activated protein (MAP) kinase and its substrate ATF2. A p38 MAP kinase inhibitor, SB203580, completely inhibited DDR1b-mediated HLA-DR expression. Activation of DDR1 endogenously expressed on macrophages also up-regulated their HLA-DR expression in a p38 MAP kinase-dependent manner. Thus, DDR1b in response to collagen transduces signals that promote maturation/differentiation of HLA-DR-positive antigen-presenting cells and contributes to the development of adaptive immunity in a tissue microenvironment.
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PMID:Interaction of discoidin domain receptor 1 isoform b (DDR1b) with collagen activates p38 mitogen-activated protein kinase and promotes differentiation of macrophages. 1972 Jun 26

Platelet-activating factor (PAF) is a potent pro-inflammatory phospholipid mediator involved in a broad range of physiological and pathophysiological processes. The receptor of PAF (PAFR) is a heptahelical G-protein-coupled receptor. We have shown previously that upon agonist stimulation, PAFR internalised through clathrin-coated vesicles in an arrestin-dependent, but G-protein-coupling-independent manner. In the current report, we demonstrate that PAF stimulates Erk1/2 phosphorylation and: (1). dominant negative mutants of arrestins and dynamin do not influence Erk1/2 activation, (2). hypertonic conditions do not decrease the extent of Erk1/2 phosphorylation, (3). internalisation-deficient and/or G-protein-coupling-deficient mutants of PAFR activate Erk1/2 as efficiently as the wild-type PAFR, and (4). inhibition of epidermal growth factor receptor (EGFR) does not block Erk1/2 activation. Taken together, our results suggest that PAFR-mediated activation of mitogen-activated protein kinases Erk1/2 does not require receptor endocytosis, receptor tyrosine kinase transactivation or G-protein activation. In addition, our studies reveal that PAFR-mediated signals of G-protein activation, receptor internalisation and MAPK activation are differentially regulated by receptor structure and/or conformation.
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PMID:Activation of ERK1/2 by platelet-activating factor receptor is independent of receptor internalisation and G-protein activation. 1283 9

Bombesin and its mammalian homologue gastrin-releasing peptide have been shown to be highly expressed and secreted by neuroendocrine cells in prostate cancer, and are thought to be related to the carcinogenesis and progression of this disease. We found, in this study, bombesin specifically induced mitogen-activated protein (MAP) kinase activation as shown by increased extracellular regulated kinase (ERK) phosphorylation and epidermal growth factor (EGF) receptor transactivation in prostate cancer cells, which express functional gastrin-releasing peptide receptor. The transactivation of EGF receptor was required for bombesin-induced ERK phosphorylation. Furthermore, non-receptor tyrosine kinase Src and cellular Ca2+ were shown to be involved in bombesin-induced EGF receptor transactivation and ERK phosphorylation. Inhibition of either EGF receptor transactivation or ERK activation blocked bombesin-induced DNA synthesis in these cells. Taken together, these data suggest bombesin may act as a mitogen in prostate cancer by activating MAP kinase pathway via EGFR transactivation.
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PMID:Activation of extracellular signal-regulated kinase mediates bombesin-induced mitogenic responses in prostate cancer cells. 1287 8

In this study, we examined the cellular and molecular responses of fibroblasts cultured on a polyelectrolyte complex (PEC) derived from sulfated chitin as a polyanion and chitosan as a polycation. On PEC-coated dishes, the fibroblasts aggregated and then developed spheroid-like structures. At earlier stages of culture, DNA synthesis of cells cultured on PEC was stimulated approximately 75% higher than control cells. Among various signaling molecules examined, including mitogen-activated protein kinases, Akt/PKB and p53, an extracellular-signal-regulated kinase (ERK) was selectively and constitutively phosphorylated in cells cultured on PEC. The constitutive phosphorylation of ERK was derived from an activation of the ERK kinase MEK, but not from an inactivation of the ERK phosphatase MKP-1. Furthermore, ERK phosphorylation was almost abolished by a membrane receptor tyrosine kinase inhibitor. The enhanced phosphorylation of focal adhesion kinase, a downstream molecule of integrins, was also observed in cells cultured on PEC. These results suggest that fibroblasts recognize PEC as a continuous mitogenic stimulant which results in the constitutive activation of the MEK-ERK pathway toward mitogenesis. Further, PEC interacts with the cell membrane leading to activation of membrane molecules, including integrins and receptor tyrosine kinases. These responses may account, at least in part, for the potential use of PEC as a biomaterial for tissue regeneration.
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PMID:Enhanced DNA synthesis accompanied by constitutive phosphorylation of the ERK pathway in human fibroblasts cultured on a polyelectrolyte complex. 1453 74

Loss-of-function mutations in the murine dominant white spotting/c-kit locus affect a diverse array of biological processes and cell lineages and cause a range of phenotypes, including severe anemia, defective pigmentation, sterility, mast cell deficits, a lack of interstitial cells of Cajal, spatial learning memory deficits, and defects in peripheral nerve regeneration. Here we show that tyrosine residues 567 and 569 in the juxtamembrane (Jx) domain of the murine Kit receptor tyrosine kinase are crucial for the function of Kit in melanogenesis and mast cell development, but are dispensable for the normal development of erythroid, interstitial cells of Cajal and germ cells. Furthermore, adult mice lacking both tyrosines exhibit splenomegaly, dysregulation of B-cell and megakaryocyte development, and enlarged stomachs. Analysis of signal transduction events induced by the mutant receptors after ligand stimulation indicates that Jx tyrosine mutations diminish receptor autophosphorylation and selectively attenuate activation of extracellular signal-regulated kinase/mitogen-activated protein kinases. Together, these observations demonstrate that the Jx domain of Kit plays a cell-type specific regulatory role in vivo and illustrate how engineered mutations in Kit can be used to understand the complex biological and molecular events that result from activating a receptor tyrosine kinase.
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PMID:Targeted mutations of the juxtamembrane tyrosines in the Kit receptor tyrosine kinase selectively affect multiple cell lineages. 1506 26

