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)

Hepatocyte growth factor/scatter factor (HGF/SF) treatment of the Madin-Darby canine kidney epithelial cell line causes scattering of cells grown in monolayer culture and the formation of branching tubules by cells grown in collagen gels. HGF/SF causes prolonged activation of both the mitogen-activated protein (MAP) kinase extracellular signal-regulated kinase 2 (ERK2) and the phosphoinositide 3-OH kinase (PI 3-kinase) target protein kinase B (PKB)/Akt; inhibition of either the MAP kinase pathway by the MAP kinase/ERK kinase inhibitor PD98059 or the PI 3-kinase pathway by LY294002 blocks HGF/SF induction of scattering, although in morphologically distinct ways. Expression of constitutively activated PI 3-kinase, Ras, or R-Ras will cause scattering, but activated Raf will not, indicating that activation of the MAP kinase pathway is not sufficient for this response. Downstream of PI 3-kinase, activated PKB/Akt and Rac are both unable to induce scattering, implicating a novel pathway. Scattering induced by Ras or PI 3-kinase is sensitive to PD98059, as well as to LY294002, suggesting that basal MAP kinase activity is required, but not sufficient, for the scattering response. Induction of MDCK cell tubulogenesis in collagen gels by HGF/SF is inhibited by PD98059; expression of activated Ras and Raf causes disorganized growth in this system, but activated PI 3-kinase or R-Ras causes branching tubule formation similar to that seen with HGF/SF treatment. These data indicate that multiple signaling pathways acting downstream of Met and Ras are needed for these morphological effects; scattering is induced primarily by the PI 3-kinase pathway, which acts through effectors other than PKB/Akt or Rac and requires at least basal MAP kinase function. Elevated PI 3-kinase activity induces tubulogenesis, but total inhibition and excess activation of the MAP kinase pathway both oppose this effect.
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PMID:Phosphoinositide 3-kinase induces scattering and tubulogenesis in epithelial cells through a novel pathway. 966 53

Experimental data suggest that dysregulation of growth factors and the cognate receptors may play an important role in hepatocarcinogenesis. The objective of the present study was to characterize the expression of two hepatotrophic growth factor/receptor systems [transforming growth factor-alpha/epidermal growth factor receptor (TGF-alpha/EGFR) and hepatocyte growth factor/c-met receptor (HGF/c-met)], both of which are implicated in the development of human liver tumors. In addition, we have analyzed the expression of transforming growth factor-beta receptor type II (TGF-beta-RII) and p53, genes associated with growth inhibition and tumor suppression, respectively. Surgical biopsy specimens from 86 human hepatocellular carcinomas were analyzed. TGF-alpha was overexpressed in 17%, equally expressed in 21%, and down-regulated in 62% of the hepatocellular carcinomas when compared to the surrounding hepatic tissue. No major changes were found with EGFR expression. HGF was over-expressed in 33% and down-regulated in 21% of the tumors. The c-met receptor was overexpressed in 20%, equally expressed in 48%, and down-regulated in 32% of the neoplasms. In contrast, TGF-beta-RII was overexpressed in only 8%, equal in 42%, and down-regulated in 50% of tumors. Nuclear staining of p53, indicative of a mutation(s), was observed in the great majority of the tumors (80%), whereas no nuclear p53 was detected in peritumoral tissues. Interestingly, simultaneous down-regulation of c-met and TGF-beta-RII was observed in 23% of the hepatocellular carcinomas, 85% of which also showed nuclear p53 staining. Taken together, our data suggest that down-regulation of c-met and TGF-beta-RII may, together with p53 mutations, play a significant role in human liver carcinogenesis.
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PMID:Analysis of transforming growth factor (TGF)-alpha/epidermal growth factor receptor, hepatocyte growth Factor/c-met,TGF-beta receptor type II, and p53 expression in human hepatocellular carcinomas. 981 84

