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)

CCN2 consists of 4 distinct modules that are conserved among various CCN family protein members. From the N-terminus, insulin-like growth factor binding protein (IGFBP), von Willebrand factor type C repeat (VWC), thrombospondin type 1 repeat (TSP1) and C-terminal cysteine-knot (CT) modules are all aligned tandem therein. The multiple functionality of CCN2 is thought to be enabled by the differential use of these modules when interacting with other molecules. In this study, we independently prepared all 4 purified module proteins of human CCN2, utilizing a secretory production system with Brevibacillus choshinensis and thus evaluated the cell biological effects of such single modules. In human umbilical vascular endothelial cells (HUVECs), VWC, TSP and CT modules, as well as a full-length CCN2, were capable of efficiently activating the ERK signal transduction cascade, whereas IGFBP was not. In contrast, the IGFBP module was found to prominently activate JNK in human chondrocytic HCS-2/8 cells, while the others showed similar effects at lower levels. In addition, ERK1/2 was modestly, but significantly activated by IGFBP and VWC in those cells. No single module, but a mixture of the 4 modules provoked a significant activation of p38 MAPK in HCS-2/8 cells, which was activated by the full-length CCN2. Therefore, the signals emitted by CCN2 can be highly differential, depending upon the cell types, which are thus enabled by the tetramodular structure. Furthermore, the cell biological effects of each module on these cells were also evaluated to clarify the relationship among the modules, the signaling pathways and biological outcomes. Our present results not only demonstrate that single CCN2 modules were potent activators of the intracellular signaling cascade to yield a biological response per se, while also providing new insight into the module-wise structural and functional relationship of a prototypic CCN family member, CCN2.
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PMID:Multiple activation of mitogen-activated protein kinases by purified independent CCN2 modules in vascular endothelial cells and chondrocytes in culture. 1693 82

CCN2 is expressed by mesenchymal cells undergoing active tissue remodeling, and is characteristically overexpressed in connective tissue pathologies such as fibrosis and cancer. However, the physiological roles and mechanism of action of CCN2 are largely unknown. Here, we probe the contribution of CCN2 to the biology of mouse embryonic fibroblasts (MEFs) using genome-wide mRNA expression profiling, proteomic and functional bioassay analyses. We show that ccn2-/- mouse embryonic fibroblasts (MEFs) have significantly reduced the expression of pro-adhesive, pro-inflammatory and pro-angiogenic genes such as interleukin-6 (IL-6), ceruloplasmin, thrombospondin-1, lipocalin-2 and syndecan 4. Anti-syndecan 4 antibody reduced ERK phosphorylation in ccn2+/+ MEFs. In ccn2+/+ MEFs, the MEK inhibitor U0126 and dominant negative ras reduced expression of IL-6 and lipocalin-2. Overexpressing syndecan 4 in ccn2-/- MEFs restored IL-6 and lipocalin-2 mRNA expression. Syndecan 4 has been shown to mediate cell migration. We found that ccn2+/+ MEFs migrated significantly faster than ccn2-/- MEFs; anti-syndecan 4 antibody and U0126 reduced the migration of ccn2+/+ MEFs to that of ccn2-/- MEFs. These results collectively support the notion that syndecan 4 acts downstream of CCN2 in MEFs, and that reduced syndecan 4 expression contributes to at least part of the ccn2-/- phenotype. Further, these results suggest that CCN2 is required for MEFs to contribute to aspects of tissue remodeling. Consistent with this notion, whereas ccn2+/+ MEFs displayed actin stress fibers and focal adhesions at the cell periphery consistent with a migratory phenotype, ccn2-/- MEFs displayed reduced focal adhesions and actin stress fibers, and a reduced ability to transduce forces across a collagen gel matrix. Collectively, these results suggest that CCN2 supplies essential, non-redundant functions required for fibroblasts to properly participate in features of embryogenesis, and further suggest that CCN2 may play essential roles in adult wound healing, tissue repair and fibrogenesis.
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PMID:CCN2 is necessary for the function of mouse embryonic fibroblasts. 1723 53

