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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chemokine receptors mediate the migration of lymphocytes through the binding of soluble ligands, and their expression is differentially regulated in lymphocyte subsets. The pattern of chemokine receptor expression in T-cell non-Hodgkin lymphoma has not been previously studied. Using a panel of mouse monoclonal antibodies, we studied the immunohistochemical expression of the Th1-associated chemokine receptor CXCR3 in 141 patients with T-cell lymphoma, and we studied the receptors CCR4 and CCR5 and some of their ligands in a subset of these tumors. Expression of CXCR3 was typical of the smaller T cells in angioimmunoblastic lymphoma (15 of 18 patients), angiocentric lymphoma (3 of 3 patients), histiocyte-rich tumors (4 of 5 patients), and unspecified T-cell lymphomas (17 of 39 patients). CXCR3 expression was seen in only 1 of 15 patients with anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma. In contrast, all ALK-positive tumors showed diffuse reactivity for the Th2-associated receptor CCR4 (5 of 5 patients). CCR4 expression was also a consistent feature of the large-cell transformation of mycosis fungoides. CCR5 expression showed no consistent association with any T-cell tumor type. The chemokines Mig (CXCR3 ligand), TARC (CCR4 ligand), and MCP-2 (CCR5 ligand) were detected in intratumoral blood vessels and histiocytes. Mig was also coexpressed by a subset of CXCR3-positive tumor cells in 6 of 20 lymphomas. MCP-2 was highly expressed in stromal cells in 3 patients with nodal involvement by cutaneous T-cell lymphoma. As with normal T-cell subsets, we demonstrated that there is frequent differential expression of chemokine receptors in T-cell tumors, which may explain, in part, the distinctive patterns of spread in different tumor subtypes. (Blood. 2000;96:685-690)
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PMID:Expression pattern of T-cell-associated chemokine receptors and their chemokines correlates with specific subtypes of T-cell non-Hodgkin lymphoma. 1088 35

A subset of blood cells from patients with B-cell chronic lymphocytic leukemia (CLL) spontaneously differentiates in vitro into large, round, or fibroblast-like adherent cells that display stromal cell markers, namely vimentin and STRO-1. These cells also express stromal cell-derived factor-1 (SDF-1), a CXC chemokine that ordinarily is secreted by marrow stromal cells. Leukemia B cells attach to these blood-derived adherent cells, down-modulate their receptors for SDF-1 (CXCR4), and are protected from undergoing spontaneous apoptosis in vitro. Neutralizing antibodies to SDF-1 inhibit this effect. Moreover, the rapid deterioration in the survival of CLL B cells, when separated from such cells, is mitigated by exogenous SDF-1. This chemokine also results in the rapid down-modulation of CXCR4 and activation of p44/42 mitogen-activated protein-kinase (ERK 1/2) by CLL B cells in vitro. It is concluded that the blood of patients with CLL contains cells that can differentiate into adherent nurse-like cells that protect leukemia cells from undergoing spontaneous apoptosis through an SDF-1-dependent mechanism. In addition to its recently recognized role in CLL B-cell migration, SDF-1-mediated CLL B-cell activation has to be considered a new mechanism involved in the microenvironmental regulation of CLL B-cell survival. (Blood. 2000;96:2655-2663)
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PMID:Blood-derived nurse-like cells protect chronic lymphocytic leukemia B cells from spontaneous apoptosis through stromal cell-derived factor-1. 1102 95

