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)

Angiotensin (Ang) II has been shown to enhance the development of atherosclerotic lesions. Migration of monocytes is an early critical step in the atherosclerotic process. To elucidate mechanisms by which Ang II promotes atherogenesis, we investigated its effects on human monocyte migration. Ang II induced migration of human peripheral blood monocytes (HPBM) and human THP-1 monocytes at concentrations between 0.01 and 1 micromol/L, with a 3.6+/-0.6-fold induction in HPBM and a 4.8+/-0.9-fold induction in THP-1 cells at 1 micromol/L Ang II (both P<0.01 versus unstimulated cells). Addition of the Ang II receptor type 1 (AT1-R) antagonist losartan (1 to 100 micromol/L) suppressed Ang II-induced migration of HPBM and THP-1 monocytes in a dose-dependent manner, demonstrating an AT1-R-mediated mechanism. Ang II-directed migration was also blocked by the Src kinase inhibitor PP2 (10 micromol/L), by the extracellular-regulated protein kinase (ERK 1/2) inhibitor PD98059 (30 micromol/L), and by the p38-MAPK inhibitor SB203580 (10 micromol/L), indicating that Src, ERK 1/2, and p38 are all involved in Ang II-induced migration of HPBM and human THP-1 monocytes. The proline-rich tyrosine kinase 2 (Pyk2) and paxillin are 2 cytoskeleton-associated proteins involved in cell movement, phosphorylated by Ang II in other cell types, and abundantly expressed in monocytes. Ang II (1 micromol/L) induced Pyk2 and paxillin phosphorylation in human THP-1 monocytes, peaking after 10 minutes for Pyk2 with a 6.7+/-0.9-fold induction and after 2 minutes for paxillin with a 3.2+/-0.4-fold induction. Ang II-induced phosphorylation of both proteins was suppressed by losartan and the Src inhibitor PP2, whereas no effect was observed with PD98059 and SB203580. This study demonstrates a novel proatherogenic action of Ang II on human monocytes by stimulating their migration, through an AT1-R-dependent process, involving signaling through Src, ERK 1/2, and p38. Furthermore, the promigratory actions of Ang II in human monocytes are associated with the phosphorylation of 2 cytoskeleton-associated proteins, Pyk2 and paxillin.
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PMID:Angiotensin II induces migration and Pyk2/paxillin phosphorylation of human monocytes. 1123 Mar 39

Transmigration of monocytes to the subendothelial space is the initial step of atherosclerotic plaque formation and inflammation. Integrin activation and chemotaxis are two important functions involved in monocyte transmigration. To delineate the signaling cascades leading to integrin activation and chemotaxis by monocyte chemoattractant protein-1 (MCP-1), we have investigated the roles of MAPK and Rho GTPases in THP-1 cells, a monocytic cell line. MCP-1 stimulated beta1 integrin-dependent, but not beta2 integrin-dependent cell adhesion in a time-dependent manner. MCP-1-mediated cell adhesion was inhibited by a MEK inhibitor but not by a p38-MAPK inhibitor. In contrast, MCP-1-mediated chemotaxis was inhibited by the p38-MAPK inhibitor but not by the MEK inhibitor. The inhibitor of Rho GTPase, C3 exoenzyme, and a Rho kinase inhibitor abrogated MCP-1-dependent chemotaxis but not integrin-dependent cell adhesion. Further, C3 exoenzyme and the Rho kinase inhibitor blocked MCP-1-dependent p38-MAPK activation. These data indicate that ERK is responsible for integrin activation, that p38-MAPK and Rho are responsible for chemotaxis mediated by MCP-1, and that Rho and the Rho kinase are upstream of p38-MAPK in MCP-1-mediated signaling. This study demonstrates that two distinct MAPKs regulate two dependent signaling cascades leading to integrin activation and chemotaxis induced by MCP-1 in THP-1 cells.
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PMID:Distinct signaling pathways for MCP-1-dependent integrin activation and chemotaxis. 1127 64