Prostaglandin E(2) blocks transforming growth factor TGF beta1-induced CCN2/CTGF expression in lung and kidney fibroblasts. PGE(2) levels are high in gingival tissues yet CCN2/CTGF expression is elevated in fibrotic gingival overgrowth. Gingival fibroblast expression of CCN2/CTGF in the presence of PGE(2) led us to compare the regulation of CCN2/CTGF expression in fibroblasts cultured from different tissues. Data demonstrate that the TGFbeta1-induced expression of CCN2/CTGF in human lung and renal mesangial cells is inhibited by 10 nm PGE(2), whereas human gingival fibroblasts are resistant. Ten nm PGE(2) increases cAMP accumulation in lung but not gingival fibroblasts, which require 1 mum PGE(2) to elevate cAMP. Micromolar PGE(2) only slightly reduces the TGFbeta1-stimulated CCN2/CTGF levels in gingival cells. EP2 prostaglandin receptor activation with butaprost blocks the TGFbeta1-stimulated expression of CCN2/CTGF expression in lung, but not gingival, fibroblasts. In lung fibroblasts, inhibition of the TGFbeta1-stimulated CCN2/CTGF by PGE(2), butaprost, or forskolin is due to p38, ERK, and JNK MAP kinase inhibition that is cAMP-dependent. Inhibition of any two MAPKs completely blocks CCN2/CTGF expression stimulated by TGFbeta1. These data mimic the inhibitory effects of 10 nm PGE(2) and forskolin that were dependent on PKA activity. In gingival fibroblasts, the sole MAPK mediating the TGFbeta1-stimulated CCN2/CTGF expression is JNK. Whereas forskolin reduces TGFbeta1-stimulated expression of CCN2/CTGF by 35% and JNK activation in gingival fibroblasts, micromolar PGE(2)-stimulated JNK in gingival fibroblasts and opposes the inhibitory effects of cAMP on CCN2/CTGF expression. Stimulation of the EP3 receptor with sulprostone results in a robust increase in JNK activation in these cells. Taken together, data identify two mechanisms by which TGFbeta1-stimulated CCN2/CTGF levels in human gingival fibroblasts resist down-regulation by PGE(2): (i) cAMP cross-talk with MAPK pathways is limited in gingival fibroblasts; (ii) PGE(2) activation of the EP3 prostanoid receptor stimulates the activation of JNK.
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PMID:Tissue-specific mechanisms for CCN2/CTGF persistence in fibrotic gingiva: interactions between cAMP and MAPK signaling pathways, and prostaglandin E2-EP3 receptor mediated activation of the c-JUN N-terminal kinase. 1742 96

Connective tissue growth factor (CTGF/CCN2) is thought to play a role in normal wound repair and bone remodeling, but also promotes fibrosis in several disease processes including diabetic nephropathy, sclerodoma and pancreatitis. A contribution to desmoplasia associated with pancreatic cancer progression has also been proposed. CTGF is induced by TGFbeta in diverse cell types, but TGFbeta receptor mediated signaling is impaired in pancreatic cancers and cell lines, usually due to DPC4/Smad4 mutations which arise during the later stages of intraepithelial neoplastic progression. Therefore, in order to define signaling pathways that mediate basal and TGFbeta-induced CTGF expression in normal and transformed cells, we compared CTGF gene regulation in pancreatic cancer cells and fibroblasts by measuring the effects of small molecule inhibitors and dominant negative mutants of signaling proteins on CTGF promoter reporter activity, message, and protein expression. We determined that the previously identified TEF-1 cis element is essential for CTGF promoter reporter activity in pancreatic cancer cell lines. Whereas p38 mediated CTGF induction by TGFbeta in fibroblasts, MEK/ERK signaling mediated TGFbeta-induced CTGF expression in pancreatic cancer cells and was also responsible for basal CTGF expression in pancreatic cancer cell lines with defective Smad signaling. Since activating Ras mutations occur in the earliest stages of pancreatic cancer, CTGF may be induced independent of Smad4 in pancreatic cancer cells.
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PMID:Expression of connective tissue growth factor in pancreatic cancer cell lines. 1778 99

