Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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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 human chemokine receptors CXCR5 and CXCR1 activate signaling pathways via pertussis toxin-sensitive as well as insensitive G proteins. CXCR5 induces Ca2+ signaling and chemotaxis independently of inhibitory G proteins, whereas the same signaling pathways are entirely dependent on inhibitory G proteins for CXCR1. In contrast, activation of the MAP kinase cascade via ERK1/2 is a pertussis toxin-sensitive signaling event for both receptors. Using chimeric CXCR1/CXCR5 receptors we investigated structural requirements for the activation of signal transduction pathways by CXCR5. Individual or multiple intracellular domains of CXCR1 were exchanged for the corresponding sequences of CXCR5, leading to receptors resembling CXCR5 at the cytoplasmic surface to a varying extent. Replacing the second intracellular domain of CXCR1 had a major influence on signaling mediated by inhibitory G proteins, whereas the exchange of the third or carboxy-terminal intracellular domain had only minor effects on signal transduction. Activation of the MAP kinase cascade via ERK1/2 and chemotaxis are largely reduced in chimeras comprising the second intracellular domain of CXCR5, although coupling to inhibitory G proteins is retained in all chimeric receptors. In summary, these data characterize the contribution of the intracellular domains of CXCR5 to receptor signaling, thereby disclosing unique structural requirements that modulate G protein coupling by the receptor.
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PMID:Signal transduction by the chemokine receptor CXCR5: structural requirements for G protein activation analyzed by chimeric CXCR1/CXCR5 molecules. 1168 22

Human immunodeficiency virus type 1 (HIV-1) uses the chemokine receptors CCR5 and CXCR4 as coreceptors for entry. It was recently demonstrated that HIV-1 glycoprotein 120 (gp120) elevated calcium and activated several ionic signaling responses in primary human macrophages, which are important targets for HIV-1 in vivo. This study shows that chemokine receptor engagement by both CCR5-dependent (R5) and CXCR4-dependent (X4) gp120 led to rapid phosphorylation of the focal adhesion-related tyrosine kinase Pyk2 in macrophages. Pyk2 phosphorylation was also induced by macrophage inflammatory protein-1beta (MIP-1beta) and stromal cell-derived factor-1alpha, chemokine ligands for CCR5 and CXCR4. Activation was blocked by EGTA and by a potent blocker of calcium release-activated Ca++ (CRAC) channels, but was insensitive to pertussis toxin (PTX), implicating CRAC-mediated extracellular Ca++ influx but not Galpha(i) protein-dependent mechanisms. Coreceptor engagement by gp120 and chemokines also activated 2 members of the mitogen-activated protein kinase (MAPK) superfamily, c-Jun amino-terminal kinase/stress-activated protein kinase and p38 MAPK. Furthermore, gp120-stimulated macrophages secreted the chemokines monocyte chemotactic protein-1 and MIP-1beta in a manner that was dependent on MAPK activation. Thus, the gp120 signaling cascade in macrophages includes coreceptor binding, PTX-insensitive signal transduction, ionic signaling including Ca++ influx, and activation of Pyk2 and MAPK pathways, and leads to secretion of inflammatory mediators. HIV-1 Env signaling through these pathways may contribute to dysregulation of uninfected macrophage functions, new target cell recruitment, or modulation of macrophage infection.
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PMID:HIV-1 gp120 and chemokine activation of Pyk2 and mitogen-activated protein kinases in primary macrophages mediated by calcium-dependent, pertussis toxin-insensitive chemokine receptor signaling. 1169 70

It has been proposed that L-selectin engagement with ligand activates p38 mitogen-activated protein kinase (MAPK) and can impact on downstream events of leukocyte rolling, including adhesion, and emigration. Using a novel chemotactic assay in vivo, we visualized slow release of chemokine from an agarose gel positioned 350 microm from a postcapillary venule, which induced directed migration (chemotaxis) of neutrophils. In this system, keratinocyte-derived cytokine induced phosphorylation of p38 MAPK, which phosphorylated a downstream protein (ATF-2). This latter event was blocked by the concentration of p38 inhibitors used in this study. Mice were treated with two different p38 inhibitors: SKF86002 and SB203580. Neither inhibitor affected rolling or adhesion in microvessels. Intravenous treatment with SFK86002 (5, 10, and 20 mg/kg) 30 min before the inflammatory stimulus inhibited the total number of emigrated cells at a dose of 20 mg/kg (62%, p < 0.05), despite the presence of many adherent cells within the vessels. A similar inhibition was observed with 20 mg/kg of a second p38 inhibitor SB203580 (67%, p < 0.05). In addition to emigration, both p38 inhibitors impaired the ability of emigrated cells to migrate through the tissue toward the chemotactic stimulus. In fact, the majority of emigrated leukocytes in p38 inhibitor-treated animals remained within 50 microm of the venule. Superfusion of the tissue with SKF86002 (0.7 mM) to impact only on emigrated and not vascular leukocytes resulted in no impairment in emigration, but in a significant reduction in chemotaxis away from the vessel wall. Again, the majority of emigrated leukocytes remained within 50 microm of the blood vessel. Our results suggest that p38 does not affect rolling or adhesion, but that it is involved in leukocyte emigration and chemotaxis through interstitium in response to keratinocyte-derived cytokine in vivo.
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PMID:Role of p38 mitogen-activated protein kinase in chemokine-induced emigration and chemotaxis in vivo. 1171 24