Integrin-mediated signals play an important but poorly understood role in regulating many leukocyte functions. In monocytes and monocytic leukemia cells, beta1 integrin-mediated adhesion results in a strong induction of immediate-early genes that are important in inflammation. To investigate the signaling pathways from integrins in monocytic cells, THP-1 cells were stimulated via beta1 integrins by binding to fibronectin and by crosslinking the integrins with specific monoclonal antibodies. The involvement of MAPK and PI 3-K on nuclear factor kappaB (NF-kappaB) activation was then analyzed. We found that integrins activated both NF-kappaB and MAPK in a PI 3-K-dependent manner, as wortmannin and LY294002 blocked these responses. However, the specific MEK inhibitor PD98059 did not prevent integrin-mediated NF-kappaB activation. In contrast, a dominant negative mutant of Rac completely prevented NF-kappaB activation, but it did not affect MAPK activation. These results indicate that integrin signaling to NF-kappaB is not mediated by the MAPK pathway, but rather by the small GTPase Rac. In addition, a dominant negative form of Rho augmented NF-kappaB activation and blocked MAPK activation, implying that these two pathways are in competition with each other. These data suggest that integrins activate different signaling pathways in monocytic cells. One uses PI 3-K and Rac to activate NF-kappaB, while the other uses PI 3-K, MEK, and MAPK to activate other nuclear factors, such as Elk-1.
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PMID:Phosphatidylinositol 3-kinase mediates integrin-dependent NF-kappaB and MAPK activation through separate signaling pathways. 1128 33

To explore the direct role of beta-amyloid (Abeta) and carboxyl-terminal fragments of amyloid precursor protein in the inflammatory processes possibly linked to neurodegeneration associated with Alzheimer's disease, the effects of the 105-amino acid carboxyl-terminal fragment (CT(105)) of amyloid precursor protein on the production of tumor necrosis factor-alpha (TNF-alpha) and matrix metalloproteinase-9 (MMP-9) were examined in a human monocytic THP-1 cell line and compared with that of Abeta. CT(105) elicited a marked increase in TNF-alpha and MMP-9 production in the presence of interferon-gamma in a dose- and time-dependent manner. Similar patterns were obtained with Abeta despite its low magnitude of induction. Autocrine TNF-alpha is likely to be a main mediator of the induction of MMP-9 because the neutralizing antibody to TNF-alpha inhibits MMP-9 production. Genistein, a specific inhibitor of tyrosine kinase, dramatically diminished both TNF-alpha secretion and subsequent MMP-9 release in response to CT(105) or Abeta. Furthermore, PD98059 and SB202190, specific inhibitors of ERK or p38 MAPK respectively, efficiently suppressed CT(105)-induced effects whereas only PD98059 was effective at reducing Abeta-induced effects. Our results suggest that CT(105) in combination with interferon-gamma might serve as a more potent activator than Abeta in triggering inflammatory processes and that both tyrosine kinase and MAPK signaling pathways may represent potential therapeutic targets for the control of Alzheimer's disease progression.
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PMID:Effects of the beta-amyloid and carboxyl-terminal fragment of Alzheimer's amyloid precursor protein on the production of the tumor necrosis factor-alpha and matrix metalloproteinase-9 by human monocytic THP-1. 1130 64

Monocyte chemoattractant protein 1 (MCP-1) has a crucial role in atherogenesis and inflammation. However, MCP-1-mediated signalling pathways in monocytes have not been fully elucidated. In the present study we investigated the role of tyrosine kinases such as proline-rich tyrosine kinase 2 (Pyk2) in MCP-1-mediated signal transduction in the monocytic cell line THP-1. Pyk2 was tyrosine phosphorylated very quickly after stimulation with MCP-1. We found that Lyn, Shc and paxillin were also tyrosine phosphorylated by MCP-1. We examined the association of these molecules by immunoprecipitation and immunoblot analysis. The association of Pyk2 with Lyn was dependent on stimulation with MCP-1 and on tyrosine phosphorylation of Pyk2. Phosphorylation of p38 was also dependent on tyrosine phosphorylation of Pyk2. However, the association of Pyk2 with paxillin and Grb2 was not affected by stimulation with MCP-1. Phosphorylation of ERK (extracellular-signal-regulated protein kinase) was not affected by overexpression of kinase-negative Pyk2. Our results indicate that Pyk2 forms a complex with paxillin, Grb2 and Lyn in THP-1 cells. However, Pyk2 is not always involved in MCP-1-mediated signalling pathways.
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PMID:Monocyte chemoattractant protein 1 causes differential signalling mediated by proline-rich tyrosine kinase 2 in THP-1 cells. 1131 Nov 38