The beneficial antioxidative, anti-inflammatory and antitumorigenic effects of curcumin have been well documented in relation to cancer and other chronic diseases. Recent evidence suggests that it may be of therapeutic interest in chronic liver disease. Hepatic fibrosis (scarring) occurs in advanced liver disease, where normal hepatic tissue is replaced with collagen-rich extracellular matrix and, if left untreated, results in cirrhosis. Curcumin inhibits liver cirrhosis in a rodent model and exerts multiple biological effects in hepatic stellate cells (HSCs), which play a central role in the pathogenesis of hepatic fibrosis. In response to liver injury, these cells proliferate producing pro-inflammatory mediators and extracellular matrix. Curcumin induces apoptosis and suppresses proliferation in HSCs. In addition, it inhibits extracellular matrix formation by enhancing HSC matrix metalloproteinase expression via PPARgamma and suppressing connective tissue growth factor (CTGF) expression. In this issue, Chen and co-workers propose that curcumin suppresses CTGF expression in HSC by inhibiting ERK and NF-kappaB activation. These studies suggest that curcumin modulates several intracellular signalling pathways in HSC and may be of future interest in hepatic fibrosis therapy.
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PMID:Curcumin: potential for hepatic fibrosis therapy? 1803 17

Connective tissue growth factor (CTGF, CCN2) is overexpressed in pancreatic cancer. We mapped the minimal CCN2 promoter active in PANC-1 cells, a human pancreatic cancer cell line. Within this region, Sp1, BCE-1 and Ets elements were important for the activity of the CCN2 promoter. Constitutive hyperactivated ras is a hallmark of cancers, including that of the pancreas. Treatment of PANC-1 cells with the MEK inhibitor U0126 or the Sp1 inhibitor mithramycin reduced CCN2 mRNA and promoter activity. Mutation of the BCE-1, but not Sp1 or Ets, site abolished the responsiveness of the CCN2 promoter to U0126. Overexpressing constitutively active MEK1 or ras activated CCN2 promoter activity. Thus CCN2 is likely to act downstream of ras in PANC-1 cells. CCN2 is overexpressed in cancer cells. Activated ras/MEK/ERK is a hallmark of cancer, and we have shown that the elevated CCN2 expression in pancreatic cancer cells is dependent on this pathway.
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PMID:Analysis of CCN2 promoter activity in PANC-1 cells: regulation by ras/MEK/ERK. 1848 Nov 99

Endothelin (ET)-1 is a vasoconstrictor involved in cardiovascular diseases. Connective tissue growth factor/CCN2 (CTGF) is a fibrotic mediator overexpressed in human atherosclerotic lesions, myocardial infarction, and hypertension. In different cell types CTGF regulates cell proliferation/apoptosis, migration, and extracellular matrix (ECM) accumulation and plays important roles in angiogenesis, chondrogenesis, osteogenesis, tissue repair, cancer and fibrosis. In the present study, we investigated the ET-1 signaling which triggers CTGF expression in cultured adult mouse atrial-muscle HL-1 cells used as a model system. ET-1 activated the CTGF promoter and induced CTGF expression at both mRNA and protein levels. Real-time PCR analysis revealed CTGF induction also in isolated rat heart preparations perfused with ET-1. Several intracellular signals elicited by ET-1 via ET receptors and even Epidermal Growth Factor Receptor (EGFR) contributed to the up-regulation of CTGF, including ERK activation and induction of the AP-1 components c-fos and c-jun, as also evaluated by ChIP analysis. Moreover, in cells treated with ET-1 the expression of ECM component decorin was abolished by CTGF silencing, indicating that CTGF is involved in ET-1 induced ECM accumulation not only in a direct manner but also through downstream effectors. Collectively, our data indicate that CTGF could be a mediator of the profibrotic effects of ET-1 in cardiomyocytes. CTGF inhibitors should be considered in setting a comprehensive pharmacological approach towards ET-1 induced cardiovascular diseases.
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PMID:Endothelin-1 induces connective tissue growth factor expression in cardiomyocytes. 1911 53

