Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The activation of eosinophils by IL-5 plays a crucial role in the pathogenesis of allergic and parasitic disorders. IL-5 has recently been shown to activate Lyn and Jak2 tyrosine kinases, MAP kinases, and STAT1 nuclear factor. We have previously reported that TGF-beta blocks the IL-5-induced activation of eosinophils. In this study, we investigated the effect of TGF-beta on the IL-5-induced signaling molecules in eosinophils. Purified eosinophils from mildly allergic patients were preincubated with TGF-beta and then stimulated with IL-5. The cell lysates were then immunoprecipitated and blotted with antiphosphotyrosine Abs. The activity of the kinases was further studied in the immune-complex kinase assay. We found that TGF-beta inhibited the tyrosine phosphorylation of multiple proteins in eosinophils. The identity of some of the proteins was established by immunoprecipitation. We found that TGF-beta inhibited tyrosine phosphorylation of Lyn, Jak2, and a 44-kDa MAP kinase. In further experiments, it blocked the activation of the above kinases as determined by immune-complex kinase assay. TGF-beta also inhibited phosphorylation of the STAT1 (p91) nuclear protein in eosinophils. We believe that the inhibition of Lyn, Jak2, MAP kinase, and the STAT1 nuclear protein may underlie the inhibitory activity of TGF-beta on eosinophils.
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PMID:Mechanism of inhibition of eosinophil activation by transforming growth factor-beta. Inhibition of Lyn, MAP, Jak2 kinases and STAT1 nuclear factor. 759 7

The peptide hormone angiotensin II (AngII) has clearly defined physiologic roles as a regulator of vasomotor tone and fluid homeostasis. In addition AngII has trophic or mitogenic effects on a variety of target tissues, including vascular smooth muscle and adrenal cells. More recent data indicate that AngII exhibits many characteristics of the 'classical' peptide growth factors such as EGF/TGF alpha, PDGF and IGF-1. These include the capacity for local generation ('autocrine or paracrine' action) and the ability to stimulate tyrosine phosphorylation, to activate MAP kinases and to increase expression of nuclear proto-oncogenes. The type 1 AngII receptor, which is responsible for all known physiologic actions of AngII, has been cloned. Activation of this receptor leads to elevated phosphoinositide hydrolysis, mobilization of intracellular Ca2+ and diacylglycerol, and activation of Ca2+/calmodulin and Ca2+/phospholipid-dependent Ser/Thr kinases, as well as Ca2+ regulated tyrosine kinases. The existence of other AngII receptor subtypes has been postulated, but the function(s) of these sites remains unclear. In vascular smooth muscle, AngII can promote cellular hypertrophy and/or hyperplasia, depending in part on the patterns of induction of secondary factors that are known to stimulate (PDGF, IGF-1, basic FGF) or inhibit (TGF-beta) mitosis. Together, these findings have suggested that AngII plays important roles in both the normal development and pathophysiology of vascular, cardiac, renal and central nervous system tissues.
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PMID:Regulation of cell proliferation and growth by angiotensin II. 791 23

Cellular processes leading to renal tubular hypertrophy may contribute to the development of progressive renal disease. Angiotensin II (ANG II) is a prime agent that has been linked to the progression of renal disease by a host of mechanisms, including the induction of tubular epithelial hypertrophy and stimulation of extracellular matrix biosynthesis. All components of a functional renin-angiotensin system reside within the renal tubule. Epithelial cells exhibit distinct patterns of growth behavior after stimulation with ANG II (namely, hypertrophy of proximal tubule segments and proliferation of more distal segments). The hypertrophic action of ANG II is mediated through high-affinity AT1-receptors, involves activation of pertussis-toxin sensitive G1 proteins, and depends on a decrease in intracellular cAMP. In addition, ANG II induces sequential activation of MAP kinases and S6 kinase, and leads to activation of early immediate genes and the modulation of a series of cyclins and cyclin-dependent kinases. There is also compelling evidence that the ANG II-induced epithelial hypertrophy and the stimulated-synthesis of collagen type IV are mediated by increased transcription and production of TGF-beta. ANG II-mediated inhibition of protein degradation may further increase protein content. The hypertrophic response to ANG II is greater in medium with high glucose concentration. Blockade of the action of ANG II prevents the renal hypertrophy and the tubulointerstitial fibrosis in animal models of chronic renal diseases (independent of changes in systemic or glomerular hemodynamics), in part through interception of ANG II-mediated induction of TGF-beta expression.
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PMID:Renal tubular hypertrophy induced by angiotensin II. 931 13

