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)

The B cell antigen receptor is a complex containing the antigen-binding immunoglobulin molecules and the Ig-alpha/Ig-beta heterodimer which presumably connects the B cell antigen receptor to intracellular signaling components. To analyze the functional properties of the cytoplasmic parts of the B cell antigen receptor, we used the K46 B lymphoma line (IgG2a, kappa) to express chimeric molecules composed of the extracellular and transmembrane part of the CD8 alpha molecule and the cytoplasmic sequence of either the Ig-alpha (CD8 alpha/Ig-alpha), the Ig-beta (CD8 alpha/Ig-beta) protein or the membrane-bound gamma 2a heavy chain (CD8 alpha/gamma 2a). From these three types of chimeric molecules only (CD8 alpha/Ig-alpha and CD8 alpha/Ig-beta, but not CD8 alpha/gamma 2a, could transduce signals, thus providing the first evidence that the cytoplasmic tail of Ig-alpha and Ig-beta have a signaling capacity. After cross-linking with anti-CD8 alpha antibodies, both molecules induced a similar increase in intracellular free calcium ion and in MAP kinase phosphorylation. Protein tyrosine kinases, however, were strongly activated via the CD8 alpha/Ig-alpha and only marginally via the CD8 alpha/Ig-beta molecule. This suggests that the Ig-alpha and Ig-beta proteins have distinct roles during signal transduction through the B cell antigen receptor.
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PMID:Differential signaling through the Ig-alpha and Ig-beta components of the B cell antigen receptor. 768 2

The heavy chain of myosin-ID isolated from Dictyostelium was identified as an in vitro substrate for members of the Ste20p family of serine/threonine protein kinases which are thought to regulate conserved mitogen-activated protein kinase pathways. Yeast Ste20p and Cla4p and mammalian p21-activated protein kinase (PAK) phosphorylated the heavy chain to 0.5-0.6 mol of Pi/mol and stimulated the actin-dependent Mg2+-ATPase activity to an extent equivalent to that of the Ste20p-like myosin-I heavy chain kinase isolated from Dictyostelium. PAK purified from rat brain required GTPgammaS-Cdc42 to express full activity, whereas recombinant mouse mPAK3 fused to glutathione S-transferase and purified from bacteria, and Ste20p and Cla4p purified from yeast extracts were fully active without GTPgammaS-Cdc42. These results suggest, together with the high degree of structural and functional conservation of Ste20p family members and myosin-I isoforms, that myosin-I activation by Ste20p family protein kinases may contribute to the regulation of morphogenetic processes in organisms ranging from yeast to mammalian cells.
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PMID:Activation of myosin-I by members of the Ste20p protein kinase family. 894 16

Freshly isolated human blood monocytes expressed neither c-src mRNA nor c-Src. However, when monocytes were incubated with anti-CD98 heavy chain (HC) mAb, expression of c-src mRNA, c-Src, and activated c-Src was induced. Many binding sites for the ubiquitous transcription factor Sp1 were identified in the promoter region of the c-src gene. Surprisingly, Sp1 and Sp1 mRNA were not found in monocytes that were freshly isolated or incubated with control antibody. Stimulation with anti-CD98HC mAb also resulted in the expression of Sp1 and its translocation to the nucleus. Herbimycin A, genistein, manumycin A, PD-98059, SB203580, and HBJ127 suppressed CD98HC-mediated c-src and Sp1 mRNA induction. On the contrary, H-7, Wortmannin, HA1077, and Y-27632 showed no effect on c-Src and Sp1 induction. Furthermore, anti-CD98HC mAb induced activation of tyrosine kinases and ERK kinases. These findings suggest that the tyrosine kinase(s)-Ras-MAPK-Sp1 pathway(s) is involved in CD98HC-mediated induction of c-Src in human blood monocytes.
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PMID:Induction of c-Src in human blood monocytes by anti-CD98/FRP-1 mAb in an Sp1-dependent fashion. 1106 18

