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)

Recently, we demonstrated that in rats treated chronically with aldosterone and salt, severe tubulointerstitial fibrosis is associated with the activation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases (ERK1/2). Here, we investigated whether aldosterone stimulates collagen synthesis via ERK1/2-dependent pathways in cultured rat renal fibroblasts. Gene expression of mineralocorticoid receptor (MR) and types I, II, III, and IV collagen was measured by real-time polymerase chain reaction (PCR). MR protein expression and ERK1/2 activity were evaluated by Western blotting analysis with anti-MR and anti-phospho-ERK1/2 antibodies, respectively. Collagen synthesis was determined by [3H]-proline incorporation. Significant levels of MR mRNA and protein expression were observed in rat renal fibroblasts. Treatment with aldosterone (0.1 to 10 nmol/L) increased ERK1/2 phosphorylation in a concentration-dependent manner with a peak at 5 minutes. Aldosterone (10 nmol/L) also increased the mRNA levels of types I, III, and IV collagen at 36 hours but had no effect on the type II collagen mRNA level. [3H]-proline incorporation was significantly increased by aldosterone in both the medium and cell layer at 48 hours. Aldosterone-induced ERK1/2 phosphorylation was markedly attenuated by pretreatment with eplerenone (10 micromol/L), a selective MR antagonist, or PD98059 (10 micromol/L), a specific inhibitor of MAPK kinase/ERK kinase, which is the upstream activator of ERK1/2. In addition, both eplerenone and PD98059 prevented the aldosterone-induced increases in types I, III, and IV collagen mRNA and [3H]-proline incorporation. These results suggest that aldosterone stimulates collagen gene expression and synthesis via MR-mediated ERK1/2 activation in renal fibroblasts, which may contribute to the progression of aldosterone-induced tubulointerstitial fibrosis.
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PMID:Aldosterone stimulates collagen gene expression and synthesis via activation of ERK1/2 in rat renal fibroblasts. 1608 86

The effect of nanofiber surface coatings on the cell's proliferation behavior was studied. Individually collagen-coated poly(epsilon-caprolactone) (PCL) nanofibers (i.e., Collagen-r-PCL in the form of a core-shell structure) were prepared by a coaxial electrospinning technique. A roughly collagen-coated PCL nanofibrous matrix was also prepared by soaking the PCL matrix in a 10 mg/mL collagen solution overnight. These two types of coated nanofibers were then used to investigate differences in biological responses in terms of proliferation and cell morphology of human dermal fibroblasts (HDF). It was found that coatings of collagen on PCL nanofibrous matrix definitely favored cells proliferation, and the efficiency is coating means dependent. As compared to PCL, the HDF density on the Collagen-r-PCL nanofiber membrane almost increased linearly by 19.5% (2 days), 22.9% (4 days), and 31.8% (6 days). In contrast, the roughly collagen-coated PCL increased only by 5.5% (2 days), 11.0% (4 days), and 21.0% (6 days). SEM observation indicated that the Collagen-r-PCL nanofibers encouraged cell migration inside the scaffolds. These findings suggest that the Collagen-r-PCL nanofibers can be used as novel functional biomimetic nanofibers toward achieving excellent integration between cells and scaffolds for tissue engineering applications.
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PMID:Characterization of the surface biocompatibility of the electrospun PCL-collagen nanofibers using fibroblasts. 1615 95

