Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia plays an important role in vascular remodeling and directly affects vascular smooth muscle cell (VSMC) functions. VSMC adhesion participates in changes of vascular structure; however, little is known about VSMC adhesion under hypoxic conditions. It was the aim of the present study to investigate the effects of hypoxia on adhesion mechanisms in human VSMCs. Compared to normoxic cells, hypoxia (1% O(2), 24h) significantly increased adhesion of VSMCs to collagen I by 30.2% and fibronectin by 58.0%. This effect was completely inhibited in the presence of the pharmacological ERK 1/2 mitogen-activated protein kinase (MAPK) pathway inhibitor PD98059 (30 microM) or the p38 MAPK inhibitor SB203580 (1 microM). Basal adhesion of normoxic cells was not affected by pretreatment with PD98059 and SB203580. Hypoxia induced a time-dependent activation of ERK 1/2 and p38 MAPK activation in human VSMCs, which were completely abolished by PD98059 or SB203580, respectively. Since adhesion of VSMCs to fibronectin and collagen I involves beta(1)-integrin receptors, we used a blocking antibody against beta(1)-integrin (P5D2) to examine potential effects of hypoxia on beta(1)-integrins. P5D2 significantly reduced VSMC adhesion to fibronectin and collagen I in normoxia and hypoxia in a comparable manner; however, beta(1)-integrin protein or mRNA levels were not affected by hypoxia. As evidenced by flow cytometry, hypoxia induced a activation of beta(1)-integrins by exposing an conformationally sensitive epitope on the beta(1)-subunit. These results demonstrate that hypoxia enhances adhesion of VSMC on extracellular matrix proteins by activating beta(1)-integrin.
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PMID:Hypoxia activates beta(1)-integrin via ERK 1/2 and p38 MAP kinase in human vascular smooth muscle cells. 1220 Jan 31

Osteoclast (OC) precursors migrate to putative sites of bone resorption to form functionally active, multinucleated cells. The preOC FLG 29.1 cells, known to be capable of irreversibly differentiating into multinucleated OC-like cells, displayed several features of primary OCs, including expression of specific integrins and the hyaluronan (HA) receptor CD44. OC-like FLG 29.1 cells adhered to and extensively migrated through membranes coated with fibronectin, vitronectin, and laminins, but, although strongly binding to HA, totally failed to move on this substrate. Moreover, soluble HA strongly inhibited OC-like FLG 29.1 cell migration on the permissive matrix substrates, and this behavior was dependent on its engagement with CD44, as it was fully restored by function-blocking anti-CD44 antibodies. HA did not modulate the cell-substrate binding affinity/avidity nor the expression levels of the corresponding integrins. MMP-9 was the major secreted metalloproteinase used by OC-like FLG 29.1 cells for migration, because this process was strongly inhibited by both TIMP-1 and GM6001, as well as by MMP-9-specific antisense oligonucleotides. After HA binding to CD44, a strong down-regulation of MMP-9 mRNA and protein was detected. These findings highlight a novel role of the HA-CD44 interaction in the context of OC-like cell motility, suggesting that it may act as a stop signal for bone-resorbing cells.
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PMID:Hyaluronan-CD44 interaction hampers migration of osteoclast-like cells by down-regulating MMP-9. 1223 27

Proper stimulation of cell cycle progression and DNA synthesis requires cooperating signals from integrin and growth factor receptors. We previously found that the proinflammatory peptide, macrophage migration inhibitory factor (MIF), functions as an autocrine mediator of growth factor-dependent ERK MAP kinase activation and cell cycle progression. We now report that MIF secretion is induced by cell adhesion to fibronectin in quiescent mouse fibroblasts. Adhesion-mediated release of MIF subsequently promotes integrin-dependent activation of MAP kinase, cyclin D1 expression, and DNA synthesis. Secretion of MIF requires protein kinase C activity, and recombinant MIF reconstitutes the activation of MAP kinases in the presence of protein kinase C inhibition. Finally, we show that cells deficient in MIF have significantly higher retinoblastoma tumor suppressor and lower E2F transcriptional activities. These results suggest that MIF is an important autocrine mediator of adhesion-dependent signaling events and may provide mechanistic insight into how MIF regulates proliferative and oncogenic processes.
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PMID:Adhesion-dependent signaling by macrophage migration inhibitory factor (MIF). 1229 13

