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)

Epidermal hyperproliferation and neutrophil infiltration are major histopathological changes observed in psoriasis. Neutrophils contain human leukocyte elastase (HLE), which is released at sites of inflammation. HLE is present in psoriatic lesions and induces keratinocyte hyperproliferation in vitro and in vivo. To determine the molecular mechanisms linking a proteolytic effect of HLE and epidermal hyperproliferation, we examined the effects of HLE-induced signaling in human keratinocytes. Application of 100 nM HLE resulted in a transient calcium influx in FURA2-loaded human HaCaT keratinocytes observed by single-cell fluorescence imaging. The calcium signal was concentration dependent and was inhibited by addition of the HLE inhibitors elafin and secretory leukocyte protease inhibitor. The calcium signal was neither inhibited by pertussis toxin, cholera, or by pre-stimulation with trypsin. Incubation with the tyrosine kinase inhibitor genistein, a protein kinase C inhibitor, as well as incubation with neutralizing EGFR antibodies abolished the HLE-induced calcium influx. The supernatants of HLE-treated keratinocytes induced a calcium signal in separately cultured keratinocytes. This could be inhibited by the addition of anti-TGF-alpha antibodies. Application of HLE-induced keratinocyte proliferation, which could be inhibited by neutralizing of anti-EGFR and anti-TGF-alpha antibodies. Herein we demonstrate that HLE induces keratinocyte proliferation by proteolytic activation of an EGFR signaling cascade involving TGF-alpha.
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PMID:Human leukocyte elastase induces keratinocyte proliferation by epidermal growth factor receptor activation. 1524 34

Tissue morphogenesis during development is regulated by growth factors and cytokines, and is characterized by constant remodeling of extracellular matrix (ECM) in response to signaling molecules, for example, growth factors, cytokines, and so forth. Proteoglycans that bind growth factors are potential regulators of tissue morphogenesis during embryonic development. In this study, we showed that transgenic mice overexpressing biglycan under the keratocan promoter exhibited exposure keratitis and premature eye opening from noninfectious eyelid ulceration due to perturbation of eyelid muscle formation and the failure of meibomian gland formation. In addition, in vitro analysis revealed that biglycan binds to TGF-alpha, thus interrupting EGFR signaling pathways essential for mesenchymal cell migration induced by eyelid epithelium. The defects of TGF-alpha signaling by excess biglycan were further augmented by the interruption of the autocrine or paracrine loop of the EGFR signaling pathway of HB-EGF expression elicited by TGF-alpha. These results are consistent with the notion that under physiological conditions, biglycan secreted by mesenchymal cells serves as a regulatory molecule for the formation of a TGF-alpha gradient serving as a morphogen of eyelid morphogenesis.
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PMID:Excess biglycan causes eyelid malformation by perturbing muscle development and TGF-alpha signaling. 1557 51

Stromal fibroblasts regulate epithelial cell behavior through direct and indirect cell-cell interactions. To clarify the role of TGF-beta signaling in stromal fibroblasts during mammary development and tumorigenesis, we conditionally knocked out the TGF-beta type II receptor gene in mouse mammary fibroblasts (Tgfbr2(fspKO)). Tgfbr2(fspKO) mice exhibit defective mammary ductal development, characterized in part by increased ductal epithelial cell turnover associated with an increase in stromal fibroblast abundance. Tgfbr2(fspKO) mammary fibroblasts transplanted with mammary carcinoma cells promote growth and invasion, which is associated with increased activating phosphorylation of the receptors: erbB1, erbB2, RON, and c-Met. Furthermore, the increased receptor phosphorylation correlates with increased secretion of the cognate ligands by Tgfbr2(fspKO) fibroblasts. Treatment of tumor cells with fibroblast-conditioned medium leads to increased tumor cell proliferation and motility, which are blocked by addition of pharmacologic inhibitors of TGF-alpha signaling or neutralizing antibodies to macrophage-stimulating protein (MSP), HGF, or c-Met. These studies characterize a significant role for stromal TGF-beta signaling in mammary tissue homeostasis and mammary tumor progression via regulation of TGF-alpha, MSP, and HGF signaling pathways.
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PMID:Loss of TGF-beta type II receptor in fibroblasts promotes mammary carcinoma growth and invasion through upregulation of TGF-alpha-, MSP- and HGF-mediated signaling networks. 1585 15