The discovery of SMAD proteins has allowed the delineation of a mechanism by which TGF-beta and related growth factors convey their signals from membrane receptors all the way into the nucleus. SMADs are directly phosphorylated and activated by the receptors and then form heteromeric SMAD-SMAD complexes that move into the nucleus where they orchestrate transcriptional responses. In rapid succession, recent reports have identified different modes of SMAD regulation by phosphorylation and have defined the SMAD domains that mediate SMAD interactions, binding to DNA or transcriptional activation. The recent discovery of antagonistic SMADs and regulatory crosstalk with Ras/MAP-kinase pathways add to our rapidly expanding understanding of this major regulatory network.
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PMID:SMADs: mediators and regulators of TGF-beta signaling. 952 13

TGFbeta can override the proliferative effects of EGF and other Ras-activating mitogens in normal epithelial cells. However, epithelial cells harboring oncogenic Ras mutations often show a loss of TGFbeta antimitogenic responses. Here we report that oncogenic Ras inhibits TGFbeta signaling in mammary and lung epithelial cells by negatively regulating the TGFbeta mediators Smad2 and Smad3. Oncogenically activated Ras inhibits the TGFbeta-induced nuclear accumulation of Smad2 and Smad3 and Smad-dependent transcription. Ras acting via Erk MAP kinases causes phosphorylation of Smad2 and Smad3 at specific sites in the region linking the DNA-binding domain and the transcriptional activation domain. These sites are separate from the TGFbeta receptor phosphorylation sites that activate Smad nuclear translocation. Mutation of these MAP kinase sites in Smad3 yields a Ras-resistant form that can rescue the growth inhibitory response to TGFbeta in Ras-transformed cells. EGF, which is weaker than oncogenic mutations at activating Ras, induces a less extensive phosphorylation and cytoplasmic retention of Smad2 and Smad3. Our results suggest a mechanism for the counterbalanced regulation of Smad2/Smad3 by TGFbeta and Ras signals in normal cells, and for the silencing of antimitogenic TGFbeta functions by hyperactive Ras in cancer cells.
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PMID:A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras. 1019 81

In addition to important roles in the regulation of cell growth and cell restitution, both pro- and anti-inflammatory effects have been ascribed to TGFbeta in intestinal epithelial cells. However, the mechanisms involved in TGFbeta-dependent anti-inflammatory activities remain to be determined. In the rat intestinal epithelial cell line IEC-6, TGFbeta attenuated the glucocorticoid-dependent increases in mRNA levels of the acute phase protein gene haptoglobin, and of C/EBP isoforms beta and delta. Supershift assays demonstrated a TGFbeta-mediated decrease in the binding of C/EBP isoforms beta and delta to the haptoA and haptoC C/EBP DNA-binding sites from the haptoglobin promoter. Mutations of both HaptoA and HaptoC sites abolished the glucocorticoid-dependent activation and the TGFbeta-mediated attenuation of the haptoglobin promoter, as assessed by transient transfection assays. TGFbeta induced p42/p44 MAP kinase activities. Treatment with the MEK 1/2 inhibitor PD 98059 abolished TGFbeta attenuation. These results suggest that C/EBP isoforms are involved both in the glucocorticoid-dependent induction and in the TGFbeta-mediated attenuation of haptoglobin expression. Furthermore, p42/p44 MAP kinases may function in a TGFbeta-dependent signaling pathway leading to attenuation of haptoglobin expression.
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PMID:Attenuation of haptoglobin gene expression by TGFbeta requires the MAP kinase pathway. 1036 55