During endochondral ossification, collagen X is deposited in the hypertrophic zone of the growth plate. Our previous results have shown that collagen X is capable of interacting directly with chondrocytes, primarily via integrin alpha2beta1. In this study, we determined whether collagen X could also interact with the non-integrin collagen receptors, discoidin domain receptors (DDRs), DDR1 or DDR2. The widely expressed DDRs are receptor tyrosine kinases that are activated by a number of different collagen types. Collagen X was found to be a much better ligand for DDR2 than for DDR1. Collagen X bound to the DDR2 extracellular domain with high affinity and stimulated DDR2 autophosphorylation, the first step in transmembrane signalling. Expression of DDR2 in the epiphyseal plate was confirmed by RT-PCR and immunohistochemistry. The spatial expression of DDR2 in the hypertrophic zone of the growth plate is consistent with a physiological interaction of DDR2 with collagen X. Surprisingly, the discoidin domain of DDR2, which fully contains the binding sites for the fibrillar collagens I and II, was not sufficient for collagen X binding. The nature of the DDR2 binding site(s) within collagen X was further analysed. In addition to a collagenous domain, collagen X contains a C-terminal NC1 domain. DDR2 was found to recognise the triple-helical region of collagen X as well as the NC1 domain. Binding to the collagenous region was dependent on the triple-helical conformation. DDR2 autophosphorylation was induced by the collagen X triple-helical region but not the NC1 domain, indicating that the triple-helical region of collagen X contains a specific DDR2 binding site that is capable of receptor activation. Our study is the first to describe a non-fibrillar collagen ligand for DDR2 and will form the basis for further studies into the biological function of collagen X during endochondral ossification.
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PMID:The discoidin domain receptor DDR2 is a receptor for type X collagen. 1680 67

Discoidin domain receptors (DDR1 and DDR2) are widely expressed cell-surface receptors, which bind to and are activated by collagens, including collagen type 1. Activation of DDRs and the resulting downstream signaling is known to regulate the extracellular matrix. However, little is known about how DDRs interact with collagen and its direct impact on collagen regulation. Here, we have established that by binding to collagen, the extracellular domain (ECD) of DDR2 inhibits collagen fibrillogenesis and alters the morphology of collagen type 1 fibers. Our in vitro assays utilized DDR2-Fc fusion proteins, which contain only the ECD of DDR2. Using surface plasmon resonance, we confirmed that further oligomerization of DDR2-Fc (by means of anti-Fc antibody) greatly enhances its binding to immobilized collagen type 1. Collagen turbidity measurements and biochemical assays indicated that DDR2 delays the formation of collagen fibrils. Atomic force microscopy of soluble collagen revealed that a predominately monomeric state of collagen was present with DDR2, while control solutions had an abundance of polymeric collagen. Transmission electron microscopy of collagen fibers, showed that the native periodic banded structure of collagen fibers was weakened and nearly absent in the presence of DDR2. Further, using a cell-based assay we demonstrate that overexpression of full length DDR2 inhibits fibrillogenesis of collagen type 1. Our results demonstrate a novel and important functional role of the DDR2 ECD that may contribute to collagen regulation via modulation of fibrillogenesis.
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PMID:Discoidin domain receptor 2 inhibits fibrillogenesis of collagen type 1. 1688 38

We recently showed by DNA microarray analysis that vascular endothelial growth factor (VEGF) receptor (VEGFR) is expressed in HCT8/S11 human colon cancer cells, suggesting that several angiogenic factors may target colon cancer cells themselves. In this study, transcripts encoding the VEGF-165 and semaphorin 3A (Sema3A) receptors and coreceptors Flt-1, KDR/Flk-1, plexin A1, and neuropilins NP-1 and NP-2 were identified by reverse transcription-PCR in the human colon cancer cell lines HCT8/S11, HT29, HCT116, and PCmsrc. Collagen invasion induced by VEGF-165 and Sema3A in HCT8/S11 cells (EC(50), 0.4-1 nmol/L) required p42/44 mitogen-activated protein kinase and signaling through RhoA/Rho-kinase-dependent and -independent pathways, respectively. As expected, the VEGFR signaling inhibitor ZD4190 selectively abrogated the proinvasive activity of VEGF in collagen gels (IC(50), 10 nmol/L) and chick heart fragments. We identify a novel function for VEGF-165 and Sema3A as proinvasive factors for human colorectal cancer cells. Interestingly, oral administration of the single drug ZD4190 to athymic mice (50 mg/kg/d, once daily) inhibited by 70% the growth of HCT8/S11 tumor cell xenografts. Combinations between the src tyrosine kinase inhibitor M475271 and ZD4190 or cisplatin resulted in additive therapeutic activity against LNM35 human lung tumor xenografts. Our data have significant implications for new therapeutic approaches and individualized treatment targeting VEGFR and src signaling pathways in combination with established clinical drugs at primary tumors and distant metastases in colon and lung cancer patients.
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PMID:Inhibition of vascular endothelial growth factor (VEGF)-165 and semaphorin 3A-mediated cellular invasion and tumor growth by the VEGF signaling inhibitor ZD4190 in human colon cancer cells and xenografts. 1692 28