The highly conserved region within the retroviral transmembrane envelope proteins has been implicated in a number of retrovirus-associated mechanisms of immunosuppression. CKS-17, a synthetic peptide representing the prototypic sequence of the immunosuppressive domain, has been found to suppress numerous immune functions, disregulate cytokines, and elevate intracellular cAMP. In this report we show that using a human monocytic cell line THP-1, CKS-17 activates mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase 1 and 2 (ERK1/2). Kinetic studies show that CKS-17 induces an acute increase of ERK1/2 activity followed by a rapid decrease and then a second sustained increase of ERK1/2. CKS-17 also activates MAP kinase/ERK kinase (MEK) with a similar induction pattern. Mutant THP-1 cells isolated in our laboratory, in which CKS-17 exclusively fails to activate cAMP, did not show the transient decrease of CKS-17-induced ERK1/2 phosphorylation. Pretreatment of THP-1 cells or mutant THP-1 cells with cAMP analog or forskolin followed by treatment with CKS-17 showed no activation of MEK or ERK1/2. These results indicate that CKS-17 activates the MEK/ERK cascade and that there is a cross-talk between CKS-17-mediated MEK/ERK cascade and cAMP in that the MEK/ERK cascade is negatively regulated by cAMP. These data present a novel molecular mechanism(s) by this highly conserved retroviral immunosuppressive component.
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PMID:A retroviral-derived immunosuppressive peptide activates mitogen-activated protein kinases. 1135 35

Heparan sulfate proteoglycans (HSPGs) promote cellular proliferation through interaction with FGF-2. To examine the role of cellular specificity of HSPG in FGF-2 function, a recombinant soluble isoform of CD44 (rsCD44v3,8-10) was expressed in various cell types; 293 T fibroblasts, the epithelial carcinoma cell lines A431 and HOTZ, the myelomonocytic cell line THP-1, and the Ig-secreting B lymphoblast IM9. The capacity of the recombinant HSPGs expressed in these cell lines to bind and present FGF-2 to the high-affinity receptor FGFR1 was addressed. This novel approach showed a minor difference in the binding and in the FGF-2 stimulating activity of rsCD44v3,8-10 HSPGs from fibroblasts and epithelial cells. However, FGF-2 binding of rsCD44v3,8-10 from IM9 and THP-1 cells was significantly lower, and stimulation of FGF-2 by rsCD44v3,8-10 from these two cell types could not be detected. We tested the possibility that the differences among cell types were related to the functional profile of endogenous HSPGs. The initial survey of a wider panel of cell types revealed high levels of HSPGs synthesis on the surface of 293 T, epithelial and IM9 cells, but low levels on the surface of other cells of hematopoietic origin. Surprisingly, native HSPGs from fibroblasts and epithelial cell lines promoted FGF-2 biological activity to vastly different extents, and cell surface HSPGs from IM9 cells induced an FGF-2 response. Altogether, the results suggested a role for cell-specific HS modification in addition to synthesis as regulatory mechanisms for the cellular specificity of proteoglycan function.
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PMID:Cellular specificity for the activation of fibroblast growth factor-2 by heparan sulfate proteoglycan. 1139 90

Although integrins are crucial for migration of leukocytes through endothelium, integrin-independent mechanisms appear to take over and mediate the migration of leukocytes through extracellular matrix (ECM) in a three-dimensional tissue microenvironment. Discoidin domain receptor (DDR) 1 is a receptor tyrosine kinase activated by collagen, the most abundant ECM protein. In the present study, we detected that peripheral blood mononuclear cells (PBMC) and polymorphonuclear neutrophils were induced to express DDR1 after incubation in RPMI 1640. The expression level of DDR1 in PBMC was increased further by stimulation with tumor necrosis factor-alpha, interleukin-1beta, granulocyte-macrophage colony-stimulating factor, lipopolysaccharide, or phytohemagglutinin, but not with interferon-gamma. In vivo, DDR1 mRNA was detectable in mononuclear leukocytes infiltrating human renal tumor tissue. Among three DDR1 isoforms, DDR1alpha was the major transcript in leukocytes. Functionally, overexpression of either DDR1alpha or DDR1beta in THP-1 cells resulted in increased adherence to collagen-coated plates in a beta1-integrin independent manner. However, only DDR1alpha-, but not DDR1beta-, overexpressing cells exhibited marked pseudopod extension and migrated successfully through three-dimensional collagen lattices. Consequently, we propose that the interaction of DDR1alpha with collagen of the ECM results in a requisite intracellular signaling that enables leukocytes to migrate in a tissue microenvironment and participate in host defense.
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PMID:Discoidin domain receptor 1 isoform-a (DDR1alpha) promotes migration of leukocytes in three-dimensional collagen lattices. 1160 78