We investigated the effect of platelet-derived growth factor B homodimer (PDGF-BB) on inorganic phosphate (Pi) transport activity, which has been reported to be involved in the mechanism of atherosclerosis, in A-10 rat aortic vascular smooth muscle cells (VSMCs). PDGF-BB time- and dose-dependently stimulated Pi transport in A-10 cells. Using northern blot analysis, the PDGF-BB-enhanced Pi transporter (PiT) in A-10 cells was identified as Pit-1 (Glvr-1), a member of the type III Na-dependent PiT. An inhibitor of PDGF beta-receptor tyrosine kinase suppressed PDGF-BB-induced Pi transport. Both a protein kinase C (PKC) inhibitor calphostin C and PKC down regulation suppressed the stimulatory effect of PDGF-BB on Pi transport. On the other hand, inhibition of mitogen-activated protein (MAP) kinases by selective inhibitors did not affect Pi transport. Ly294002, a phosphatidylinositol (PI) 3-kinase inhibitor, partially attenuated PDGF-BB-induced Pi transport. A selective inhibitor of S(6) kinase, rapamycin, reduced this effect of PDGF-BB, while Akt kinase inhibitor did not. In summary, these results indicated that PDGF-BB is a potent and selective stimulator of Pi transport in VSMCs. The mechanism responsible for this effect is not mediated by MAP kinase, but involves activation of PKC, PI 3-kinase and S(6) kinase.
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PMID:Stimulation of Na-dependent phosphate transport by platelet-derived growth factor in rat aortic smooth muscle cells. 1513 46

H(2)O(2) has been shown to act as a signaling molecule involved in many cellular functions such as apoptosis and proliferation. In the present study, we characterized the effects of H(2)O(2) on the activation of mitogen-activated protein (MAP) kinases and examined the factors involved in the process of extracellular signal-regulated kinase (ERK) activation by H(2)O(2) in ileal smooth muscle cells (ISMC). ISMC were cultured and exposed to H(2)O(2). Western blot analysis was performed with phosphospecific MAP kinase antibodies. Potent activation of ERK and moderate activation of stress-activated protein kinase/c-Jun NH(2)-terminal kinase occurred within 30 min of 1 mM H(2)O(2) treatment. However, p38 MAP kinase was not activated by H(2)O(2). The activation of ERK by H(2)O(2) was reduced by the mitogen-activated/ERK-activating kinase inhibitor PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one], Ras inhibitor S-farnesylthiosalicylic acid, removal of extracellular Ca(2+), depletion of the intracellular Ca(2+) pool by thapsigargin, or pretreatment of ISMC with the calmodulin antagonist W-7. Also, H(2)O(2)-induced ERK activation was attenuated by a receptor tyrosine kinase inhibitor, tyrphostin 51, but not by down-regulation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate or by a PKC inhibitor, GF109203X [3-[1-(dimethylaminopropyl)indol-3-yl]-4-(indol-3-yl)maleimide hydrochloride]. Growth factor receptor antagonist suramin pretreatment inhibited H(2)O(2)-induced ERK activation, highlighting a role for growth factor receptors in this activation. Furthermore, the ERK activation by H(2)O(2) was blocked by pretreatment with either N-acetyl-cysteine, o-phenanthroline, or mannitol indicating that metal-catalyzed free radical formation may mediate the initiation of signal transduction by H(2)O(2). These data suggest that short-term stimulation with H(2)O(2) activates the signaling pathways of cell mitogenic effects which are thought to be a protective response against intestinal oxidative stress.
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PMID:Hydrogen peroxide-induced extracellular signal-regulated kinase activation in cultured feline ileal smooth muscle cells. 1532 80

The receptor tyrosine kinase ERBB2 plays a central role in the development of breast cancer and other epithelial malignancies. Elevated ERBB2 activity is believed to transform cells by transmitting mitogenic and antiapoptotic signals. Here we show that tightly regulated overexpression of oncogenic ERBB2 in human breast carcinoma cells does not stimulate proliferation but provokes premature senescence, accompanied by up-regulation of the cyclin-dependent kinase inhibitor P21(WAF1/CIP1). A similar effect was caused by retrovirus-mediated overexpression of oncogenic ERBB2 in low-passage murine embryonic fibroblasts. In contrast to previous observations based on constitutively overexpressing cell lines, P21 induced by tetracycline-regulated ERBB2 localizes to the nucleus in arrested cells. P21 up-regulation seems to be independent of the P53 tumor suppressor protein, and senescence-associated phenotypic alterations are reversed by specific inhibition of P38 mitogen-activated protein kinases. Functional inactivation of P21 by antisense oligonucleotides is sufficient to prevent cell cycle arrest as well as the senescent phenotype, thereby identifying the P21 protein as the key mediator of hypermitogenic cell cycle arrest and premature senescence in breast carcinoma cells. Our results may thus indicate that premature senescence represents an inherent anticarcinogenic program during ERBB2-driven mammary tumorigenesis. We propose a multistep model for the process of malignant transformation by ERBB2 wherein secondary lesions either target P21 or downstream effectors of senescence to bypass this primary fail-safe mechanism.
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PMID:Premature senescence is a primary fail-safe mechanism of ERBB2-driven tumorigenesis in breast carcinoma cells. 1570 82


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