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)

We have investigated cellular signalling events induced by urokinase-type plasminogen activator (uPA) independent of its proteolytic activity. Treatment of the human fibrosarcoma cell line HT 1080 with diisopropylphosphorofluoridate-inactivated uPA (Dip-F-uPA) triggers a cascade of intracellular signals which are mediated by the specific cell surface receptor for uPA (uPAR). We have found that anti-uPAR Ig precipitate the src-type protein tyrosine kinases fyn, hck and lck, which belong to a family of structurally and functionally related effectors participating in signalling from antigen and cytokine receptors. Of the three uPAR-associated kinases, only hck is activated by uPA, whereas no changes in the activities of either fyn or lck could be detected by an in vitro immune complex kinase assay. We identified p38 and extracellular-signal-regulated kinase 2 from the mitogen-activated protein kinase family as downstream components of a set of consecutive signalling molecules which teleologically alter the program of gene expression. Exposure of cells to uPA results in a significant increase in c-fos mRNA that is partially due to an elevated rate of gene transcription. Presumably, the activation of the c-fos gene leads to the subsequent formation of the transcription factor activator protein-1 (AP-1), since accumulation of c-fos mRNA is followed by induction of target genes sensitive to AP-1 such as plasminogen activator inhibitor type 2 (PAI-2). These results provide new insights into proteolysis-independent cytokine-like effects of uPA.
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PMID:Downstream targets of urokinase-type plasminogen-activator-mediated signal transduction. 965 92

We have investigated the adaptive changes of the human central cannabinoid receptor (CB1) stably expressed in Chinese hamster ovary cells (CHO-CB1), after agonist (CP 55,940) or selective CB1 inverse agonist (SR 141716) treatment. CB1 receptor density and affinity constant as measured by binding assays with both tritiated ligands remained essentially unchanged after varying period exposure of CHO-CB1 cells (from 30 min to 72 hr) to saturating concentrations of CP 55,940 or SR 141716. However, using a C-myc-tagged version of the CB1 receptor, FACS analysis and confocal microscopy studies on CB1 expression indicated that the agonist promoted a disappearance of cell surface receptor although inverse agonist increased its cell surface density. Taken together these results suggest that 1) agonist induces internalization of the receptor into a cellular compartment that would be still accessible to both the hydrophobic ligands CP 55,940 or SR 141716; 2) inverse-agonist promotes externalization of the receptor from an intracellular preexisting pool to the cell surface. In parallel, we also investigated the associated effects of CP 55,940 and SR 141716 on CB1 receptor-coupled second messengers. We showed that preexposure of cells to CP 55,940 induced a rapid desensitization of the CB1 to the agonist response. The ability of CP 55,940 to inhibit the forskolin-stimulated adenylyl cyclase and to activate the mitogen-activated protein kinase activity was dramatically reduced. By striking contrast, SR 141716 pretreatment of CHO-CB1 cells not only had no significant effect on the potency of CP 55,940 to inhibit the forskolin-stimulated adenylyl cyclase but also induced a significant enhancement of the CP 55,940 ability to stimulate the mitogen-activated protein kinase activity. These results suggest that the modulation of the number of cell surface receptor could lead to functional desensitization or sensitization of the CB1 receptors.
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PMID:Modulation of CB1 cannabinoid receptor functions after a long-term exposure to agonist or inverse agonist in the Chinese hamster ovary cell expression system. 986 90

It is known that steroids can induce cell surface receptor aggregation followed by activation of receptor and nonreceptor tyrosine kinases. It has been shown recently that 17beta-estradiol (E2) can stimulate the Src/p21ras/mitogen-activated protein kinase pathway in breast cancer cells, and this effect is supposed to mediate the E2-induced stimulation of breast cancer cell proliferation, possibly via activation of the c-fos and c-jun early genes or of genes involved in cell cycle control. Here we demonstrate the existence of an alternative mechanism of the cancer-promoting effect of E2. Human breast cancer cells (MCF-7) were exposed to the known proapoptotic agent vitamin E succinate (VES), added alone or together with different concentrations of E2. E2 conjugated with bovine serum albumin (E2-BSA), which cannot cross the plasma membrane of living cells, was also used in some experiments to assess whether E2 acted on the cell surface or at intracellular receptors. Apoptosis was analyzed by fluorescence-activated cell sorting after cell staining with propidium iodide and FITC-labeled annexin V. E2 showed a concentration-dependent stimulatory effect on spontaneous apoptosis but inhibited the VES-induced apoptosis. However, effects produced by the same molar concentrations of E2 were different when the hormone was free and when it was used in the form of the E2-BSA conjugate. The effects of E2 and E2-BSA were sensitive to genistein, a tyrosine kinase inhibitor. These data show that E2 modulates apoptosis of breast cancer cells, probably acting both at the cell surface and inside the cells. Tyrosine phosphorylation is involved in the signaling pathways mediating this E2 effect.
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PMID:Estradiol modulates breast cancer cell apoptosis: a novel nongenomic steroid action relevant to carcinogenesis. 1032 69