Pattern formation of the limb muscles involves a network between intrinsic programs of gene expression in myogenic precursor cells and extrinsic signals derived from the surrounding tissue. The cells at the lateral edge of the somite are specified to the precursors of the hypaxial muscles by intercelluler interaction with the dorsal ectoderm and the lateral mesoderm. At the level of the limb bud, these premyogenic cells expressing c-MET and Pax-3 are induced to invade into the limb bud by HGF/SF and unknown chemotactic signal(s) exerted by the limb mesenchyme. It is likely that N-cadherin and some extracellular matrixes are involved in this phenomena. In the limb bud, myogenic cells proliferate under influence of the limb ectoderm and congregate into the premuscle masses. BMPs expressed in limb ectoderm may maintain the proliferative phase of the myogenic cells by inhibition of the myogenic differentiation. Recently, detailed analysis of expression of Hox genes in the chick limb musculature suggests that Hoxa-11 and Hoxa-13 autonomously regulate the pattern formation of the limb muscles. Hoxa-11 is induced in the myogenic cells by an interaction with the limb mesenchyme as soon as they invade into the limb. It is possible that Hoxa-11 may confer a limb-specific property on these myogenic cells. After the formations of muscle masses, Hoxa-11 and Hoxa-13 are expressed in the muscle masses in region-specific manner along the anteroposterior and proximodistal axes under the control of the limb mesenchyme and the polarizing signal(s). They are candidates for intrinsic regulator of myogenic cells that control 1) the splitting processes of the muscle masses and 2) the specification of each muscle.
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PMID:[Molecular mechanism of limb muscle patterning]. 999 Feb 4

The mechanisms governing development of neural crest-derived melanocytes, and how alterations in these pathways lead to hypopigmentation disorders, are not completely understood. Hepatocyte growth factor/scatter factor (HGF/SF) signaling through the tyrosine-kinase receptor, MET, is capable of promoting the proliferation, increasing the motility, and maintaining high tyrosinase activity and melanin synthesis of melanocytes in vitro. In addition, transgenic mice that ubiquitously overexpress HGF/SF demonstrate hyperpigmentation in the skin and leptomenigenes and develop melanomas. To investigate whether HGF/ SF-MET signaling is involved in the development of neural crest-derived melanocytes, transgenic embryos, ubiquitously overexpressing HGF/SF, were analyzed. In HGF/SF transgenic embryos, the distribution of melanoblasts along the characteristic migratory pathway was not affected. However, additional ectopically localized melanoblasts were also observed in the dorsal root ganglia and neural tube, as early as 11.5 days post coitus (p.c.). We utilized an in vitro neural crest culture assay to further explore the role of HGF/SF-MET signaling in neural crest development. HGF/SF added to neural crest cultures increased melanoblast number, permitted differentiation into pigmented melanocytes, promoted melanoblast survival, and could replace mast-cell growth factor/Steel factor (MGF) in explant cultures. To examine whether HGF/SF-MET signaling is required for the proper development of melanocytes, embryos with a targeted Met null mutation (Met-/-) were analysed. In Met-/- embryos, melanoblast number and location were not overtly affected up to 14 days p.c. These results demonstrate that HGF/SF-MET signaling influences, but is not required for, the initial development of neural crest-derived melanocytes in vivo and in vitro.
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PMID:Hepatocyte growth factor/scatter factor-MET signaling in neural crest-derived melanocyte development. 1019 78

HGF/SF is a multifunctional cytokine which through binding to its cellular receptor, c-MET, can elicit mitogenic, morphogenic and motogenic responses in target cells. Expression of HGF/SF and c-MET has been shown to be critical in early embryogenesis affecting development of many organs and tissues. The effects of HGF/SF4 on established human and mouse mammary cell lines have previously been reported. This review describes the source and targets for HGF/SF in both human and mouse mammary tissue and discusses the effects of HGF/SF on primary mouse and human mammary epithelial cells in vitro, detailing the individual response of the two epithelial sub-population of cells which comprise this organ. Additionally, the effects of HGF/SF overexpression on mouse mammary gland development in vivo, are summarized.
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PMID:HGF/SF in mammary epithelial growth and morphogenesis: in vitro and in vivo models. 1021 7

