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)

Organ cultures of human skin were incubated for 8 days under growth factor-free conditions or exposed to 10 ng ml(-1) of human recombinant epidermal growth factor (EGF) during the incubation period. Normal histological features were preserved in the absence of growth factor, while epithelial cells underwent a proliferative response and invaded the underlying stroma in the presence of exogenous EGF. The same concentrations of EGF that induced stromal invasion also resulted in up-regulation of matrix metalloproteinase-9 (MMP-9; 92-kD gelatinase B) in organ culture and keratinocyte monolayer culture, and expression of MMP-1 (interstitial collagenase) in organ culture and fibroblast monolayer culture. When skin organ cultures were exposed to a potent, irreversible EGF-receptor tyrosine kinase (EGF-RTK) antagonist along with EGF, abnormal histological features were reversed, and MMP-9 production was suppressed. In contrast, EGF-RKT antagonism had only a modest inhibitory effect on MMP-1 production. Culture fluid from keratinocytes grown in monolayer culture stimulated fibroblast proliferation and MMP-1 elaboration. Treatment of fibroblasts with the same EGF-RTK antagonist inhibited keratinocyte-induced fibroblast proliferation but had only a modest inhibitory effect (approximately 20% inhibition) on MMP-1 production. In contrast, treatment of dermal fibroblasts with Interleukin-1 Receptor Antagonist had no effect on keratinocyte-induced fibroblast growth but strongly inhibited MMP-1 production (greater than 70% inhibition). These data indicate that stromal invasion by epithelial cells in EGF-treated skin is associated with events occurring in both the epidermis and dermis. The direct effect of the exogenous growth factor appears to be primarily on the epidermis. Dermal events reflect, at least in part, a response to factors elaborated in the epidermis.
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PMID:Induction of matrix metalloproteinase-1 (MMP-1) during epidermal invasion of the stroma in human skin organ culture: keratinocyte stimulation of fibroblast MMP-1 production. 1172 Apr 51

The accumulation of extracellular matrix in the glomerular mesangium reflects the net balance between the synthesis and degradation of matrix components. We have shown that estradiol suppresses the synthesis of types I and IV collagen by cultured mesangial cells (Kwan G, Neugarten J, Sherman M, Ding Q, Fotadar U, Lei J, and Silbiger S. Kidney Int 50: 1173-1179, 1996; Neugarten J, Acharya A, Lei J, and Silbiger S. Am J Physiol Renal Physiol 279: F309-F318, 2000; Neugarten J, Medve I, Lei J, and Silbiger SR. Am J Physiol Renal Physiol 277: F1-F8, 1999; Neugarten J and Silbiger S. Am J Kidney Dis 26: 147-151, 1995; Silbiger S, Lei J, and Neugarten J. Kidney Int 55: 1268-1276, 1998; Silbiger S, Lei J, Ziyadeh FN, and Neugarten J. Am J Physiol Renal Physiol 274: F1113-F1118, 1998). In the present study, we evaluated the effects of sex hormones on the activity of matrix metalloproteinase-2 (MMP-2) in murine mesangial cells, the synthesis of which is regulated by the transcription factor activator protein-2 (AP-2). Estradiol stimulated MMP-2 activity by increasing MMP-2 protein levels in a dose-dependent manner. These effects occurred at physiological concentrations of estradiol and were receptor mediated. Estradiol also increased AP-2 protein levels and increased binding of mesangial cell nuclear extracts to an AP-2 consensus binding sequence oligonucleotide. The ability of estradiol to increase AP-2 protein expression, AP-2/DNA binding activity, MMP-2 protein expression, and metalloproteinase activity was reversed by PD-98059, a selective inhibitor of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling cascade. We conclude that estradiol upregulates the MAPK cascade, which in turn stimulates the synthesis of AP-2 protein. The resultant increased AP-2/DNA binding activity leads to increased synthesis of MMP-2 and increased metalloproteinase activity. Stimulation of metalloproteinase activity by estradiol may contribute to the protective effect of female gender on renal disease progression.
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PMID:Estradiol upregulates mesangial cell MMP-2 activity via the transcription factor AP-2. 1173 24