Malignant plasma cells (PC) from multiple myeloma (MM) patients characteristically home to the bone marrow (BM). High numbers of tumour cells are found in the peripheral blood (PB) only at end-stage disease (secondary plasma cell leukaemia, PCL) in a minority of patients. Using flow cytometric and fluorescence in situ hybridization (FISH) analysis, a high percentage of tumoral BM PC from untreated patients was found to express CD106. In addition, these cells also expressed an activated form of CD29, as determined using the CD29 activation reporter monoclonal antibody HUTS-21. Adhesion-binding experiments showed that CD106+-activated CD29+ BM PC from these patients adhered to fibronectin (FN) in a CD29/CD49d-dependent manner. In contrast, marrow PC from progressive patients and BM or circulating malignant cells from secondary PCL patients expressed lower levels or were negative for CD106 and activated CD29, respectively, with a decreased or zero ability to adhere to FN. The expression of constitutive CD29 and CD49d, however, was similar during disease progression. We conclude that BM myelomatous cells co-express CD106 and a functionally active form of CD29. Moreover, our results suggest that the loss of expression and/or function of these antigens are associated with the progression of MM and may explain the exit of tumoral cells from the BM.
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PMID:CD106 and activated-CD29 are expressed on myelomatous bone marrow plasma cells and their downregulation is associated with tumour progression. 1235 5

Heparin is a well established growth inhibitor of arterial smooth muscle cells (SMCs) both in animal models and in vitro. Even though the cellular mechanisms involved in the anti-proliferative properties of heparin are being resolved, the structural requirements for the biological effects of heparin are not known in detail. Here, we have studied the effect of chemically modified heparins of different molecular weights and anticoagulant activities on proliferation and adhesion of rat aortic SMCs in vitro. The effects of native heparin (NH) and chemically modified heparins were examined after stimulation with fetal calf serum (FCS), platelet-derived growth factor BB (PDGF BB), basic fibroblast growth factor (bFGF), and heparin-binding epidermal growth factor (hbEGF) with respect to DNA synthesis and expression of phosphorylated and activated mitogen-activated protein kinase (pERK1 and 2). In a similar manner as NH, the modified heparins were capable of inhibiting activation of ERK1 and 2 and DNA synthesis induced by FCS and hbEGF whereas the modified heparins potentiated the mitogenic effect of bFGF and no compound affected PDGF BB-induced ERK activity and SMC growth. In contrast, cell adhesion to fibronectin was inhibited by NH and modified heparins in a size-dependent manner with the lowest effect by the smallest compound. The results show that heparins with varying anticoagulant activities and molecular weights but with similar sulfate content can retain anti-proliferative properties while the effect on some other biological processes such as cell adhesion is lost. Possibly, such chemical alterations may yield useful substances for the prevention of SMC proliferation after arterial injury.
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PMID:Inhibition of rat smooth muscle cell adhesion and proliferation by non-anticoagulant heparins. 1238 88

Kinases that associate with integrins are likely to mediate the assembly/disassembly of cell:matrix junctions during cell migration. Here we show that ERK1 associates with alpha(v)beta(3) integrin following the addition of platelet-derived growth factor to serum-starved Swiss or NIH 3T3 fibroblasts in an interaction that is mediated by the central region of the beta(3) integrin cytodomain. alpha(v)beta(3).ERK1 association occurred prior to focal complex formation and was seen to initiate in small punctate complexes primarily in the peripheral regions of the plasma membrane. Expression of a dominant negative mutant of ERK1 (but not ERK2) significantly reduced the spreading of cells on vitronectin, whereas cell spreading on fibronectin was unaffected by inhibition of ERK1. In contrast, inhibition of ERK activation by PD98059 had no effect on the platelet-derived growth factor-regulated Rab4-dependent flux of alpha(v)beta(3) integrin from early endosomes to the plasma membrane, an event that is also necessary for cells to spread efficiently on vitronectin. We propose that alpha(v)beta(3) integrin must recycle to the plasma membrane via the Rab4 pathway and recruit active ERK1 in order to function efficiently.
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PMID:ERK1 associates with alpha(v)beta 3 integrin and regulates cell spreading on vitronectin. 1239 86

The development of fibrosis is a common response to a variety of injuries and results in the net accumulation of matrix proteins and impairment of normal organ function. We previously reported that the integrin alpha8beta1 is expressed by alveolar interstitial cells in normal lung and is upregulated during the development of fibrosis. TGFbeta1 is an important mediator of the inflammatory response in pulmonary fibrosis. TGFbeta1 is secreted as a latent protein that is non-covalently associated with latency-associated peptide (LAP) and requires activation to exert its effects. LAP-TGFbeta1 and LAP-TGFbeta3 contain the tripeptide sequence, arginine-glycine-aspartic acid (RGD), a known integrin recognition motif. The integrin alpha8beta1 binds to several ligands such as fibronectin and vitronectin through the RGD sequence. Recent reports demonstrate that the integrins alphavbeta1, alphavbeta6 and alphavbeta8 adhere to LAP-TGFbeta1 through the RGD site. Therefore, we asked whether LAP-TGFbeta1 might be a ligand for alpha8beta1 and whether this may be important in the development of fibrosis. We found that cell lines transfected with alpha8 subunit were able to spread on and adhere to recombinant LAP-TGFbeta1 significantly better than mock transfected cell lines. alpha8-transfected cells were also able to adhere to LAP-TGFbeta3 significantly better than mock transfected cells. Adhesion to LAP-TGFbeta1 was enhanced by activation of alpha8beta1 by Mn(2+), or 8A2, an integrin beta1 activating antibody. Furthermore, cell adhesion was abolished when we used a recombinant LAP-TGFbeta1 protein in which the RGD site was mutated to RGE. alpha8beta1 binding to LAP-TGFbeta1 increased cell proliferation and phosphorylation of FAK and ERK, but did not activate of TGFbeta1. These data strongly suggest that LAP-TGFbeta1 is a ligand of alpha8beta1 and interaction of alpha8beta1 with LAP-TGFbeta1 may influence cell behavior.
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PMID:Integrin alpha8beta1 mediates adhesion to LAP-TGFbeta1. 1241 8