In the present study subcutaneous fibrosarcomas were induced by the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) in rats from F1 generation cross breedings of two different inbred strains. Comparative genomic hybridization (CGH) analysis, which allows detection of DNA sequence copy changes, was applied to one of the tumors and it was found that there were increased copy numbers of sequences at chromosome 4q12-q21 in this tumor. We have previously determined that the loci for the hepatocyte growth factor (Hgf) and hepatocyte growth factor receptor (Hgfr/Met), a protooncogene, are situated in this particular chromosome region. Using probes for the two genes in FISH (fluorescence in situ hybridization) and in Southern blots we found that the Hgfr/Met gene was amplified in five of the 19 sarcomas studied, and that the Hgf gene was coamplified in two of them. Northern and Western blots and tyrosine phosphorylation analysis showed that the HGF receptor was overexpressed and functional in all five tumors, as well as in two additional tumors. In summary, both amplification and overexpression of the Hgfr/Met gene was found in about 25% of DMBA-induced experimental rat sarcomas, and HGF receptor overexpression alone was seen in two additional tumors. Possibly this reflects an involvement in paracrine or autocrine stimulation of growth and invasiveness by HGF. Our finding could provide a rodent model system to increased knowledge about causality and therapy, which may be applicable to the sizeable fraction of human musculoskeletal tumors displaying MET overexpression.
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PMID:Amplification and overexpression of the hepatocyte growth factor receptor (HGFR/MET) in rat DMBA sarcomas. 1035 28

Activation of Met by its ligand HGF has been shown to elicit both mitogenic and motogenic responses in thyrocytes in vitro. In the present study we have investigated the expression of Met in human anaplastic thyroid carcinoma cells in culture. There was a variation in expression level and size of Met in the different cell lines; high Met expression was found in four cell lines, compared to non-neoplastic human thyrocytes. Treatment with glucoproteinase F showed that the size differences observed were due to variances in the degree of glycosylation. Interestingly, in cell lines with high expression of Met, the receptor proteins were found to be constitutively tyrosine phosphorylated. None of these cell lines expressed HGF mRNA, and addition of suramin did not affect the level of tyrosine phosphorylation of Met in unstimulated cells, suggesting the absence of autocrine stimulatory pathways. Furthermore, we did not observe MET gene amplification, activating mutations or phosphatase defects. The tyrosine phosphorylated receptors appeared functionally active since the receptors associated with the adaptor molecule Shc. In summary, we have found ligand-independent constitutively activated Met in four out of six anaplastic thyroid carcinoma cell lines.
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PMID:Non-autocrine, constitutive activation of Met in human anaplastic thyroid carcinoma cells in culture. 1036 Jun 40

Permanent human osteosarcoma cell lines are important tools for the study of bone cancer. As representative of an osteoblastic phenotype, they partly reflect their normal osteoblastic counterparts and, thus, may represent appropriate models to investigate the mechanisms involved in bone remodelling and in haematopoietic differentiation. In the present work, we describe a new human cell line, CAL 72, obtained from an osteosarcoma of the knee of a 10-year-old boy. These cells grow in continuous culture, and karyotypic analysis has revealed clonal abnormalities in number and structure, especially loss of chromosome Y. These cells exhibit morphological, immuno-histochemical and molecular characteristics of the osteoblastic lineage. Using RT-PCR, we have shown that the CAL 72 cell line expresses high levels of mRNA coding for several cytokines, such as G-CSF, GM-CSF, IL-1beta and IL-6. In view of this expression profile, the CAL 72 phenotype appears to be closer to normal primary osteoblasts than other reported osteosarcomas. Moreover, these cells express mRNA for both HGF and its receptor c-MET, suggesting that this autocrine loop might contribute to the invasiveness of the tumour from which CAL 72 originated.
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PMID:Establishment, characterisation and partial cytokine expression profile of a new human osteosarcoma cell line (CAL 72). 1038 64

