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)

While it is thought that advanced glycation end products (AGEs) act by stimulating transforming growth factor (TGF)-beta to mediate diabetic injury, we report that AGEs can activate TGF-beta signaling, Smads, and mediate diabetic scarring directly and independently of TGF-beta. AGEs activate Smad2/3 in renal and vascular cells at 5 min, peaking over 15-30 min before TGF-beta synthesis at 24 h and occurs in TGF-beta receptor I and II mutant cells. This is mediated by RAGE and ERK/p38 mitogen-activated protein kinases (MAPKs). In addition, AGEs also activate Smads at 24 h via the classic TGF-beta-dependent pathway. A substantial inhibition of AGE-induced Smad activation and collagen synthesis by ERK/p38 MAPK inhibitors, but not by TGF-beta blockade, suggests that the MAPK-Smad signaling crosstalk pathway is a key mechanism in diabetic scarring. Prevention of AGE-induced Smad activation and collagen synthesis by overexpression of Smad7 indicates that Smad signaling may play a critical role in diabetic complications. This is further supported by the findings that activation of Smad2/3 in human diabetic nephropathy and vasculopathy is associated with local deposition of AGEs and up-regulation of RAGE. Thus, AGEs act by activating Smad signaling to mediate diabetic complications via both TGF-beta-dependent and -independent pathways, shedding new light on the pathogenesis of diabetic organ injury.
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PMID:Advanced glycation end products activate Smad signaling via TGF-beta-dependent and independent mechanisms: implications for diabetic renal and vascular disease. 1270 99

Cyclooxygenase-2 (COX-2) enzyme and its inflammatory products such as prostaglandin E2 (PGE2) have been implicated in the pathogenesis of several inflammatory diseases. However their role in diabetic vascular disease is unclear. Advanced glycation end products (AGEs) act via their receptor, RAGE, to play a major role in diabetic complications. In this study, we investigated the effect of AGEs and S100b, a specific RAGE ligand, on the expression of COX-2 and the molecular mechanisms involved in cultured THP-1 monocytes and human peripheral blood monocytes. S100b treatment of THP-1 cells led to a significant 3-5-fold induction of COX-2 mRNA (p < 0.001). COX-2 protein and its product PGE2 were also increased, whereas COX-1 expression was unaffected. In vitro prepared AGE also induced COX-2 mRNA. S100b-induced COX-2 mRNA was blocked by an anti-RAGE antibody and by inhibitors of NF-kappa B (Bay11-7082), oxidant stress, protein kinase C, ERK, and p38 MAPKs. S100b (4-h treatment) significantly increased transcription from a human COX-2 promoter-luciferase construct (4-fold, p < 0.001). Promoter deletion analyses and inhibition of transcription by an NF-kappa B superrepressor mutant confirmed NF-kappa B involvement. This was further supported by inhibition of S100b-induced PGE2 by Bay11-7082. Additionally, S100b-induced adherence of THP-1 monocytes to vascular smooth muscle cells was blocked by the COX-2 inhibitor NS-398, Bay11-7082, inhibitors of ERK and p38 MAPK, and protein kinase C thereby indicating functional relevance. S100b also increased COX-2 mRNA expression in human peripheral blood monocytes from healthy donors. Moreover, COX-2 mRNA levels were clearly evident in monocytes obtained from diabetic patients but not from normal subjects. These results show for the first time that AGEs can augment inflammatory responses by up-regulating COX-2 via RAGE and multiple signaling pathways, thereby leading to monocyte activation and vascular cell dysfunction.
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PMID:Regulation of cyclooxygenase-2 expression in monocytes by ligation of the receptor for advanced glycation end products. 1283 57