Signaling events arising from the B cell antigen receptor (BCR) complex are critical for the normal progression of a B cell through its stages of maturation. These stages are characterized by the generation and expression of BCR components. Initially, the heavy chain is formed and expressed along with the surrogate light chain and VpreB. This pre-BCR may initiate events that induce the cell to generate the light chain molecules. Proper expression of these molecules triggers the cell to develop into a mature B cell. If a key signal is absent at any stage of B cell development, maturation ceases, and either the defects are corrected or the cell undergoes apoptosis. A deficiency in the expression of several intracellular proteins required for these signaling events leads to the arrest of B cell development. Advancement to specific stages of maturation relies on a particular intensity of signal through pathways leading to the activation of a set of transcription factors. These pathways include the calcium and MAPK family pathways. Factors such as the concentration and avidity of the antigen, the coligation of co-receptors, and the formation of signaling complexes dictate the intensity of these signals and thereby the fate of the B cell at each stage of development.
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PMID:Signaling through the B cell antigen receptor in developing B cells. 1125 17

The mechanism of cardioprotection with red wine consumption was studied by examining the antideath signaling cascade of one of the principle components of red wine, proanthocyanidins. Grape seed proanthocyanidin extract (GSPE) was administered orally (100 mg/kg/d) supplemented with regular diet for 3 weeks to a group of rats while the other group was given the regular diet only for the same period of time. After 3 weeks, rats were sacrificed, hearts excised, and perfused via Langendorff mode. After stabilization, hearts were perfused in the working mode for baseline measurement of contractile function. Hearts were then made globally ischemic for 30 min followed by 2 h of reperfusion. Contractile function was continuously monitored during reperfusion, and free radical production was examined by electron spin resonance (ESR) technique. Cardiomyocyte apoptosis was examined by TUNEL staining in conjunction with an antibody against myocin heavy chain to specifically detect myocytes. Induction of JNK-1 and c-fos proteins was studied by Western blot analysis using respective antibodies followed by densitometric scanning. The results indicated significant induction of JNK-1 and c-fos proteins in the ischemic/reperfused myocardium, which was inhibited by the proanthocyanidin extract. In concert, GSPE significantly reduced the appearance of apoptotic cardiomyocytes in the ischemic/reperfused hearts. GSPE also significantly reduced the appearance of the reactive oxygen species in the hearts. Improved postischemic contractile recovery was achieved with GSPE suggesting its cardioprotective action. The results of this study indicated that GSPE functioned as an in vivo antioxidant, and its cardioprotective properties may be at least partially attributed to its ability to block antideath signal through the inhibition of proapoptotic transcription factor and gene, JNK-1 and c-Jun.
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PMID:Grape seed proanthocyanidin reduces cardiomyocyte apoptosis by inhibiting ischemia/reperfusion-induced activation of JNK-1 and C-JUN. 1155 10

Vascular smooth muscle cells (SMCs) undergo phenotype change with the development of atherosclerosis. The phenotype changes of SMCs have been observed in various culture conditions, such as collagen-coated dishes. Here, we report the morphological and functional features of SMCs in a novel culture system using type I-collagen in a characteristic three-dimensional structure designated as honeycombs. The number of ribosome and mitochondria in SMCs cultured in honeycombs was one half or third of those cultured on collagen-coated plastic plates. DNA and protein synthesis of SMCs cultured in honeycombs were less than 1 and 30-40%, respectively, of those cultured on plastic plates. In addition, PDGF-BB did not increase the amount of DNA synthesis in SMCs in honeycombs. SMCs in honeycombs were shown to express several proteins, which are known to express in SMCs in medial layers of arteries. Particularly, caldesmon heavy chain was expressed in SMCs cultured in honeycombs, whereas not in those on plastic plates. Although focal adhesion kinase (FAK) was clearly detected in SMCs in honeycomb, the phosphotyrosine content of focal adhesion kin ase decreased in the process of culture. Immunoblot analysis showed dear different expression of ERK1 and ERK2 of mitogen-activated protein kinase in SMCs. SMCs in honeycombs expressed ERK2, more abundantly compared to ERK1, whereas SMCs in plates show the same levels of expressions for both proteins. Thus, the histological and functional feature of SMCs in the novel culture system is different from SMCs in plastic plates. The three-dimensional culture system described here may be indicating that cultured SMCs are able to express different proteins responding to the surrounding structures.
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PMID:Histological and functional analysis of vascular smooth muscle cells in a novel culture system with honeycomb-like structure. 1158 16