Tyrosine kinases belonging to the discoidin domain receptor (DDR) family are activated upon stimulation with various types of collagen. In response to collagen treatment, immunoprecipitation of DDR1 with an antibody specific to the juxtamembrane region results in co-purification of a previously unrecognized tyrosine phosphorylated protein of 62 kDa molecular weight. Here, this protein is identified as C-terminal cleavage product of the full-length DDR1 receptor and a DDR1-specific shedding enzyme postulated. Shedding of DDR1 can be partially blocked by the furin inhibitor decanoyl-RVKR-chloromethylketone and completely inhibited by the hydroxamate-based inhibitor batimastat. The characteristic of the DDR1 sheddase to be blocked by batimastat suggests that it belongs to the membrane-bound matrix metalloproteinase or disintegrin and metalloproteinase family of proteases.
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PMID:Ligand-induced shedding of discoidin domain receptor 1. 1194 46

According to current theory, endometriosis is initiated during retrograde menstruation when menstrual fragments flow out of the fimbriated end of the fallopian tubes and become established on the ovarian surface or other sites in the peritoneal cavity. In recent years, new data have accumulated on the properties of menstruating tissue itself, and several laboratories agree that this tissue is rich in matrix metalloproteinases (MMPs) that may facilitate endometriotic implantation. Recently, we found that vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (KDR) were dramatically upregulated in the stromal cells of the superficial endometrial zones by progesterone (P) withdrawal during the premenstrual phase. A unique role of VEGF at this stage of the cycle may be to stimulate MMP expression in stromal cells because VEGF, KDR, and MMPs were all coordinately induced in these cells in the superficial zone of the primate endometrium by P withdrawal. The rich content of MMPs and VEGF in the menstrual fragments could facilitate attachment and angiogenesis of menstrual fragments in ectopic sites. In addition, a variety of chemokines, cytokines, and cellular regulators are induced by P withdrawal in the premenstrual human endometrium. These include NFKB, prostaglandins, interleukin-8 (IL-8), cyclooxygenase-2 (COX-2), and monocyte chemotactic peptide-1 (MCP-1), among others. The perivascular expression of several of these factors may facilitate the rapid invasion of leukocytes into the endometrium, especially in the superficial zones. Consequently, menstrual fragments may be rich in IL-8 and MCP-1, both of which would add to the angiogenic potential of such fragments in ectopic sites. In sum, menstrual tissue is rich in VEGF, KDR, MMPs, leukocytes, chemokines, cytokines, and prostaglandins, all factors that may facilitate attachment and angiogenesis when menstrual fragments exit from the tubes and implant on pelvic sites. Additional research on these and other factors in premenstrual and menstrual endometrium may deepen our understanding of both the establishment and progression of this debilitating disease.
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PMID:Premenstrual and menstrual changes in the macaque and human endometrium: relevance to endometriosis. 1194 66

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) activity and are considered to exert antitumor actions in a variety of cancer cells, although the effects are unlikely entirely due to COX inhibition. Because clinical observations suggest that hepatocyte growth factor (HGF) can promote metastasis of hepatoma cells while stimulating tumor invasiveness, we investigated the effect of aspirin and NS-398, a selective COX-2 inhibitor, on HGF-mediated invasiveness of HepG2 human hepatoma cells. HGF stimulated the invasiveness of HepG2 cells in Matrigel cell invasion assay, together with increased expression of matrix metalloproteinase (MMP) 9. Addition of aspirin or NS-398, similar to PD98059, which acts as a specific inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK), an upstream kinase regulating extracellular signal-regulated kinase (ERK)1/2, abrogated such actions of HGF without affecting cell viability. Aspirin and NS-398, in contrast to PD98059, did not suppress ERK1/2 phosphorylation induced by HGF. However, both agents inhibited the kinase activity of ERK1/2 induced by HGF and repressed HGF-induced phosphorylation of 90-kd ribosomal S6 kinase (RSK) and Elk-1, key downstream substrates of ERK1/2, resulting in the suppression of transcriptional activity of Elk-1 as well as nuclear factor kappaB (NF-kappaB) and AP-1, which are involved in MMP-9 gene regulation. In conclusion, our results suggest that aspirin and NS-398 inhibit HGF-induced invasiveness of HepG2 human hepatoma cells through ERK1/2.
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PMID:Aspirin and NS-398 inhibit hepatocyte growth factor-induced invasiveness of human hepatoma cells. 1198 61