An increase in the interaction between advanced glycation end-products (AGEs) and their receptor RAGE is believed to contribute to the pathogenesis of chronic complications of Diabetes mellitus, which can include bone alterations such as osteopenia. We have recently found that extracellular AGEs can directly regulate the growth and development of rat osteosarcoma UMR106 cells, and of mouse calvaria-derived MC3T3E1 osteoblasts throughout their successive developmental stages (proliferation, differentiation and mineralisation), possibly by the recognition of AGEs moieties by specific osteoblastic receptors which are present in both cell lines. In the present study we examined the possible expression of RAGE by UMR106 and MC3T3E1 osteoblastic cells, by immunoblot analysis. We also investigated whether short-, medium- or long-term exposure of osteoblasts to extracellular AGEs, could modify their affinity constant and maximal binding for AGEs (by 125I-AGE-BSA binding experiments), their expression of RAGE (by immunoblot analysis) and the activation status of the osteoblastic ERK 1/2 signal transduction mechanism (by immunoblot analysis for ERK and P-ERK). Our results show that both osteoblastic cell lines express readily detectable levels of RAGE. Short-term exposure of phenotypically mature osteoblastic UMR106 cells to AGEs decrease the cellular density of AGE-binding sites while increasing the affinity of these sites for AGEs. This culture condition also dose-dependently increased the expression of RAGE and the activation of ERK. In proliferating MC3T3E1 pre-osteoblasts, 24-72 h exposure to AGEs did not modify expression of RAGE, ERK activation or the cellular density of AGE-binding sites. However, it did change the affinity of these binding sites forAGEs, with both higher- and lower-affinity sites now being apparent. Medium-term ( 1 week) incubation of differentiated MC3T3E1 osteoblasts with AGEs, induced a simultaneous increase in RAGE expression and in the relative amount of P-ERK. Mineralising MC3T3E1 cultures grown for 3 weeks in the presence of extracellular AGEs showed a decrease both in RAGE and P-ERK expression. These results indicate that, in phenotypically mature osteoblastic cells, changes in ERK activation closely follow the AGEs-induced regulation of RAGE expression. Thus, the AGEs-induced biological effects that we have observed previously in osteoblasts, could be mediated by RAGE in the later stages of development, and mediated by other AGE receptors in the earlier pre-osteoblastic stage.
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PMID:Advanced glycation end-products (AGEs) induce concerted changes in the osteoblastic expression of their receptor RAGE and in the activation of extracellular signal-regulated kinases (ERK). 1296 37

Author's studies and literature references indicate that the DNA-binding cytokine: amphoterine, being a non-histone component of chromatin, acts in extracellular milieu as cytokine regulating gene expression in target cells. The amphoterine effects are mediated by its interaction with the cell surface receptors including those of the final glucosiding product (RAGE), which leads to activation of the ERK and p38 MAP-kinases as well as NF-kappaB. Amphoterine prompts inflammatory response by means of activating synthesis of interleukins-1, -6 and -8 as well as tumour necrosis factors (TNF-alpha) and activates tissue regeneration by means of involvement of the precursor cells into the damage foci and induction of the cells' differentiation. These properties of amphoterine suggest that appearance of this protein in extracellular space signals of a tissue damaging.
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PMID:[Participation of the DNA-binding cytokine amphoterine in triggering the processes of tissue reparation]. 1661 56

This study aimed to determine the effects of advanced glycation end products (AGEs) on endothelial cytoskeleton morphology and permeability, and to detect the underlying signaling mechanisms involved in these responses. Cultured endothelial cells (ECs) were exposed to AGE-modified human serum albumin (AGE-HSA), and EC cytoskeletal changes were evaluated by observing fluorescence of F-actin following ligation with labeled antibodies. Endothelial permeability was detected by measuring the flux of TRITC-albumin across the EC monolayers. To explore the signaling pathways behind AGE-induced EC alteration, ECs were treated with either soluble anti-AGE receptor (RAGE) IgG, or the MAPK inhibitors PD98059 and SB203580 before AGE-HSA administration. To further elucidate possible involvement of the ERK and p38 pathways in AGE-induced EC changes, adenovirus-carried recombinant constitutive dominant-negative forms of upstream ERK and p38 kinases, namely MEK1(A) and MKK6b(A), were pre-infected into ECs 24 h prior to AGE-HSA exposure. AGE-HSA induced actin cytoskeleton rearrangement, as well as EC hyperpermeability, in a dose and time-dependent manner. The effects were attenuated in cells pretreated with anti-RAGE IgG, PD98059 or SB203580, respectively. EC pre-infection with MEK1(A) and MKK6b(A) also alleviated the effect of AGEs. Furthermore, adenovirus-mediated administration of activated forms of either MEK1 or MKK6b alone induced rearrangement of F-actin and hyperpermeability. The results indicate that ERK and p38 MAPK play important roles in the mediation of AGE-induced EC barrier dysfunction associated with morphological changes of the F-actin.
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PMID:Advanced glycation end products induce actin rearrangement and subsequent hyperpermeability of endothelial cells. 1959 96