Adaptive increases in intracellular glutathione (GSH) in response to oxidative stress are mediated by induction of L-cystine uptake via the anionic amino acid transport system x(c)(-). The recently cloned transporter xCT forms a heteromultimeric complex with the heavy chain of 4F2 cell surface antigen (4F2hc/CD98). Depletion of GSH by the electrophile diethylmaleate (DEM) induces the activity and expression of xCT in peritoneal macrophages. We here examine the effects of vitamin C on induction of xCT by DEM in human umbilical artery smooth muscle cells. DEM caused time- (3-24 h) and concentration- (25-100 microM) dependent increases in L-cystine transport, with GSH depleted by 50% after 6 h and restored to basal values after 24 h. xCT mRNA levels increased after 4 h DEM treatment with negligible changes detected for 4F2hc mRNA. DEM caused a rapid (5-30 min) phosphorylation of p38(MAPK). Inhibition of p38(MAPK) by SB203580 (10 microM) enhanced DEM-induced increases in L-cystine transport and GSH, whereas inhibition of p42/p44(MAPK) (PD98059, 10 microM) had no effect. Pretreatment of cells with vitamin C (100 microM, 24 h) attenuated DEM-induced adaptive increases in L-cystine transport and GSH levels. Inhibition of p38(MAPK), but not p42/p44(MAPK), reduced the cytoprotective action of vitamin C. Our findings suggest that DEM induces activation of xCT via intracellular signaling pathways involving p38(MAPK), and that vitamin C, in addition to its antioxidant properties, may modulate this signaling pathway to protect smooth muscle cells from injury.
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PMID:Vitamin C inhibits diethylmaleate-induced L-cystine transport in human vascular smooth muscle cells. 1249 85

Release of transcellular tension upon disruption of actin stress fibers with cytochalasin D (CD) and associated changes in cell morphology are reflected in the rapid transcription of "deformation-responsive" genes. For certain genes (e.g., urokinase plasminogen activator and its type-1 inhibitor PAI-1), de novo mRNA synthesis appears to require cell shape-dependent activation of the MAP kinases ERK1/2. ERK activation in response to microfilament disruption was inhibited completely by the broad-spectrum tyrosine kinase inhibitor genistein and the relatively src-kinase selective compound PP1. Such inhibitor sensitivity profiles suggested that src-family members, likely pp60(c-src), were important upstream elements in deformation-related ERK activation. pp60(c-src) kinase activity was elevated fourfold within 15 min after CD addition to quiescent R22 smooth muscle cells and declined quickly thereafter. CD-induced increases in the phosphorylation levels of both pp60(c-src) and IgG heavy chain (a substrate target in the coupled immunoprecipitation/in vitro pp60(c-src) kinase assay) were ablated completely by pretreatment with the src-type kinase inhibitor PP1. Prior PP1 exposure similarly repressed CD-stimulated PAI-1 transcript accumulation. Consistent with the pharmacologic findings, transfection of a dominant-negative pp60(c-src) expression construct (DN-Src) effectively suppressed (in a concentration-dependent manner) CD-induced PAI-1 synthesis in R22 cells. To more specifically address the potential involvement of src kinases in CD-initiated ERK mobilization, R22 cells were transiently co-transfected with DN-Src and Myc-tagged ERK2 expression constructs, serum-deprived then stimulated with CD. The effect of DN-Src expression on endogenous ERK1/2 activation and nuclear translocation was assessed in separate experiments. The phosphorylation levels of both exogenous (Myc-ERK2) and endogenous ERK1/2 targets was significantly reduced by DN-Src; nuclear accumulation of pERK1/2 was completely inhibited. These data indicate that pp60(c-src) is a critical upstream activator of the ERK cascade leading to PAI-1 transcription in response to cellular deformation stimuli.
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PMID:Pp60c-src mediates ERK activation/nuclear localization and PAI-1 gene expression in response to cellular deformation. 1270 50