The matricellular protein CCN2 (connective tissue growth factor, CTGF) has been previously implicated in tumorigenesis. In pancreatic cancer cells, CCN2 expression occurs downstream of ras/MEK/ERK. Direct evidence that CCN2 mediates tumor progression in pancreatic cancer has been lacking. An exciting recent report by Bennewith et al. (Cancer Res 69:775-784, 2009) has used shRNA knockdown of CCN2 to illustrate that CCN2 contributes to growth of pancreatic tumor cells, both in vitro and in vivo. This report briefly summarizes these findings.
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PMID:Death of a tumor: targeting CCN in pancreatic cancer. 1926 21

Matrix metalloproteinase-2 (MMP-2) is an important extracellular matrix remodeling enzyme, and it has been involved in different fibrotic disorders. The connective tissue growth factor (CTGF/CCN2), which is increased in these pathologies, induces the production of extracellular matrix proteins. To understand the fibrotic process observed in diverse pathologies, we analyzed the fibroblast response to CTGF when MMP-2 activity is inhibited. CTGF increased fibronectin (FN) amount, MMP-2 mRNA expression, and gelatinase activity in 3T3 cells. When MMP-2 activity was inhibited either by the metalloproteinase inhibitor GM-6001 or in MMP-2-deficient fibroblasts, an increase in the basal amount of FN together with a decrease of its levels in response to CTGF was observed. This paradoxical effect could be explained by the fact that the excess of FN could block the access to other ligands, such as CTGF, to integrins. This effect was emulated in fibroblasts by adding exogenous FN or RGDS peptides or using anti-integrin alpha(V) subunit-blocking antibodies. Additionally, in MMP-2-deficient cells CTGF did not induce the formation of stress fibers, focal adhesion sites, and ERK phosphorylation. Anti-integrin alpha(V) subunit-blocking antibodies inhibited ERK phosphorylation in control cells. Finally, in MMP-2-deficient cells, FN mRNA expression was not affected by CTGF, but degradation of (125)I-FN was increased. These results suggest that expression, regulation, and activity of MMP-2 can play an important role in the initial steps of fibrosis and shows that FN levels can regulate the cellular response to CTGF.
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PMID:Matrix metalloproteinase-2-deficient fibroblasts exhibit an alteration in the fibrotic response to connective tissue growth factor/CCN2 because of an increase in the levels of endogenous fibronectin. 1927 73

Preptin, a newly isolated 34-amino-acid peptide hormone that is cosecreted with insulin and amylin from pancreatic beta-cells, has emerged as a regulatory element in bone metabolism, but its mechanism remains unclear. We assessed the effects of preptin on proliferation and differentiation of human osteoblasts and investigated the mechanism involved. Our results demonstrated that preptin promoted human osteoblasts proliferation and alkaline phosphatase activity. Suppression of connective tissue growth factor (CTGF), which was upregulated by preptin in a dose- and time-dependent manner, with small interfering RNA (siRNA) abolished the preptin-induced human osteoblasts proliferation and differentiation. Preptin induced activation of ERK mitogen-activated protein kinase (MAPK), but not p38 or JNK in human osteoblasts. Furthermore, pretreatment of human osteoblasts with the ERK inhibitor PD98059 abolished the preptin-induced CTGF secretion and blocked the promoting effect of preptin on osteoblasts proliferation and differentiation. These data demonstrated that preptin is involved in bone anabolism mediated by ERK/CTGF in human osteoblasts and may contribute to the preservation of bone mass observed in hyperinsulinemic states, such as obesity.
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PMID:Connective tissue growth factor is a downstream mediator for preptin-induced proliferation and differentiation in human osteoblasts. 1933 18


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