Erythropoietin (Epo) controls the proliferation, differentiation and survival of the erythroid progenitors. Epo exerts its effects by binding to a cell surface receptor. The Epo receptor includes a p66 chain, which is dimerized upon Epo activation, and two accessory proteins, which have been defined by cross-linking. Epo binding induces stimulation of the Jak2 tyrosine kinase. Jak2 activation leads to the tyrosine phosphorylation of several proteins, including the Epo receptor itself. Different intracellular pathways are activated: Ras/MAP kinase, phosphatidylinositol 3-kinase and STAT transcription factors. However, the exact mechanisms by which the proliferation and/or differentiation of erythroid cells are regulated after Epo stimulation are not known. Target disruption of both Epo and Epo receptors showed that Epo is not involved in the commitment of the erythroid lineage; it seems to act mainly as a survival factor. Epo is synthesized largely by the kidney and the liver, and sequences required for tissue-specific expression have been localized in the Epo gene. A 3' enhancer is responsible for hypoxia-inducible Epo gene expression. Hypoxia-induced factor-1 (HIF-1) protein binds to this enhancer. In addition to anaemia of renal failure, the indication for treatment with epoetin has been extended to the anaemia of chronic diseases.
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PMID:The molecular biology of erythropoietin. 1033 64

MHC class I molecules are a necessary component of the cell surface receptor for simian virus 40 (SV40). After binding to class I molecules, SV40 enters cells via a unique endocytic pathway that involves caveolae, rather than clathrin-coated pits. This pathway is dependent on a transmembrane signal that SV40 transmits from the cell surface. Furthermore, it delivers SV40 to the endoplasmic reticulum, rather than to the endosomal/lysosomal compartment, which is the usual target for endocytic traffic. The glycosphingolipid and cholesterol-enriched plasma membrane domains that contain caveolae are also enriched for class I molecules, relative to whole plasma membrane. Nevertheless, although class I molecules bind SV40, they do not enter with SV40, nor do they enter spontaneously into uninfected SV40 host cells. Instead, they are shed from the cell surface by the activity of a metalloprotease. These results imply the existence of a putative secondary receptor for SV40 that might mediate SV40 entry. It is not yet clear whether class I molecules are active in transmitting the SV40 signal. Monoclonal antibodies against class I molecules also induce a signal in the SV40 host cells. However, the antibody-induced signal is mediated by mitogen-activated protein kinase (MAP kinase), whereas the SV40 signal is independent of MAP kinase.
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PMID:Simian virus 40 infection via MHC class I molecules and caveolae. 1039 61

Signal transduction induced by activated factor VII (FVIIa) was studied with baby hamster kidney (BHK) cells transfected with human tissue factor (TF). FVIIa induced phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) in cells expressing TF, BHK(+TF), but not in wild-type BHK(-TF) cells. BHK(+TF) cells responded to FVIIa in a dose-dependent manner, with detectable phosphorylation above 10-20 nM FVIIa. BHK cells transfected with a cytoplasmic domain-deleted version of TF, (des248-263)TF, or a C245S substitution variant of TF also supported FVIIa-induced MAPK activation. Experiments with active site-inhibited FVIIa, thrombin, factor Xa, and hirudin confirmed that the catalytic activity of FVIIa was mandatory for p44/42 MAPK activation. Furthermore, a high concentration of FVIIa in complex with soluble TF induced p44/42 MAPK phosphorylation in BHK(-TF) cells. These data suggest that TF was not directly involved in FVIIa-induced p44/42 MAPK phosphorylation but rather served to localize the action of FVIIa to the cell surface, potentially to cleave a cell surface receptor. Desensitization experiments with sequential addition of proteases suggested that the p44/42 MAPK response induced by FVIIa was distinctly different from the thrombin response, possibly involving a novel member of the protease-activated receptor family.
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PMID:Factor VIIa-induced p44/42 mitogen-activated protein kinase activation requires the proteolytic activity of factor VIIa and is independent of the tissue factor cytoplasmic domain. 1040 95

It has been shown that deletion of the chemokine receptor, CXCR4, causes disordered angiogenesis in mouse models. In the present studies, we examined the distribution and trafficking of CXCR4 in human endothelial cells, tested their responses to the CXCR4 ligand, SDF-1, and asked whether endothelial cell CXCR4 can serve as a cell surface receptor for the binding of viruses. The results show that CXCR4 is present on endothelial cells from coronary arteries, iliac arteries and umbilical veins (HUVEC), but expression was heterogeneous, with some cells expressing CXCR4 on their surface, while others did not. Addition of SDF-1 caused a rapid decrease in CXCR4 surface expression. It also caused CXCR4-mediated activation of MAPK, release of PGI(2), endothelial migration, and the formation of capillary-like structures by endothelial cells in culture. Co-culture of HUVEC with lymphoid cells that were chronically infected with a CD4-independent/CXCR4-tropic variant of HIV-2 resulted in the formation of multinucleated syncytia. Formation of the syncytia was inhibited by each of several different CXCR4 antibodies. Thus, our findings indicate: (1) that CXCR4 is widely expressed on human endothelial cells; (2) the CXCR4 ligand, SDF-1, can evoke a wide variety of responses from human endothelial cells; and (3) CXCR4 on endothelial cells can serve as a receptor for isolates of HIV that can utilize chemokine receptors in the absence of CD4.
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PMID:CXCR4 on human endothelial cells can serve as both a mediator of biological responses and as a receptor for HIV-2. 1065 92