Regeneration of the urothelium is rapid and effective in order to maintain a barrier to urine following tissue injury. Whereas normal human urothelial (NHU) cells are mitotically quiescent and G0 arrested in situ, they rapidly enter the cell cycle upon seeding in primary culture and show reversible growth arrest at confluency. We have used this as a model to investigate the role of EGF receptor signaling in urothelial regeneration and wound-healing. Transcripts for HER-1, HER-2, and HER-3 were expressed by quiescent human urothelium in situ. Expression of HER-1 was upregulated in proliferating cultures, whereas HER-2 and HER-3 were more associated with a growth-arrested phenotype. NHU cells could be propagated in the absence of exogenous EGF, but autocrine signaling through HER-1 via the MAPK and PI3-kinase pathways was essential for proliferation and migration during urothelial wound repair. HB-EGF was expressed by urothelium in situ and HB-EGF, epiregulin, TGF-alpha, and amphiregulin were expressed by proliferating NHU cells. Urothelial wound repair in vitro was attenuated by neutralizing antibodies against HER-1 ligands, particularly amphiregulin. By contrast, the same ligands applied exogenously promoted migration, but inhibited proliferation, implying that HER-1 ligands provoke differential effects in NHU cells depending upon whether they are presented as soluble or juxtacrine ligands. We conclude that proliferation and migration during wound healing in NHU cells are mediated through an EGFR autocrine signalling loop and our results implicate amphiregulin as a key mediator.
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PMID:Autocrine regulation of human urothelial cell proliferation and migration during regenerative responses in vitro. 1587 46

Inactivating mutations in the von Hippel-Lindau (VHL) tumor suppressor gene are associated with clear cell renal cell carcinoma (VHL-/- RCC), the most frequent malignancy of the human kidney. The VHL protein targets the alpha subunits of hypoxia-inducible factor (HIF) transcription factor for ubiquitination and degradation. VHL-/- RCC cells fail to degrade HIF resulting in the constitutive activation of its target genes, a process that is required for tumorigenesis. We recently reported that HIF activates the transforming growth factor-alpha/epidermal growth factor receptor (TGF-alpha/EGFR) pathway in VHL-defective RCC cells. Here, we show that short hairpin RNA (shRNA)-mediated inhibition of EGFR is sufficient to abolish HIF-dependent tumorigenesis in multiple VHL-/- RCC cell lines. The 2alpha form of HIF (HIF-2alpha), but not HIF-1alpha, drives in vitro and in vivo tumorigenesis of VHL-/- RCC cells by specifically activating the TGF-alpha/EGFR pathway. Transient incubation of VHL-/- RCC cell lines with small interfering RNA directed against EGFR prevents autonomous growth in two-dimensional culture as well as the ability of these cells to form dense spheroids in a three-dimensional in vitro tumor assay. Stable expression of shRNA against EGFR does not alter characteristics associated with VHL loss including constitutive production of HIF targets and defects in fibronectin deposition. In spite of this, silencing of EGFR efficiently abolishes in vivo tumor growth of VHL loss RCC cells. These data identify EGFR as a critical determinant of HIF-2alpha-dependent tumorigenesis and show at the molecular level that EGFR remains a credible target for therapeutic strategies against VHL-/- renal carcinoma.
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PMID:Silencing of epidermal growth factor receptor suppresses hypoxia-inducible factor-2-driven VHL-/- renal cancer. 1595 67