Human CMV (HCMV) retinitis frequently leads to blindness in iatrogenically immunosuppressed patients and in the end stage of AIDS. Despite the general proinflammatory potential of HCMV, virus infection is associated with a rather mild cellular inflammatory response in the retina. To investigate this phenomenon, the influence of HCMV (strains AD169 or Hi91) infection on C-X-C chemokine secretion, ICAM-1 expression, and neutrophil recruitment in cultured human retinal pigment epithelial (RPE) cells was studied. Supernatants from infected cultures contained enhanced levels of IL-8 and melanoma growth-stimulating activity/Gro alpha and induced neutrophil chemotaxis compared with supernatants from uninfected RPE cells. Despite HCMV-induced ICAM-1 expression on RPE cells, binding of activated neutrophils to HCMV-infected RPE cells and subsequent transepithelial penetration were significantly reduced. Reduced neutrophil adhesion to infected RPE cells correlated with HCMV-induced up-regulation of constitutive Fas ligand (FasL) expression. Functional blocking of FasL on RPE cells with the neutralizing mAbs NOK-1 and NOK-2 or of the Fas receptor on neutrophils with mAbB-D29 prevented the HCMV-induced impairment of neutrophil/RPE interactions. Fas-FasL-dependent impairment of neutrophil binding had occurred by 10 min after neutrophil/RPE coculture without apoptotic signs. Neutrophil apoptosis was first detected after 4 h. Treatment of neutrophils with a specific inhibitor of caspase-8 suppressed apoptosis, whereas it did not prevent impaired neutrophil binding to infected RPE. The current results suggest a novel role for FasL in the RPE regulation of neutrophil binding. This may be an important feature of virus escape mechanisms and for sustaining the immune-privileged character of the retina during HCMV ocular infection.
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PMID:Decreased neutrophil adhesion to human cytomegalovirus-infected retinal pigment epithelial cells is mediated by virus-induced up-regulation of Fas ligand independent of neutrophil apoptosis. 1103 78

The destruction of newly forming tumor vasculature is a promising approach to inhibit tumor growth. The goal of the present study was to investigate whether human lymphocytes gene modified to express a chimeric receptor specific for the angiogenic endothelial cell receptor, KDR, could react against KDR(+) cells. Gene-modified lymphocytes specifically lysed KDR(+) cells and secreted cytokines in response to KDR(+) target cells including human umbilical vein endothelial cells (HUVECs). Anti-KDR lymphocytes induced HUVECs to secrete the chemokine interleukin 8 and upregulate the adhesion molecules VCAM and E-selectin, which may be important in the recruitment of further immune effector cells to tumor. These KDR-specific lymphocytes may be useful in the adoptive immunotherapy of a broad range of cancers by inducing immune-mediated destruction of tumor neovasculature.
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PMID:Generation of gene-modified T cells reactive against the angiogenic kinase insert domain-containing receptor (KDR) found on tumor vasculature. 1111 16

Hepatic stellate cells (HSC) and glomerular mesangial cells (MC) are tissue-specific pericytes involved in tissue repair, a process that is regulated by members of the chemokine family. In this study, we explored the signal transduction pathways activated by the chemokine receptor CXCR3 in vascular pericytes. In HSC, interaction of CXCR3 with its ligands resulted in increased chemotaxis and activation of the Ras/ERK cascade. Activation of CXCR3 also stimulated Src phosphorylation and kinase activity and increased the activity of phosphatidylinositol 3-kinase and its downstream pathway, Akt. The increase in ERK activity was inhibited by genistein and PP1, but not by wortmannin, indicating that Src activation is necessary for the activation of the Ras/ERK pathway by CXCR3. Inhibition of ERK activation resulted in a decreased chemotactic and mitogenic effect of CXCR3 ligands. In MC, which respond to CXCR3 ligands with increased DNA synthesis, CXCR3 activation resulted in a biphasic stimulation of ERK activation, a pattern similar to the one observed in HSC exposed to platelet-derived growth factor, indicating that this type of response is related to the stimulation of cell proliferation. These data characterize CXCR3 signaling in pericytes and clarify the relevance of downstream pathways in the modulation of different biologic responses.
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PMID:Signal transduction by the chemokine receptor CXCR3: activation of Ras/ERK, Src, and phosphatidylinositol 3-kinase/Akt controls cell migration and proliferation in human vascular pericytes. 1113 32