We identified five human T-lymphoid cell lines (PB-1, Sez-4, C19PL, HUT 102B and ATL-2) which highly express CD4 in addition to CXCR4 and CCR5. In order to evaluate if these cells are infectabile by human immunodeficiency virus (HIV) and could be employed as a model in HIV research we exposed these cell lines to X4 (T-cell tropic) and R5 (macrophage tropic) and subsequently tried to correlate their infectability with (i) level of chemokine coreceptor (CXCR4 and CCR5) expression, (ii) coreceptor functionality (calcium flux, chemotaxis and phosphorylation of MAPK p42/44 and AKT) and (iii) endogenous expression and secretion of HIV-related chemokines which compete with the virus for binding to CXCR4 (SDF-1/CXCL12) or CCR5 (MIP-1beta/CCL4, MIP-1alpha/CCL3, RANTES/CCL5, MCP-2/CCL8, MCP-3/CCL7 and MCP-4/CCL13). We demonstrated that while PB-1 cells are infectable by both X4 and R5 HIV, Sez-4, C91PL, HUT 102B and ATL-2 cells were infected by X4 HIV only. Moreover, we noticed that the susceptibility of these cells to HIV did not correspond either with the level of surface expression or with the functionality of CXCR4 or CCR5; however, it was modulated to some degree by the endogenously secreted HIV-related chemokines. Thus all five mature T-cell lines described here may provide useful new models for studying various aspects of HIV infection. In addition we demonstrate that the infectability of cells by HIV is modulated by so far unidentified intrinsic factors as well as some already known endogenously secreted chemokines. The identification of these factors may be important for developing new strategies to protect cells from HIV infection.
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PMID:New T-lymphocytic cell lines for studying cell infectability by human immunodeficiency virus. 1173 46

The ligand-induced trafficking of chemokine receptors plays a significant role in the regulation of inflammatory processes and human immunodeficiency infection. Although many chemokine receptors have been demonstrated to internalize through clathrin-coated vesicles, a process that involves the binding of arrestins to the receptors, accumulating evidence has suggested the possible existence of other regulators. In a yeast two-hybrid screening using the C-terminal domain of CXCR2 as a bait, the Hsc70-interacting protein (Hip) was identified to interact with CXCR2. Hip binds CXCR2 through its C-terminal domain binding to the C-terminal leucine-rich domain (KILAIHGLI) of CXCR2. Hip associates with CXCR2 or CXCR4 in intact cells, and agonist stimulation increases the association. Mutation of the Ile-Leu motif in the C-terminal domain of CXCR2 blocks the agonist-dependent association of the mutant receptor with Hip. Overexpression of a tetratricopeptide repeat (TPR) deletion mutant form of Hip (Delta TPR), which is unable to bind Hsc70 (Prapapanich, V., Chen, S., Nair, S. C., Rimerman, R. A., and Smith, D. F. (1996) Mol. Endocrinol. 10, 420-431), but retains the ability to bind CXCR2, does not affect CXCR2-mediated mitogen-activated protein kinase activation. However, overexpression of Delta TPR significantly attenuates the agonist-induced internalization of CXCR2 and CXCR4 and attenuates CXCR2-mediated chemotaxis. These findings open the possibility for regulation of chemokine receptor signaling and trafficking by protein chaperone molecules.
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PMID:Hsc/Hsp70 interacting protein (hip) associates with CXCR2 and regulates the receptor signaling and trafficking. 1175 89

Inflammation has been implicated in the pathogenesis of Alzheimer's disease (AD) and other neurodegenerative diseases. We have examined the potential role of some chemokine/chemokine receptors in this process. It is known that CXCR2 is a strongly expressed chemokine receptor on neurons and is strongly upregulated in AD in a subpopulation of neuritic plaques. Here, we show that one of the CXCR2 ligand GROalpha/KC can be a potent trigger for the ERK1/2 and PI-3 kinase pathways, as well as tau hyperphosphorylation in the mouse primary cortical neurons. GROalpha immunoreactivity can be detected in a subpopulation of neurons in normal and AD. Therefore, the CXCR2-ligand pair may have a potent pathophysiological role in neurodegenerative diseases.
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PMID:GROalpha/KC, a chemokine receptor CXCR2 ligand, can be a potent trigger for neuronal ERK1/2 and PI-3 kinase pathways and for tau hyperphosphorylation-a role in Alzheimer's disease? 1177 43