The purpose of this study was to assess quantitatively the role of the small GTPase Rho on cell morphology, f-actin organization, and cell-induced matrix remodeling in 3D culture. Human corneal fibroblasts (HTK) were infected with adenoviruses that express green fluorescent protein (GFP) or GFP-N19Rho (dominant negative Rho). One day later cells were plated inside collagen matrices and allowed to spread for 24 h. Cells were fixed and stained for f-actin. Fluorescent (for f-actin) and reflected light (for collagen fibrils) images were acquired using confocal microscopy. Fourier transform analysis was used to assess local collagen fibril alignment, and changes in cell morphology and collagen density were measured using MetaMorph. The decrease in matrix height was used as an indicator of global matrix contraction. HTK and HTK-GFP cells induced significant global matrix contraction; this was inhibited by N19Rho. HTK and HTK-GFP fibroblasts generally had a bipolar morphology and occasional intracellular stress fibers. Collagen fibrils were compacted and aligned parallel to stress fibers and pseudopodia. In contrast, HTK-GFPN19 cells were elongated, and had a more cortical f-actin distribution. Numerous small extensions were also observed along the cell body. In addition, both local collagen fibril density and alignment were significantly reduced. Rho plays a key role in regulating both the morphology and mechanical behavior of corneal fibroblasts in 3D culture. Overall, the data suggest that Rho-kinase dependent cell contractility contributes to global and local matrix remodeling, whereas Rho dependent activation of mDia and/or other downstream effectors regulates the structure and number of cell processes.
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PMID:Rho plays a central role in regulating local cell-matrix mechanical interactions in 3D culture. 1734 62

The mechanisms by which beta1 integrins modulate T cell costimulation are still poorly defined. In this study, we examined the role of collagen-binding integrins alpha1 beta1 and alpha2 beta1 in the regulation of interferon-gamma (IFN-gamma). We demonstrated that ligation of alpha2 beta1 integrin with Collagen type I (Coll I) but not alpha1 beta1 integrin with Collagen IV (Coll IV) significantly augmented T cell receptor (TCR)-dependent expression and production of IFN-gamma by effector T cells. The effect of Coll I was not due to cell adhesion as soluble Coll I also augmented TCR-dependent production of IFN-gamma. Inhibition studies indicated that activation of ERK and JNK MAPKs and PI3K/AKT are necessary for both TCR- and TCR+alpha2 beta1 integrin-dependent IFN-gamma production and that Coll I increases TCR-dependent activation of ERK and JNK MAPKs, and AKT. In addition, our results showed that Coll IV is less potent than Coll I in augmenting TCR-dependent activation of JNK/MAPK, which may explain the differential effect of collagen matrices on TCR-dependent IFN-gamma production. Together, these results indicate that the costimulatory effect of Coll I on IFN-gamma expression is integrated at the levels of ERK and JNK MAPKs and PI3K/AKT signaling pathways and suggest JNK/MAPK as a major signaling pathway of Coll I costimulation. Thus, our study identifies alpha2 beta1 integrin as an important regulatory pathway of IFN-gamma expression and provides novel insights into the signaling mechanisms of integrin costimulation in T cells. As such, this study further supports the functional importance that Coll I interactions may have on the control of T cell-dependent Th1 inflammatory diseases.
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PMID:Alpha2 beta1 integrin signaling augments T cell receptor-dependent production of interferon-gamma in human T cells. 1752 31