HMGB1 (high mobility group box 1 protein) is a nuclear protein that can also act as an extracellular trigger of inflammation, proliferation and migration, mainly through RAGE (the receptor for advanced glycation end products); HMGB1-RAGE interactions have been found to be important in a number of cancers. We investigated whether HMGB1 is an autocrine factor in human glioma cells. Western blots showed HMGB1 and RAGE expression in human malignant glioma cell lines. HMGB1 induced a dose-dependent increase in cell proliferation, which was found to be RAGE-mediated and involved the MAPK/ERK pathway. Moreover, in a wounding model, it induced a significant increase in cell migration, and RAGE-dependent activation of Rac1 was crucial in giving the tumour cells a motile phenotype. The fact that blocking DNA replication with anti-mitotic agents did not reduce the distance migrated suggests the independence of the proliferative and migratory effects. We also found that glioma cells contain HMGB1 predominantly in the nucleus, and cannot secrete it constitutively or upon stimulation; however, necrotic glioma cells can release HMGB1 after it has translocated from the nucleus to cytosol. These findings provide the first evidence supporting the existence of HMGB1/RAGE signalling pathways in human glioblastoma cells, and suggest that HMGB1 may play an important role in the relationship between necrosis and malignancy in glioma tumours by acting as an autocrine factor that is capable of promoting the growth and migration of tumour cells.
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PMID:HMGB1 as an autocrine stimulus in human T98G glioblastoma cells: role in cell growth and migration. 1797 8

AGEs (advanced glycation end-products) accumulate in collagen molecules during uraemia and diabetes, two diseases associated with high susceptibility to bacterial infection. Because neutrophils bind to collagen during their locomotion in extravascular tissue towards the infected area we investigated whether glycoxidation of collagen (AGE-collagen) alters neutrophil migration. Type I collagen extracted from rat tail tendons was used for in vitro glycoxidation (AGE-collagen). Neutrophils were obtained from peripheral blood of healthy adult volunteers and were used for the in vitro study of adhesion and migration on AGE- or control collagen. Glycoxidation of collagen increased adhesion of neutrophils to collagen surfaces. Neutrophil adhesion to AGE-collagen was inhibited by a rabbit anti-RAGE (receptor for AGEs) antibody and by PI3K (phosphoinositide 3-kinase) inhibitors. No effect was observed with ERK (extracellular-signal-regulated kinase) or p38 MAPK (mitogen-activated protein kinase) inhibitors. AGE-collagen was able to: (i) induce PI3K activation in neutrophils, and (ii) inhibit chemotaxis and chemokinesis of chemoattractant-stimulated neutrophils. Finally, we found that blocking RAGE with anti-RAGE antibodies or inhibiting PI3K with PI3K inhibitors restored fMLP (N-formylmethionyl-leucyl-phenylalanine)-induced neutrophil migration on AGE-collagen. These results show that RAGE and PI3K modulate adhesion and migration rate of neutrophils on AGE-collagen. Modulation of adhesiveness may account for the change in neutrophil migration rate on AGE-collagen. As neutrophils rely on their ability to move to perform their function as the first line of defence against bacterial invasion, glycoxidation of collagen may participate in the suppression of normal host defence in patients with diabetes and uraemia.
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PMID:Receptor for advanced glycation end-products (RAGE) modulates neutrophil adhesion and migration on glycoxidated extracellular matrix. 1864 77