Transmigration of monocytes to the subendothelial space is the initial step in atherosclerotic plaque formation and inflammation. Integrin activation and chemotaxis are two important functions in monocyte transmigration. To delineate the signaling cascades leading to integrin activation and chemotaxis by monocyte chemoattractant protein-1 (MCP-1), we investigated the roles of MAPK in THP-1 cells, a monocytic cell line. MCP-1 stimulated beta1 integrin-dependent, but not beta2 integrin-dependent cell adhesion in a time-dependent manner. MCP-1-mediated cell adhesion was inhibited by a MEK inhibitor, but not by a p38-MAPK inhibitor. By contrast, MCP-1-mediated chemotaxis was inhibited by the p38-MAPK inhibitor, but not by the MEK inhibitor. These data indicate that ERK is responsible for integrin activation and that p38-MAPK is responsible for chemotaxis mediated by MCP-1. This study demonstrates that two distinct MAPKs regulate two dependent signaling cascades, leading to integrin activation and chemotaxis induced by MCP-1 in THP-1 cells.
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PMID:Differential signaling for MCP-1-dependent integrin activation and chemotaxis. 1179 97

Ehrlichia chaffeensis, a bacterium that cannot survive outside the eukaryotic cell, proliferates exclusively in human monocytes and macrophages. In this study, signaling events required for ehrlichial infection of human monocytic cell line THP-1 were characterized. Entry and proliferation of E. chaffeensis in THP-1 cells were significantly blocked by various inhibitors that can regulate calcium signaling, including 8-(diethylamino)octyl-3,4,5-trimethoxybenzoate and 2-aminoethoxydiphenyl borate (intracellular calcium mobilization inhibitors), verapamil and 1-[beta-[3-(4-methoxyphenyl)propyl]-4-methoxyphenethyl]-1H-imidazole (SKF-96365) (calcium channel inhibitors), neomycin and 1-(6-[[17beta-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl)-1H-pyrrole-2,5-dione (U-73122) (phospholipase C [PLC] inhibitors), monodansylcadaverine (a transglutaminase [TGase] inhibitor), and genistein (a protein tyrosine kinase [PTK] inhibitor). Addition of E. chaffeensis resulted in rapid increases in the level of inositol 1,4,5-trisphosphate (IP(3)) and the level of cytosolic free calcium ([Ca(2+)](i)) in THP-1 cells, which were prevented by pretreatment of THP-1 cells with inhibitors of TGase, PTK, and PLC. E. chaffeensis induced rapid tyrosine phosphorylation of PLC-gamma2, and the presence of a PLC-gamma2 antisense oligonucleotide in THP-1 cells significantly blocked ehrlichial infection. Furthermore, tyrosine-phosphorylated proteins and PLC-gamma2 were colocalized with ehrlichial inclusions, as determined by double-immunofluorescence labeling. The heat-sensitive component of viable E. chaffeensis cells was essential for these signaling events. E. chaffeensis, therefore, can recruit interacting signal-transducing molecules and induce the following signaling events required for the establishment of infection in host cells: protein cross-linking by TGase, tyrosine phosphorylation, PLC-gamma2 activation, IP(3) production, and an increase in [Ca(2+)](i).
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PMID:Rapid activation of protein tyrosine kinase and phospholipase C-gamma2 and increase in cytosolic free calcium are required by Ehrlichia chaffeensis for internalization and growth in THP-1 cells. 1179 24


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