Glutathione plays important roles as an intracellular antioxidant and in the maintenance of cellular thiol-disulfide balance. In addition, glutathione may regulate cell growth signaling induced by oxidative stress. We previously reported that cellular glutathione is up-regulated by bleomycin in bovine pulmonary artery endothelial cells. The present study examined effects of hydrogen peroxide (H(2)O(2)) on cell growth and glutathione levels. Exogenous addition of H(2)O(2) induced biphasic effects on cell growth; 1 micro M was stimulatory and >10 micro M was inhibitory. However, both growth-promoting and inhibitory levels of H(2)O(2) increased cellular glutathione levels. Whereas 1 micro M H(2)O(2) moderately but significantly increased glutathione, 30 micro M caused a more substantial increase. Like bleomycin, both concentrations of H(2)O(2) activated DNA binding of antioxidant response element (ARE), a regulatory element in the promoter of the gamma-glutamylcysteine synthetase heavy chain subunit, a key regulator of glutathione synthesis. However, only high concentrations of H(2)O(2) activated p44/42 mitogen-activated protein (MAP) kinase. Thus, cellular glutathione is up-regulated by H(2)O(2), perhaps via activating ARE-binding factors in a mechanism independent of MAP kinase. H(2)O(2)-mediated increase in glutathione and activation of ARE binding may play important roles in growth and death of pulmonary artery endothelial cells.
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PMID:Regulation of glutathione by oxidative stress in bovine pulmonary artery endothelial cells. 1458 42

Cardiac surgery with extracorporeal circulation is associated with neutrophil activation, inflammation, and edema. Endothelial hyperpermeability elicited by the interaction of activated neutrophils and/or cytokines with endothelial cells may be critical in this regard. However, the immune and cellular mechanisms involved are not fully understood. Cocultures with human endothelial cells and neutrophils from cardiac surgery patients were used to evaluate the role of beta1 integrin activity and the proinflammatory cytokine tumor necrosis factor (TNF)-alpha in neutrophil transendothelial migration and in impairment of the integrity of endothelial cell-to-cell contacts. Blocking of CD29 (heavy chain of beta1 integrins) totally prevented neutrophil adhesion and transendothelial migration. Pretreatment of neutrophils with either a CD29-stimulating monoclonal antibody or the addition of TNF-alpha (0.1-10 U/ml) to the coculture failed to induce transendothelial migration. However, coculture of endothelial cells with CD29-stimulated neutrophils in the presence of 0.1-10 U/ml TNF-alpha strongly induced neutrophil transmigration. CD29/TNF-alpha-mediated transmigration was associated with intracellular redistribution of endothelial beta-catenin. We further showed that CD29/TNF-alpha-mediated effects involved PI3K and tyrosine kinase-dependent signaling via MAPK but were independent of nuclear transcription factor (NF)-kappaB activity. Inhibition of CD29/TNF-alpha might be a therapeutic option to limit endothelial dysfunction following cardiac surgery with extracorporeal circulation.
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PMID:Cardiac surgery with extracorporeal circulation: neutrophil transendothelial migration is mediated by beta1 integrin (CD29) in the presence of TNF-alpha. 1538 57


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