Chemokines constitute a superfamily of proteins that function as chemoattractants and activators of leukocytes. Astrocytes, the major glial cell type in the CNS, are a source of chemokines within the diseased brain. Specifically, we have shown that primary human astrocytes and human astroglioma cell lines produce the CXC chemokines IFN-gamma-inducible protein-10 and IL-8 and the CC chemokines monocyte chemoattractant protein-1 and RANTES in response to stimuli such as TNF-alpha, IL-1beta, and IFN-gamma. In this study, we investigated chemokine receptor expression and function on human astroglioma cells. Enhancement of CXC chemokine receptor 4 (CXCR4) mRNA expression was observed upon treatment with the cytokines TNF-alpha and IL-1beta. The peak of CXCR4 expression in response to TNF-alpha and IL-1beta was 8 and 4 h, respectively. CXCR4 protein expression was also enhanced upon treatment with TNF-alpha and IL-1beta (2- to 3-fold). To study the functional relevance of CXCR4 expression, stable astroglioma transfectants expressing high levels of CXCR4 were generated. Stimulation of cells with the ligand for CXCR4, stromal cell-derived factor-1alpha (SDF-1alpha), resulted in an elevation in intracellular Ca(2+) concentration and activation of the mitogen-activated protein kinase cascade, specifically, extracellular signal-regulated kinase 2 (ERK2) mitogen-activated protein kinase. Of most interest, SDF-1alpha treatment induced expression of the chemokines monocyte chemoattractant protein-1, IL-8, and IFN-gamma-inducible protein-10. SDF-1alpha-induced chemokine expression was abrogated upon inclusion of U0126, a pharmacological inhibitor of ERK1/2, indicating that the ERK signaling cascade is involved in this response. Collectively, these data suggest that CXCR4-mediated signaling pathways in astroglioma cells may be another mechanism for these cells to express chemokines involved in angiogenesis and inflammation.
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PMID:CXC chemokine receptor 4 expression and function in human astroglioma cells. 1116 Mar 34

Hyperhomocysteinemia has been identified as an independent risk factor for atherosclerosis. The infiltration of monocytes into the arterial wall is one of the key events during atherogenesis. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine that stimulates the migration of monocytes into the intima of the arterial wall. The mechanism by which increased monocyte infiltration occurs in atherosclerotic lesions in patients with hyperhomocysteinemia has not been delineated. The objective of the present study was to investigate the effect of homocysteine on MCP-1 production in endothelial cells. Cells were incubated with homocysteine. The secretion of MCP-1 protein was significantly increased (195% as compared to the control) in cells treated with pathological concentrations of homocysteine. Such effect was accompanied by an increased expression of MCP-1 mRNA (176% as compared to the control) in endothelial cells which resulted in enhanced monocyte chemotaxis. The p38 MAP kinase as well as other members of the p38 MAP kinase pathway, including MKK3, MKK6, ATF-2 and Elk-1, were activated in homocysteine-treated cells. Homocysteine-induced MCP-1 expression and subsequent monocyte chemotaxis were blocked by a p38 MAP kinase inhibitor (SB203580) suggesting that the p38 MAP kinase pathway might be involved in homocysteine-induced MCP-1 expression in endothelial cells. In contrast, staurosporine, a protein kinase C inhibitor, had no effect on homocysteine-induced MCP-1 expression. In conclusion, our results indicate that homocysteine stimulates MCP-1 expression in endothelial cells leading to enhanced monocyte chemotaxis.
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PMID:Homocysteine stimulates the expression of monocyte chemoattractant protein-1 in endothelial cells leading to enhanced monocyte chemotaxis. 1121 56