The discoidin domain receptor (DDR) is a class of receptor tyrosine kinases that binds to several collagens. DDR1 is widely expressed in fast-growing invasive tumors of the breast, ovary, esophagus, brain and lung. However, there is little information on the expression of DDR1 in hepatocellular carcinoma (HCC) or its function in migration and invasion. Western blot analysis was performed to determine if four HCC cell lines (HLE, Huh-7, HepG2 and SH-J1) express DDR1. The HLE and Huh-7 cell lines were transfected with two isoforms of DDR1, DDR1a and DDR1b. Immunoprecipitation for DDR1 was then performed. Migration and invasion assays were carried out and the number of migrating cells was counted in 6 randomly selected fields per well under an optical microscope. Zymography was used to determine the level of the matrix metalloproteinase (MMP)-2 and -9 expression. DDR1 was expressed in all four cell lines. In the migration assay, the number of migrating cells was significantly higher in the DDR1a- or DDR1b-overexpressing HLE and Huh-7 cells, particularly after collagen type I stimulation (P<0.001). Collagen type I stimulation activated DDR1. In the invasion assay, there was a significantly higher number of invading cells in the DDR1a- or DDR1b-overexpressing HLE cells and DDR1a-overexpressing Huh-7 cells than in the control (P<0.01). The DDR1a- and DDR1b-overexpressing HLE cells showed a remarkable increase in the MMP-9 and -2 expression, particularly the active MMP-2. The DDR1a- and DDR1b-overexpressing Huh-7 cells showed a slight increase in the MMP-9 and -2 expression. The increased invasiveness of the HCC may be associated with the overexpression of either DDR1a or DDR1b mediated by MMP-2 and -9. Although this study provided one possible mechanism for the invasion of HCC cells, more studies are needed to understand the signal through which DDR1a and DDR1b act in invasion.
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PMID:Overexpression of discoidin domain receptor 1 increases the migration and invasion of hepatocellular carcinoma cells in association with matrix metalloproteinase. 1798 27

Centrifugation is an important step in biochemical and molecular biological researches. But the effects of centrifugal stress on cells are still unclear. In this study, osteoblastic cells UMR-106 were subjected to a moderate centrifugal stress at 209 x g for 10 min. Then the cell proliferation and gene transcription after centrifugation were analyzed with flow cytometry and Real-time RT-PCR techniques, respectively. The result showed that the cell proliferation and mRNA expression of Runx2/Cbfa1, Collagen I and osteocalcin changed shortly after centrifugal loading, but recovered to pre-load levels within 24 h. A dose-response study of exposure cells to centrifugal force at 209, 253 and 301 x g showed that the centrifugal forces within usually-used range can rapidly influenced the mRNA expression of the osteoblast-specific genes, but no statistical differences were found among the three centrifugal magnitudes. And the fast regulation in the investigated genes was proved to be related to increased c-fos mRNA levels and subsequent activation of RTK and integrity of cytoskeleton construction. The result showed that the osteoblastic cells displayed a fast auto-regulation to usually-used centrifugal stress through multiple signal pathways.
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PMID:Centrifugal forces within usually-used magnitude elicited a transitory and reversible change in proliferation and gene expression of osteoblastic cells UMR-106. 1803 72

Achondroplasias are the most common genetic forms of dwarfism in humans. They are associated with activating mutations in FGFR3, which signal through the Stat and MAPK pathways in a ligand-independent manner to impair chondrocyte proliferation and differentiation. Snail1 has been implicated in chondrocyte differentiation as it represses Collagen II and aggrecan transcription in vitro. Here we demonstrate that Snail1 overexpression in the developing bone leads to achondroplasia in mice. Snail1 acts downstream of FGFR3 signaling in chondrocytes, regulating both Stat and MAPK pathways. Moreover, FGFR3 requires Snail1 during bone development and disease as the inhibition of Snail1 abolishes its signaling even through achondroplastic- and thanatophoric-activating FGFR3 forms. Significantly, Snail1 is aberrantly upregulated in thanatophoric versus normal cartilages from stillborns. Thus, Snail activity may likely be considered a target for achondroplasia therapies.
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PMID:Snail1 is a transcriptional effector of FGFR3 signaling during chondrogenesis and achondroplasias. 1806 68


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