Various mechanisms of epithelial cell plasticity in morphogenesis have been studied at the genetic and molecular levels. Several control genes have been identified including genes encoding transcription factors and growth factor receptors. These mechanisms may be reactivated during the progression of carcinomas. One of the mechanisms underlying epithelial plasticity is the epithelial-mesenchymal transition. This process has been extensively studied using the NBT-II bladder carcinoma cell line. Cells of this line undergo a reversible transition following exposure to several growth factors including FGF-1, EGF, TGFalpha and SF/HGF, which activate tyrosine kinase surface receptors. Two separate transduction pathways have been identified. The transient activation of c-Src is involved in cytoskeleton remodeling whereas the Ras pathway controls the transcription of genes such as the transcription factor Slug which is involved in the internalization of desmosomes. These two pathways cooperate to induce the morphological transition, scattering and locomotion of fibroblast-like cells. Growth/scatter factor-producing NBT-II cells are more invasive than cells that do not contain this factor, in orthotopic confrontation assay. In vivo, these cells are very tumorigenic and may confer a more malignant phenotype on parental cells via a community effect. The role of several growth factors and their receptors has been investigated in human bladder carcinomas. A subset of these tumors with poor outcomes produce low levels of FGFR2-IIIb. The synthesis of this receptor de novo in bladder cell lines reduces proliferation in vitro and tumor growth in nude mice. FGFR2-IIIb functions as a tumor suppressor, consistent with the differentiation-inducing capacities of FGF receptors in the suprabasal cells of the skin. FGFR2-IIIb signaling may be involved in the maintenance of E-cadherin, the prototype epithelial adhesion molecule, which is only downregulated in a fraction of tumors with low FGFR2-IIIb synthesis. Human bladder tumors may also activate autocrine loops such as that for EGFR and their ligands, as already demonstrated for murine bladder tumors. Therefore, our results suggest that multifunctional growth factors and their receptors are involved in cell proliferation and epithelial cell plasticity, acting either as positive or negative regulators of tumor progression. The effect on the morphological transition is also clearly relevant to the mechanism governing dissemination and the formation of micrometastatic tumor cells. The extrapolation of these discoveries to human carcinomas should provide markers facilitating the more accurate prediction of the biological behavior of a given tumor and identify clinically and pathologically significant parameters. The identification of critical changes in the growth factor pathways involved in tumor progression will not only provide insight into the genetic and molecular basis of this process, but should also identify targets for new therapies.
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PMID:Epithelial cell plasticity in development and tumor progression. 1050 44

Long-term cultures of human hepatocytes were maintained serum-free in a chemically defined medium in the presence of HGF and EGF for up to 30 days. STAT 1alpha/1beta, STAT 3, and STAT 5 were present and tyrosine phosphorylated throughout the culture period in the cytosol as well as the nucleus. We show by co-immunoprecipitation that a portion of the cellular pools of STAT 1alpha/1beta and STAT 5 is physically associated with c-MET and EGF-receptor. Co-immunoprecipitation of STAT 3 with STAT 5 did occur in the cytosol but not in the nucleus, suggesting dimerization of the two STAT family members. The observed differences of protein amounts and tyrosine phosphorylation between cytosol and nucleus, the association of STAT proteins with EGF-receptor and c-MET and with each other may all be involved in regulating the activity of the STAT transcription factors. It is intriguing to speculate that STAT 5 may have a modulating role in the regulation of STAT 3 activity.
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PMID:STAT 1alpha/1beta, STAT 3 and STAT 5: expression and association with c-MET and EGF-receptor in long-term cultures of human hepatocytes. 1055 75


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