The chemokine stroma-derived factor-1 (SDF-1) is produced within the bone marrow and mediates chemokinesis and chemotaxis on a variety of cell types that express the CXCR4 receptor. SDF-1-responsive cell types include monocytes and macrophages, B and T lymphocytes, platelets and megakaryocytes, and CD34+ cells, including both hematopoietic progenitors and stem cells. We have used intravenous injection of a replication-incompetent adenovector expressing the SDF-1 gene to elevate serum levels of SDF-1 in Balb/c and SCID mice. Within 3 to 5 days there was a marked leukocytosis, predominantly involving monocytes, and a three-fold increase in platelets. In addition, AdSDF-1 mobilized CFU-GM, CFU-s, and cells with long-term repopulating potential. We have identified a bone marrow-derived, circulating endothelial stem cell characterized by expression of the VEGFR2 (Flk-1/KDR). This cell exhibits a chemotactic and chemokinetic response to SDF-1 and VEGF. We have elevated serum levels of VEGF165 using intravenous adenovector gene delivery and compared this to an adenovector expressing angiopoietin-1 alone or in combination with VEGF. VEGF elevation was associated with rapid mobilization of hematopoietic stem and progenitor cells and a population of Flk-1-positive endothelial progenitors. In contrast angiopoietin induced a delayed mobilization of endothelial and hematopoietic progenitors. The combination of VEGF and angiopoietin produced a more prolonged elevation of these progenitors in the circulation with increased proliferation of capillaries and expansion of sinusoidal spaces in the marrow.
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PMID:Mobilization of endothelial and hematopoietic stem and progenitor cells by adenovector-mediated elevation of serum levels of SDF-1, VEGF, and angiopoietin-1. 1145 24

Extracellular Tat acts as a pleiotropic molecule inducing several biological effects on different target cells. Tat stimulates the chemotaxis of numerous cell types and it appears to have oncogenic activities, including acting as a co-factor for Kaposi's sarcoma. The Tat protein has been shown to bind integrins through an RGD amino acid motif. Tat is an angiogenic factor able to induce the migration and invasion of endothelial and KS cells through the interaction of its basic domain with the VEGF receptor VEGFR2 (Flk-1/KDR). We have also found that Tat is able to mimic chemokines, activating monocyte migration through the chemokine like' cysteine-core domain. Tat is a chemoattractant for dendritic cells, and both the RGD and basic domains appear to be involved in this response. In a recent study we demonstrated that Tat is chemotactic for PMN and induces Ca2+ mobilization in vitro. Experiments using synthetic peptides showed that Tat activities on PMN are mediated by the chemokine like' region. Finally Tat is also able to induce B cell chemotaxis, while its activity on helper T cells has not yet been clarified. Here we review data on Tat-dependent chemotaxis and discuss the possible implications in Tat mediated pathogenesis.
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PMID:HIV-Tat dependent chemotaxis and invasion, key aspects of tat mediated pathogenesis. 1168 57

Hypoxia, a strong inducer for vascular endothelial growth factor (VEGF)/vascular permeable factor (VPF) expression, regulates leukocyte infiltration through the up-regulation of adhesion molecules and chemokine release. To determine whether VEGF/VPF is directly involved in chemokine secretion, we analyzed its effects on chemokine expression in human brain microvascular endothelial cells (HBMECs) by using a human cytokine cDNA array kit. Cytokine array analysis revealed a significant increase in expression of monocyte chemoattractant protein-1 and the chemokine receptor CXCR4 in HBMECs, a result similar to that described previously in other endothelial cells. Interestingly, we also observed that VEGF/VPF induced interleukin-8 (IL-8) expression in HBMECs and that IL-8 mRNA was maximal after 1 h of VEGF/VPF treatment of the cells. Enzyme-linked immunosorbent assay data and immunoprecipitation analysis revealed that although VEGF/VPF induced IL-8 expression at the translational level in HBMECs, basic fibroblast growth factor failed to induce this protein expression within 12 h. VEGF/VPF increased IL-8 production in HBMECs through activation of nuclear factor-KB via calcium and phosphatidylinositol 3-kinase pathways, whereas the ERK pathway was not involved in this process. Supernatants of the VEGF/VPF-treated HBMECs significantly increased neutrophil migration across the HBMEC monolayer compared with those of the untreated control. Furthermore, addition of anti-IL-8 antibody blocked this increased migration, indicating that VEGF/VPF induced the functional expression of IL-8 protein in HBMECs. Taken together, these data demonstrate for the first time that VEGF/VPF induces IL-8 expression in HBMECs and contributes to leukocyte infiltration through the expression of chemokines, such as IL-8, in endothelial cells.
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PMID:Vascular endothelial growth factor modulates neutrophil transendothelial migration via up-regulation of interleukin-8 in human brain microvascular endothelial cells. 1178 13


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