We examined the signaling pathway by which hepatocyte growth factor (HGF) induces cell motility, with special focus on the role of extracellular signal-regulated kinase (ERK) in the nucleus. We used Madin-Darby canine kidney cells overexpressing ERK2 because of their prominent motility response to HGF. HGF stimulation of the cells induces not only a rapid, marked, and sustained activation and rapid nuclear accumulation of ERK1/2, but also a prolonged nuclear retention of the activated ERK1/2. Interruption of the ERK1/2 activation by PD98059 treatment of the cells 30 min after HGF stimulation abolishes the HGF-induced cell motility. Enforced cytoplasmic retention of the activated ERK1/2 by the expression of an inactive form of MKP-3 cytoplasmic phosphatase inhibits the cell motility response. Although epidermal growth factor stimulation of the cells induces the activation and nuclear accumulation of ERK1/2, it does not induce the prolonged nuclear retention of the activated ERK1/2, and fails to induce cell motility. In the nucleus, activated ERK1/2 continuously phosphorylate Elk-1, leading to the prolonged expression of c-fos, which results in the expression of several genes such as matrix metalloproteinase (mmp)-9; MMP-9 activity is required for the induction of the cell motility response. Our results indicate that the sustained activity of ERK1/2 in the nucleus is required for the induction of HGF-induced cell motility.
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PMID:Prolonged nuclear retention of activated extracellular signal-regulated kinase 1/2 is required for hepatocyte growth factor-induced cell motility. 1203 50

Our previous data showed that nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit matrix metalloproteinase-2 (MMP-2) expression via repression of gene transcription in lung cancer cells. In this study, we investigate the molecular mechanism by which NSAIDs inhibit MMP-2. Promoter deletion and mutation analysis indicate that NSAIDs act via the Sp1 transcription factor binding site located between -91 and -84 in the MMP-2 promoter to suppress gene expression. Electrophoretic mobility shift assays show that Sp1 and Sp3 proteins constitutively bind to this consensus sequence and overexpression of Sp1 may enhance MMP-2 expression. NSAID treatment reduces Sp1 DNA binding activity and phosphorylation and attenuates MMP-2 expression. We also investigate the signaling pathway that mediates the effect of NSAIDs. Our results suggest that ERKs are involved in this process. First, NSAIDs suppress basal and serum-stimulated ERK activity. Second, a MEK inhibitor PD98059 inhibits MMP-2 promoter activity and Sp1 phosphorylation. Third, overexpression of constitutively active MEK1 stimulates Sp1 phosphorylation and MMP-2 promoter activity and antagonizes the inhibition of NSAIDs. Collectively, our data suggest that NSAIDs inhibit MMP-2 by blocking ERK/Sp1-mediated transcription.
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PMID:Nonsteroidal anti-inflammatory drugs inhibit matrix metalloproteinase-2 via suppression of the ERK/Sp1-mediated transcription. 1208 91