Systemin, an 18-amino-acid polypeptide released from wound sites on tomato leaves caused by insects or other mechanical damage, systemically regulates the activation of over 20 defensive genes in tomato plants in response to herbivore and pathogen attacks. Systemin is processed from a larger prohormone protein, called prosystemin, by proteolytic cleavages. However, prosystemin lacks a signal sequence and glycosylation sites and is apparently not synthesized through the secretory pathway, but in the cytoplasm. The polypeptide activates a lipid-based signal transduction pathway in which the 18:3 fatty acid, linolenic acid, is released from plant membranes and converted to the oxylipin signaling molecule jasmonic acid. A wound-inducible systemin cell surface receptor with an M(r) of 160,000 has recently been identified. The receptor regulates an intracellular cascade including, depolarization of the plasma membrane, the opening of ion channels, an increase in intracellular Ca(2+), activation of a MAP kinase activity and a phospholipase A(2) activity. These rapid changes appear to play important roles leading to the intracellular release of linolenic acid from membranes and its subsequent conversion to jasmonic acid, a potent activator of defense gene transcription. Although the mechanisms for systemin processing, release, and transport are still unclear, studies of the timing of the synthesis and of the intracellular localization of wound- and systemin-inducible mRNAs and proteins indicates that differential syntheses of signal pathway genes and defensive genes are occurring in different cell types. This signaling cascade in plants exhibits extraordinary analogies with the signaling cascade for the inflammatory response in animals.
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PMID:The systemin signaling pathway: differential activation of plant defensive genes. 1070 53

Vascular endothelial cell growth factor (VEGF) is a potent angiogenic factor expressed during embryonic development, during wound healing, and in pathologies dependent on neovascularization, including cancer. Regulation of the receptor tyrosine kinases, KDR and Flt-1, to which VEGF binds on endothelial cells is incompletely understood. Chronic incubation with tumor-conditioned medium or VEGF diminished (125)I-VEGF binding to human umbilical vein endothelial cells, incorporation of (125)I-VEGF into covalent complexes with KDR and Flt1, and immunoreactive KDR in cell lysates. Receptor down-regulation desensitized VEGF activation of mitogen-activated protein kinase (extracellular signal-regulated kinases 1 and 2) and p38 mitogen-activated protein kinase. Preincubation with VEGF or tumor-conditioned medium down-regulated cell surface receptor expression but up-regulated KDR and Flt-1 mRNAs, an effect abrogated by a neutralizing VEGF antibody. Removal of VEGF from the medium led to recovery of (125)I-VEGF binding and resensitization of human umbilical vein endothelial cells. Recovery of receptor expression was inhibited by cycloheximide, indicating that augmented VEGF receptor mRNAs, and not receptor recycling from a cytoplasmic pool, restored responsiveness. As the VEGF receptors promote endothelial cell survival, proliferation, and other events necessary for angiogenesis, the noncoordinate regulation of VEGF receptor proteins and mRNAs suggests that human umbilical vein endothelial cells are protected against inappropriate or prolonged loss of VEGF receptors by a homeostatic mechanism important to endothelial cell function.
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PMID:Homeostatic modulation of cell surface KDR and Flt1 expression and expression of the vascular endothelial cell growth factor (VEGF) receptor mRNAs by VEGF. 1074 50

Signaling through its widely distributed cell surface receptor, interleukin (IL)-17 enhances the transcription of genes encoding proinflammatory molecules. Although it has been well documented that IL-17 activates the transcription factor nuclear factor (NF)-kappaB and c-Jun NH(2)-terminal kinase (JNK), the upstream signaling events are largely unknown. Here we report the requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in IL-17-induced NF-kappaB and JNK activation. In embryonic fibroblasts (EFs) derived from TRAF6 knockout mice, IL-17 failed to activate the IkappaB kinases (IKKs) and JNK. Consequently, IL-17-induced IL-6 and intercellular adhesion molecule 1 expression in the TRAF6-deficient cells was abolished. Lack of TRAF6 appeared to be the sole defect responsible for the observed failure to respond to IL-17, because transient transfection of TRAF6 expression plasmid into the TRAF6-deficient cells restored IL-17-induced NF-kappaB activation in a luciferase reporter assay. Furthermore, the levels of IL-17 receptor (IL-17R) on the TRAF6-deficient EFs were comparable to those on the wild-type control cells. Defect in IL-17 response was not observed in TRAF2-deficient EFs. Moreover, when TRAF6 and IL-17R were coexpressed in 293 cells, TRAF6 coimmunoprecipitated with IL-17R. Together, these results indicate that TRAF6, but not TRAF2, is a crucial component in the IL-17 signaling pathway leading to proinflammatory responses.
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PMID:Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. 1074 40


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