To investigate the behavior of hematopoietic stem cells (HSCs) in cord blood (CB), we analyzed the expression and function of TIE2, a tyrosine kinase receptor. A subpopulation of Lineage (Lin)(-/low)CD34(+) cells in CB expressed TIE2 (18.8%). Assays for long-term culture-initiating cells (LTC-IC) and cobble-stone formation revealed that Lin(-/low)CD34(+)TIE2(+) cells showed to have a capacity of primitive hematopoietic precursor cells in vitro. When Lin(-/low)CD34(+)TIE2(+) cells were cultured on the stromal cells, they transmigrated under the stromal layers and kept an immature character for a few weeks. By contrast, Lin(-/low)CD34(+)TIE2(-) cells differentiated immediately within a few weeks. Finally, we confirmed that 1x10(4)Lin(-/low)CD34(+)TIE2(+) cells were engrafted in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, while 1x10(4)Lin(-/low)CD34(+)TIE2(-) cells were not. Taken together, we conclude that TIE2 is a marker of HSCs in CB. A ligand for TIE2, Ang-1 promoted the adhesion of sorted primary Lin(-/low)CD34(+)TIE2(+) cells to fibronectin (FN), and this adhesion may play a critical role in keeping HSCs in an immature status under the stromal cells.
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PMID:Analysis of human TIE2 function on hematopoietic stem cells in umbilical cord blood. 1241 14

MEK kinase 1 (MEKK1) has been shown to contribute to the regulation of cell migration, whereas focal adhesion kinase (FAK) is a major player involved in both cell migration and integrin signaling. Here we show that MEKK1 and FAK are co-immunoprecipitated from mouse fibroblasts. Moreover, the association between MEKK1 and FAK appears to be physiologically relevant, as it is enhanced by treatment with epidermal growth factor (EGF). Targeting FAK to the membrane also enhanced its association with MEKK1, indicating that MEKK1 is localized to a membrane-related subcellular domain, perhaps focal adhesions. Interestingly, the expression of insulin receptor substrate-1 (IRS-1) was diminished in MEKK1-deficient fibroblasts, which is similar to an earlier finding in FAK-deficient fibroblasts. Insulin-like growth factor 1 (IGF-1)-induced ERK activation was diminished in MEKK1-deficient cells, but phosphatidylinositol 3-kinase/Akt activation was not. Although integrin reportedly regulates the transcription of the IRS-1 gene via FAK-mediated JNK activation, no impairment of fibronectin-stimulated activation of FAK, ERK, or JNK was observed in MEKK1-deficient cells. Reconstitution of MEKK1 expression restored IRS-1 expression as well as IGF-1-induced ERK activation. Taken together, these findings indicate that MEKK1 interacts with FAK in focal adhesions and regulates IRS-1 expression.
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PMID:MEK kinase 1 interacts with focal adhesion kinase and regulates insulin receptor substrate-1 expression. 1245 13

Epithelial cells require contact with extracellular matrix (ECM) to inhibit detachment-induced apoptosis (anoikis). The ERK and PI-3K/Akt signaling pathways have been identified to inhibit anoikis. We present here a different story. An adult rat liver cell line, ARLJ301-3, underwent apoptosis within 4h under suspension conditions even with active forms of Akt and ERK1/2. Once ARLJ301-3 cells are plated on tissue culture plates coated with synthetic polymer, such as poly-(N-p-vinyl benzyl-O-beta-D-galactopyranosyl-D-gluconamide) (PVLA), poly-L-lysine or polystyrene, instead of functional ECM such as fibronectin, they could survive and proliferate without activation of Akt and ERK1/2. The expression of Fas receptor ligand (FasL) is specifically detected in cells under suspension conditions or treated with cytochalasin-D. We present here the first report that FasL expression is up-regulated by the cytoskeletal disruption directed by cytochalasin-D treatment or cell detachment from ECM.
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PMID:Cell adhesion aside from integrin system can abrogate anoikis in rat liver cells by down-regulation of FasL expression, not by activation of PI-3K/Akt and ERK signaling pathway. 1248 May 44


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