The mechanism by which angiogenic factors recruit bone marrow (BM)-derived quiescent endothelial and hematopoietic stem cells (HSCs) is not known. Here, we report that functional vascular endothelial growth factor receptor-1 (VEGFR1) is expressed on human CD34(+) and mouse Lin(-)Sca-1(+)c-Kit(+) BM-repopulating stem cells, conveying signals for recruitment of HSCs and reconstitution of hematopoiesis. Inhibition of VEGFR1, but not VEGFR2, blocked HSC cell cycling, differentiation and hematopoietic recovery after BM suppression, resulting in the demise of the treated mice. Placental growth factor (PlGF), which signals through VEGFR1, restored early and late phases of hematopoiesis following BM suppression. PlGF enhanced early phases of BM recovery directly through rapid chemotaxis of VEGFR1(+) BM-repopulating and progenitor cells. The late phase of hematopoietic recovery was driven by PlGF-induced upregulation of matrix metalloproteinase-9, mediating the release of soluble Kit ligand. Thus, PlGF promotes recruitment of VEGFR1(+) HSCs from a quiescent to a proliferative BM microenvironment, favoring differentiation, mobilization and reconstitution of hematopoiesis.
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PMID:Placental growth factor reconstitutes hematopoiesis by recruiting VEGFR1(+) stem cells from bone-marrow microenvironment. 1215 25

The expression and activity of epithelial proteinases is under stringent control to prevent aberrant hydrolysis of structural proteins and disruption of tissue architecture. E-cadherin-dependent cell-cell adhesion is also important for maintenance of epithelial structural integrity, and loss of E-cadherin expression has been correlated with enhanced invasive potential in multiple tumor models. To address the hypothesis that there is a functional link between E-cadherin and proteinase expression, we have examined the role of E-cadherin in proteinase regulation. By using a calcium switch protocol to manipulate junction assembly, our data demonstrate that initiation of de novo E-cadherin-mediated adhesive contacts suppresses expression of both relative matrix metalloproteinase-9 levels and net urinary-type plasminogen activator activity. E-cadherin-mediated cell-cell adhesion increases both phosphatidylinositol 3'-kinase (PI3-kinase)-dependent AKT phosphorylation and epidermal growth factor receptor-dependent MAPK/ERK activation. Pharmacologic inhibition of the PI3-kinase pathway, but not the epidermal growth factor receptor/MAPK pathway, prevents E-cadherin-mediated suppression of proteinases and delays junction assembly. Moreover, inhibition of junction assembly with a function-blocking anti-E-cadherin antibody stimulates proteinase-dependent Matrigel invasion. As matrix metalloproteinase-9 and urinary-type plasminogen activator potentiate the invasive activity of oral squamous cell carcinoma, these data suggest E-cadherin-mediated signaling through PI3-kinase can regulate the invasive behavior of cells by modulating proteinase secretion.
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PMID:Proteinase suppression by E-cadherin-mediated cell-cell attachment in premalignant oral keratinocytes. 1213 62

Focal adhesion kinase (FAK) was first identified as a viral Src (v-Src) substrate, but the role of FAK in Src transformation events remains undefined. We show that stable expression of the FAK C-terminal domain (termed FRNK) in v-Src-transformed NIH 3T3 fibroblasts inhibited cell invasion through Matrigel and blocked experimental metastases in nude mice without effects on cell motility. FRNK inhibitory activity was dependent upon its focal contact localization. FRNK expression disrupted the formation of a v-Src-FAK signaling complex, inhibited p130Cas tyrosine phosphorylation, and attenuated v-Src-stimulated ERK and JNK kinase activation. However, FRNK did not affect v-Src-stimulated Akt activation, cell growth in soft agar, or subcutaneous tumor formation in nude mice. FRNK-expressing cells exhibited decreased matrix metalloproteinase-2 (MMP-2) mRNA levels and MMP-2 secretion. Transient FRNK expression in human 293 cells inhibited exogenous MMP-2 promoter activity and overexpression of wild-type but not catalytically-inactive (Ala-404) MMP-2 rescued v-Src-stimulated Matrigel invasion in the presence of FRNK. Our findings show the importance of FAK in Src-stimulated cell invasion and support a role for Src-FAK signaling associated with elevated tumor cell metastases.
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PMID:FRNK blocks v-Src-stimulated invasion and experimental metastases without effects on cell motility or growth. 1245 36


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