Myocardium consists of diverse cell types suggesting a role for cell-cell interaction in maintaining the structural and functional integrity of the heart. Cardiac fibroblasts are the source of extracellular matrix, growth factors and cytokines in the heart and their interactions with cardiac myocytes are recognized. Their effects on biological responses of endothelial cells, however, are vastly unexplored. Proliferation of endothelial cells is an essential stage of angiogenesis and contributes to development of coronary collaterals. This study was designed to evaluate the effect of soluble factors produced by cardiac fibroblasts on endothelial cell proliferation. Human cardiac fibroblast-conditioned medium (CF-CM) caused a significant increase (47%, P < 0.0001) in DNA synthesis in human umbilical vein endothelial cells (HUVEC), as determined by [(3)H]thymidine incorporation. This effect was dependent on de novo protein synthesis and activation of MAP kinases. Consistently, CF-CM induced the expression and activation of ERK2 in HUVEC. The CF-CM from which heparin-binding proteins were removed, had a significantly enhanced stimulatory effect on DNA synthesis in HUVEC compared to that of 'whole CF-CM'. Western analysis showed the presence of VEGF, bFGF, PDGF, TGF-beta(1), fibronectin and thrombospondin-1 in whole CF-CM. The individual immunodepletion of each factor from whole CF-CM showed that all were necessary for full activity of CF-CM. CF-CM caused a significant reversal of hypoxia-induced inhibition of DNA synthesis and enhanced expression of survival-associated protein, Bcl(2), in HUVEC. Together, these data show that cardiac fibroblasts release inhibitory and stimulatory factors, the net effect of which is an enhancement of DNA synthesis in endothelial cells. These results point to the role that cardiac fibroblasts may play in angiogenesis in the heart.
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PMID:Release of pro- and anti-angiogenic factors by human cardiac fibroblasts: effects on DNA synthesis and protection under hypoxia in human endothelial cells. 1133 98

Bone morphogenetic proteins (BMPs), members of the TGF-beta superfamily of secreted signaling molecules, have important functions in many biological contexts. They bind to specific serine/threonine kinase receptors, which transduce the signal to the nucleus through Smad proteins. The question of how BMPs can have such diverse effects while using the same canonical Smad pathway has recently come closer to an answer at the molecular level. Nuclear cofactors have been identified that cooperate with the Smads in regulating specific target genes depending on the cellular context. In addition, the pivotal role BMP signaling plays is underscored by the identification of factors that regulate members of this pathway at the cell surface, in the cytoplasm, and in the nucleus. Many of these factors are BMP-inducible and inhibit the BMP pathway, thus establishing negative feedback loops. Members of the BMP-Smad pathway can also physically interact with components of other signaling pathways to establish crosstalk. Finally, there is accumulating evidence that an alternative pathway involving MAP kinases can transduce BMP signals. The evidence and implications of these findings are discussed with an emphasis on early embryonic development of Xenopus and vertebrates.
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PMID:Intracellular BMP signaling regulation in vertebrates: pathway or network? 1178 15