How circulating T cells infiltrate into the brain in Alzheimer disease (AD) remains unclear. We previously reported that amyloid beta (Abeta)-dependent CCR5 expression in brain endothelial cells is involved in T cell transendothelial migration. In this study, we explored the signaling pathway of CCR5 up-regulation by Abeta. We showed that inhibitors of JNK, ERK, and PI3K significantly decreased Abeta-induced CCR5 expression in human brain microvascular endothelial cells (HBMECs). Chromatin immunoprecipitation assay revealed that Abeta-activated JNK, ERK, and PI3K promoted brain endothelial CCR5 expression via transcription factor Egr-1. Furthermore, neutralization Ab of receptor for advanced glycation end products (RAGE; an Abeta receptor) effectively blocked Abeta-induced JNK, ERK, and PI3K activation, contributing to CCR5 expression in HBMECs. Abeta fails to induce CCR5 expression when truncated RAGE was overexpressed in HBMECs. Transendothelial migration assay showed that the migration of MIP-1alpha (a CCR5 ligand)-expressing AD patients' T cells through in vitro blood-brain barrier model was effectively blocked by anti-RAGE Ab, overexpression of truncated RAGE, and dominant-negative PI3K, JNK/ERK, or Egr-1 RNA interference in HBMECs, respectively. Importantly, blockage of intracerebral RAGE abolished the up-regulation of CCR5 on brain endothelial cells and the increased T cell infiltration in the brain induced by Abeta injection in rat hippocampus. Our results suggest that intracerebral Abeta interaction with RAGE at BBB up-regulates endothelial CCR5 expression and causes circulating T cell infiltration in the brain in AD. This study may provide a new insight into the understanding of inflammation in the progress of AD.
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PMID:Amyloid beta interaction with receptor for advanced glycation end products up-regulates brain endothelial CCR5 expression and promotes T cells crossing the blood-brain barrier. 1938 Aug 26

HMGb1 is a DNA-binding protein whose role as an extracellular cytokine in inflammation and tissue regeneration has also been reported. Given the importance of keratinocytes in wound healing, we have studied the mechanism of action of HMGb1 on HaCaT keratinocytes during in vitro scratch wound repair. Western blot and confocal immunofluorescence microscopy showed that these cells express significant amounts of HMGb1, that the protein is prevalently localized in the nucleus, and that its release by cells is negligible. Western blot also showed that these cells express the HMGb1 receptor RAGE. Cell exposure to HMGb1 in the absence of serum resulted in a stimulation of cell proliferation and ERK1/2 activation. HMGb1 also accelerated the wound closure of scratch wounded cells and promoted cell migration, as evaluated by a transwell assay. The HMGb1-induced increases of cell proliferation, cell migration, and wound closure were abolished by the MEK inhibitor PD98059. Taken together, data show that, although HMGb1 is not released by HaCaT, when applied exogenously it can induce a marked increase of the wound repair of these cells. Data also suggest that HMGb1 acts via the RAGE/MEK/ERK pathway. These results bring scientific support to the potential application of HMGb1 in regenerative medicine.
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PMID:HMGb1 promotes scratch wound closure of HaCaT keratinocytes via ERK1/2 activation. 1958 30

Advanced glycation end-products (AGEs) can induce expression of connective tissue growth factor (CTGF), which seems to promote the development of diabetic nephropathy, but the exact signaling mechanisms that mediate this induction are unknown. Here, AGEs induced CTGF expression in tubular epithelial cells (TECs) that either lacked the TGF-beta1 gene or expressed dominant TGF-beta receptor II, demonstrating independence of TGF-beta. Furthermore, conditional knockout of the gene encoding TGF-beta receptor II from the kidney did not prevent AGE-induced renal expression of CTGF and collagen I. More specific, AGEs induced CTGF expression via the receptor for AGEs-extracellular signal-regulated kinase (RAGE-ERK)/p38 mitogen-activated protein kinase-Smad cross-talk pathway because inhibition of this pathway by several methods (anti-RAGE antibody, specific inhibitors, or dominant negative adenovirus to ERK1/2 and p38) blocked this induction. Overexpressing Smad7 abolished AGE-induced Smad3 phosphorylation and CTGF expression, demonstrating the necessity for activation of Smad signaling in this process. More important, knockdown of either Smad3 or Smad2 demonstrated that Smad3 but not Smad2 is essential for CTGF induction in response to AGEs. In conclusion, AGEs induce tubular CTGF expression via the TGF-beta-independent RAGE-ERK/p38-Smad3 cross-talk pathway. These data suggest that overexpression of Smad7 or targeting Smad3 may have therapeutic potential for diabetic nephropathy.
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PMID:Advanced glycation end-products induce tubular CTGF via TGF-beta-independent Smad3 signaling. 1995 9


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