Gastric cancers with liver metastasis are fatal diseases with rapid progression and poor patient outcome. To date, however, the molecular basis of their growth and metastasis remains essentially unknown, largely because of the presence of few available gastric cancer cell lines established from liver metastasis. In the present study, we developed two novel cultured cell lines (designated GLM-1 and GLM-2) and one transplantable line in nude mice (designated GLM-3) derived from liver metastasis of gastric cancer patients. These GLM cell lines share unique biological features such as differentiation, growth and metastasis. They form moderately differentiated tumors with CD10 positive and MUC2 negative intestinal absorptive phenotype when injected into nude mice. Their growth is stimulated by EGF and TGF-alpha in vitro like other gastric cancer cell lines. However, GLM cells differ from conventional gastric cancer cell lines in their high apoptotic rate, even in the absence of apoptosis inducing stimuli as revealed by Caspase3/7 assay and the TUNEL method. This apoptosis is further enhanced by phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), but not by MEK1/2 inhibitor (U0126), indicating the strong dependency of their survival on PI3K/Akt pathway rather than MAPK pathway, the major downstream signaling pathways of EGFR. GLM-1 cells can metastasize to the liver after intrasplenic injection, and GLM-3 cells have spontaneous lung metastatic potential after subcutaneous transplantation, respectively. These results indicate that the GLM series are the first cell lines reflecting the intestinal-type differentiated adenocarcinoma, a major subtype of gastric cancer with liver metastasis. Therefore, they would be excellent models for understanding the mechanism of metastatic growth and the development of a new molecular targeting therapy for gastric cancer with liver metastasis.
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PMID:Establishment and characterization of three novel human gastric cancer cell lines with differentiated intestinal phenotype derived from liver metastasis. 1608 34

It was reported that the parathyroid gland hyperplasia correlated with enhanced co-expression of TGF-alpha and its receptor EGFR at early stages of renal failure. This time, we investigated the time course for EGFR and its ligands, TGF-alpha, and EFG expression, and the influence of high-phosphorus (P) diet to EGFR and EGF expression, and the effect of EGFR-tyrosine kinase inhibitor (Gefitinib, [IRESSA; AstraZeneca]; TKI) in rat PTGs with established stage of renal failure. The levels of EGFR, EGF, TGF-alpha mRNA in rat PTGs were increased for the time periods. The serum intact PTH levels, and EGFR, EGFmRNA in rat PTGs were suppressed in normal-P diet group. Nuclei positive cells for PCNA in TKI group were suppressed. The levels of p21mRNA were increased in TKI group. These results suggested that the enhanced expression of EGFR, TGF-alpha and EGF participate in the cell proliferation of hyperplastic PTGs in established stage of renal failure.
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PMID:[Enhanced expression of EGFR, TGF-alpha, EGF in hyperplastic parathyroid glands in established stage of renal failure in rats]. 1641 40

The conventional form of renal cell carcinoma (RCC) is a highly vascular tumour with an extremely poor prognosis in the presence of metastases. Significant progress has recently been made in the understanding of the molecular mechanisms leading to the vascular phenotype of renal cancer In particular, VHL disease constitutes a useful study model, as inactivation of the VHL gene leads to accumulation of HIF factor, inducing activation of genes such as: VEGF, PDGF, EPO, CaIX and TGF-alpha. The fact that VHL inactivation has been found in about 70% of sporadic renal cancers constitutes the best rationale to target the products of these genes. Candidate drugs currently target VEGF, VEGFR, PDGFR and tyrosine kinase receptors, which are necessary for intracellular signal transduction. The preliminary results of phase II trials in metastatic renal cancer, usually as second-line therapy, are very encouraging. The results of phase III trials will soon be available, but many studies are already evaluating these drugs either as first-line or in combination. Urologists have an opportunity to become familiar with these drugs by actively participating in trials of adjuvant therapy that will be initiated in the near future.
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PMID:[Molecular pathways of tumour angiogenesis and new targeted therapeutic approaches in renal cancer]. 1673 53