Serotonin [5-hydroxytryptamine (5-HT)]-mediated cardiac valvular disease has been commonly observed in patients with carcinoid tumors. Previous research by others using reverse transcriptase-polymerase chain reaction demonstrated that aortic valve cells expressed predominantly 5-HT(2A/2B) receptors (5-HT(2A)R). Related investigations by our group using sheep aortic valve interstitial cell (SAVIC) cultures demonstrated that 5-HT both up-regulates transforming growth factor (TGF)-beta1 expression and activity, and also results in increased phospholipase C (PLC) activity. Thus, the present study investigated the hypothesis that the 5-HT signaling pathway in SAVICs involves 5-HT(2)Rs with associated G-protein signal transduction. The objectives were to functionally characterize in SAVIC cultures the native serotonin receptor subtypes using specific agonists and antagonists, and to delineate the serotonin-signaling pathway. 5-HT administration caused a marked stimulation of PLC activity. SAVIC studies of specific agents that target the 5-HT(2)R subtypes indicate that this response seemed to be mediated predominantly by 5-HT(2A)Rs. Furthermore, the sheep 5-HT(2A)R was identified by reverse transcriptase-polymerase chain reaction with sequence confirmation including comparisons to pig and human 5-HT(2A)R. Extracellular signal-regulated kinase (Erk 1/2) is a signaling molecule downstream from the 5-HT(2A)R. Both a protein kinase C inhibitor, GF109203X, and a Src inhibitor, PP1, attenuated 5-HT-stimulated Erk 1/2 activation. However, a 5-HT(2A)R antagonist, MDL 100907, inhibited 5-HT up-regulation of PLC and TGF-beta1, while having far less pronounced effects on Erk 1/2. In conclusion, these studies of the signal transduction activity of SAVICs in response to 5-HT have demonstrated that the 5-HT(2A)Rs are the most functionally active of the 5-HT(2)Rs in this cell type. Furthermore, 5-HT(2A)Rs are also involved in 5-HT up-regulation of active TGF-beta. 5-HT also mediated strong Erk 1/2 signaling via the MAP-kinase pathway, which was only in part because of 5-HT(2A)R activity. Thus, major 5-HT Erk 1/2 signaling beyond that controlled by 5-HT(2)Rs must involve other serotonin receptor types and/or secondary signaling events.
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PMID:Serotonin mechanisms in heart valve disease II: the 5-HT2 receptor and its signaling pathway in aortic valve interstitial cells. 1246 35

Gap junction channels are essential for intercellular communication. Among the most abundant gap junction channel proteins is connexin 43 (Cx43). The goal of our study was to find out, whether Cx43 content may be regulated via adenylyl cyclase (AC)/cAMP/protein kinase A (PKA), protein kinase C (PKC) pathways or by a tyrosine kinase coupled pathway, i.e. TNF alpha-receptor dependent pathway. Therefore, we used HeLa cells transfected with Cx43 and exposed these cells for 24 h to either db-cAMP (10(-4)M), forskolin (10(-5)M), the phorbolester phorbol-12,13-didecanoate PDD (10(-7)M) (or its inactive form 4 alpha-PDD), TNF alpha (10 U/ml) with or without additional treatment with the MAP kinase inhibitors SB203580 (10(-5) M, p38 MAP-kinase inhibitor) or the MEK1-inhibitor PD98059 (10(-5)M). Cx43 content was analysed using Western blot analysis. All results were confirmed by a second series of identical experiments using Cx43 immunohistochemistry. We found significantly enhanced Cx43 content in cells treated with db-cAMP, forskolin, PDD or TNF alpha (p<0.05), while 4 alpha-PDD or the solvent DMSO exerted no effect. These increases in Cx43 content could be completely suppressed by SB203580 (p<0.05) but not by PD98059. In absence of a stimulating drug, these inhibitors (SB203580 or PD98059) did not affect Cx43 content. Additional PCR experiments revealed increases in Cx43-mRNA under the influence of db-cAMP, forskolin, PDD or TNFalpha (p<0.05), which all could be completely suppressed by SB203580. From these results we conclude that 1.Cx43 content can be regulated via AC/cAMP/PKA, PKC and TNF alpha-receptor-dependent pathways 2. Activation of p38 MAP kinase is a common pathway for regulation of Cx43 content in HeLa cells
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PMID:Chronic regulation of the expression of the gap junction protein connexin 43 in transfected HeLa cells. 1282 13


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