Chemokines and their receptors play a critical role in host immune surveillance and are important mediators of human immunodeficiency virus (HIV) pathogenesis and inflammatory response. The chemokine receptors CCR5 and CXCR4, which act as co-receptors along with CD4 for HIV docking and entry, are down-modulated by their respective ligands, MIP-1beta/SDF-1alpha or by the HIV envelope protein, gp120. We have studied the role of the proteasome pathway in the down-regulation of these receptors. Using the yeast and mammalian two-hybrid systems, we observed that the CCR5 receptor is constitutively associated with the zeta subunit of proteasome. Immunoprecipitation studies in CCR5 L1.2 cells revealed that this association was increased with MIP-1beta stimulation. The proteasome inhibitors, lactacystin and epoxomicin, attenuated MIP-1beta induced CCR5 down-modulation as detected by fluorescence-activated cell sorter analysis and confocal microscopy. The proteasome inhibitors also inhibited the SDF-1alpha and gp120 protein-induced down-modulation of the CXCR4 receptor in Jurkat cells. However, the inhibitors had no significant effect on the gp120-induced internalization of the CD4 receptor. These inhibitors also blocked cognate ligand-mediated chemotaxis but had no effect on SDF-1alpha-induced p44/42 MAP kinase or MIP-1beta-induced p38 kinase activities, thus indicating differential effects of the inhibitors on signaling mediated by these receptors. These results indicate that the CCR5 and CXCR4 receptor down-modulation mechanism and chemotaxis mediated by these receptors are dependent upon proteasome activity.
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PMID:CXCR4/CCR5 down-modulation and chemotaxis are regulated by the proteasome pathway. 1187 45

RANTES (regulated on activation normal T cell expressed and secreted) (> or =10 ng/ml) stimulates the induction of KC and other chemokines in astrocytes. Elements of the signal transduction pathway controlling this response were identified. RANTES induced phosphorylation of MEK, ERK1/2, p90 ribosomal S6 kinases (RSK), and cAMP-response element-binding protein (CREB) in astrocytes. U0126, a pharmacological inhibitor of MEK, blocked the phosphorylation of the downstream elements ERK, RSK, and CREB, inhibited chemokine synthesis, and reduced transcription from a KC promoter construct. Dominant negative mutants of RSK or CREB blocked the transcription driven by the KC promoter. Finally, RANTES treatment induces nuclear translocation of phosphorylated RSK in astrocytes. This novel role for RSK in signaling chemokine responses and synthesis in astrocytes may contribute to the amplification mechanisms responsible for prolonging inflammatory responses in the central nervous system.
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PMID:RANTES-mediated chemokine transcription in astrocytes involves activation and translocation of p90 ribosomal S6 protein kinase (RSK). 1189 39

Platelet activating factor (PAF) interacts with cell surface G protein-coupled receptors on leukocytes to induce degranulation, leukotriene C(4) (LTC(4)) generation, and chemokine CCL2 production. Using a basophilic leukemia RBL-2H3 cell line expressing wild-type PAF receptor (PAFR) and a phosphorylation-deficient mutant (mPAFR), we have previously demonstrated that receptor phosphorylation mediates desensitization of PAF-induced degranulation. Here, we sought to determine the role of receptor phosphorylation on PAF-induced LTC(4) generation and CCL2 production. We found that PAF caused a significantly enhanced LTC(4) generation in cells expressing mPAFR when compared with PAFR cells. In contrast, PAF-induced CCL2 production was greatly reduced in mPAFR cells. Pertussis toxin and U0126, which inhibit G(i) and p44/42 mitogen-activated protein kinase (ERK) activation, respectively, caused very little inhibition of PAF-induced CCL2 production (approximately 20% inhibition). In contrast, these inhibitors almost completely blocked both PAF-induced ERK phosphorylation and LTC(4) generation in PAFR cells. However, in mPAFR cells pertussis toxin only partially inhibited PAF-induced ERK phosphorylation. A Ca(2+)/calmodulin inhibitor had no effect on PAF-induced ERK phosphorylation in PAFR cells but completely blocked the response in mPAFR cells. These data demonstrate that receptor phosphorylation, which serves to desensitize PAF-induced LTC(4) generation, is required for chemokine CCL2 production. They also indicate a previously unrecognized selectivity in G protein usage and ERK activation for PAF-induced responses. Whereas PAF-induced CCL2 production is, in large part, mediated independently of G(i) activation or ERK phosphorylation, LTC(4) generation requires ERK phosphorylation, which is mediated by different G proteins depending on the phosphorylation status of the receptor.
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PMID:Distinct roles of receptor phosphorylation, G protein usage, and mitogen-activated protein kinase activation on platelet activating factor-induced leukotriene C(4) generation and chemokine production. 1193 80

In this study, we examined chemokine receptor expression and function in rat cerebellar neurons. Calcium imaging experiments demonstrated that a wide variety of chemokines elicited [Ca(2+)](i) transients in acutely isolated and cultured cerebellar Purkinje and granule neurons. In many cases, these chemokine responses were pertussis toxin (PTX) insensitive. In addition, chemokines activated the Ca(2+) and cAMP-dependent transcription factor CREB and the extracellular response kinases ERK1/ERK2. Chemokines increased the survival of Purkinje neurons deprived of their trophic support. Thus, the presence of chemokine receptors and the signaling pathways they activate suggest that chemokines play a role in the control of cerebellar neuron survival and development and may mediate communication between the CNS and the immune system.
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PMID:Expression of functional chemokine receptors by rat cerebellar neurons. 1195 18


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