Neutrophil elastase (NE) plays an important role in emphysema, a pulmonary disease associated with excessive elastolysis and ineffective repair of interstitial elastin. Besides its direct elastolytic activity, NE releases soluble epidermal growth factor receptor (EGFR) ligands and initiates EGFR/MEK/ERK signaling to downregulate tropoelastin mRNA in neonatal rat lung fibroblasts (DiCamillo SJ, Carreras I, Panchenko MV, Stone PJ, Nugent MA, Foster JA, and Panchenko MP. J Biol Chem 277: 18938-18946, 2002). We now report that NE downregulates tropoelastin mRNA in the rat fetal lung fibroblast line RFL-6. The tropoelastin mRNA downregulation is preceded by release of EGF-like and TGF-alpha-like polypeptides and requires EGFR/MEK/ERK signaling, because it is prevented by the EGFR inhibitor AG1478 and the MEK/ERK uncoupler U0126. Tropoelastin expression in RFL-6 fibroblasts is governed by autocrine TGF-beta signaling, because TGF-beta type I receptor kinase inhibitor or TGF-beta neutralizing antibody dramatically decreases tropoelastin mRNA and protein levels. Half-life of tropoelastin mRNA in RFL-6 cells is >24 h, but it is decreased to approximately 8 h by addition of TGF-beta neutralizing antibody, EGF, TGF-alpha, or NE. Tropoelastin mRNA destabilization by NE, EGF, or TGF-alpha is abolished by AG1478 or U0126. EGF-dependent tropoelastin mRNA downregulation is reversed upon ligand withdrawal, whereas chronic EGF treatment leads to persistent downregulation of tropoelastin mRNA and protein levels and decreases insoluble elastin deposition. We conclude that NE-initiated EGFR/MEK/ERK signaling cascade overrides the autocrine TGF-beta signaling on tropoelastin mRNA stability and, therefore, decreases the elastogenic response in RFL-6 fibroblasts. We hypothesize that persistent EGFR/MEK/ERK signaling could impede the TGF-beta-induced elastogenesis/elastin repair in the chronically inflamed, elastase/anti-elastase imbalanced lung in emphysema.
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PMID:Neutrophil elastase-initiated EGFR/MEK/ERK signaling counteracts stabilizing effect of autocrine TGF-beta on tropoelastin mRNA in lung fibroblasts. 1647 61

Activation of the epidermal growth factor receptor (EGFR) and/or its family member(s) stimulates many processes of carcinogenesis, including cell invasion and the formation of new blood vessels, events that are critically involved in angiogenesis. Interference with the activation of EGFRs, therefore, represents a promising strategy for the development of novel and selective anticancer therapies. Previously, we reported that EGFR-related protein (ERRP), which we have isolated and characterized as a pan-erbB inhibitor, is a potential therapeutic agent for colorectal and other epithelial cancers. The present investigation was undertaken to determine whether ERRP would affect the invasion of colon cancer cells and formation of tubules, and the regulation of these processes. ERRP inhibited tubule formation by aortic endothelial cells and invasion of HCT-116 colon cancer cells through matrigel. These changes were associated with marked reductions in the synthesis and secretion of bFGF, VEGF and TGF-alpha by HCT-116 cells. Secretion of bFGF and VEGF by aortic endothelial cells was also inhibited by ERRP. Microarray analysis of ERRP-treated HCT-116 cells showed reduced levels of several growth regulatory proteins such as p21Rac1, Stratifin (14-3-3 Sigma), focal adhesion kinase (FAK) and mediators of the Ras-Raf-ERK pathway. ERRP treatments resulted in reduced expression of p21Rac1 and inhibited the constitutive activation of FAK and MEK2 in HCT-116 cells. Transfection of constitutively activate p21Rac1 or MEK2 into HCT-116 cells abrogated ERRP-induced inhibition of growth. In summary, it was demonstrated that ERRP not only inhibits cell growth, but also the processes of cell invasion and blood vessel formation that are critical for the development and progression of carcinogenesis.
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PMID:EGF receptor-related protein (ERRP) inhibits invasion of colon cancer cells and tubule formation by endothelial cells in vitro. 1661 3


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