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)

Kaposi's sarcoma is a highly vascularized multifocal tumor which frequently appears as a complication of HIV infection. It has been suggested that a disorder in the cytokine network may contribute to the development of the disease. We examined the expression of several cytokines in human sporadic Kaposi's-sarcoma specimens, as well as in spindle cells cultured from human lesions, and consistently found high levels of expression of hepatocyte growth factor (HGF). In addition, human lesion-derived spindle cells synthesize and secrete biologically active hepatocyte growth factor and express the hepatocyte-growth-factor receptor (c-MET). Moreover, elevated levels of transforming growth factor beta 1 (TGF beta 1) mRNA were found in lesions of human sporadic Kaposi's sarcoma and in lesion-derived spindle cells which also over-express urokinase. Since HGF, TGF beta 1 and urokinase are all involved in capillary-vessel organization, dysregulation of these interacting agents may play a role in the initiation and/or progression of Kaposi's sarcoma, stimulating the growth of spindle cells and recruiting endothelial cells into the lesion.
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PMID:Over-expression of hepatocyte growth factor in human Kaposi's sarcoma. 856 12

+/- -Higenamine (demethylcoclaurine), a cardiotonic principle from aconite root, chronotropic and inotropic actions mediated through beta 1-adrenergic receptors. We have investigated the influence of cholera toxin (CTX), a Gs-protein activator, and pertussis toxin (PTX), a Gi-protein inhibitor on the chronotropic interaction between higenamine and a muscarinic agonist, acetylcholine (ACh) in the isolated right atria of mice. CTX (100nm, 1h) pretreatment accentuated the inhibitory responses to cumulative applications of ACh (30nM--30 microns for the positive chronotropic effects induced by higenamine (100nM), isoproterenol (3 and 10 nM) or dobutamine (100nM). In normal atria (CTX-untreated), ACh physiologically antagonized the positive chronotropic effects of these beta-adrenergic agonists. Pretreatment with PTX (150 microgram/kg, i.p., 3d) abolished the CTX (100nm, 1 h)-induced accentuation in the inhibitory effect of ACh against higenamine. PTX pretreatment also attenuated the physiological antagonism by ACh against higenamine in normal atria. The negative chronotropic effect of ACh was not affected by a submaximal concentration of forskolin (1 micron). The These results suggest an accentuated antagonism between higenamine and ACH in CTX-treated, but not in untreated, isolated right atria of mice, which may occur through a functional interaction between the beta1-adrenergic-Gs and muscarinic-Gi systems.
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PMID:Cholera toxin accentuates the antagonism by acetylcholine of higenamine-induced positive chronotropy is isolated right atria of mice. 859 68

Three beta-adrenergic receptor subtypes are now known to be functionally expressed in mammals. All three belong to the R7G family of receptors coupled to G-proteins, and characterized by an extracellular glycosylated N-terminal and an intracellular C-terminal region and seven transmembrane domains, linked by three extra- and three intracellular loops. The catecholamine ligand binding domain, studied using affinity-labeling and site-directed mutagenesis, is a pocket lined by residues belonging to the transmembrane domains. The region responsible for the interaction with the Gs protein which, when activated, stimulates adenylyl cyclase, is composed of residues belonging to the parts most proximal to the membrane of intracellular loop i3 and the C-terminal region. The pharmacology of the three subtypes is quite distinct: in fact most of the potent beta 1/beta 2 antagonists (the well known beta blockers) act as agonists on beta 3. The subtype is resistant to short-term desensitization mediated by phosphorylation through PKA or beta ARK, in stark contrast to the beta 1 or beta 2 subtypes. Various compounds (dexamethasone, butyrate, insulin) upregulate beta 1 or beta 2 subtypes while down-regulating beta 3 whose expression strictly correlates with differentiation of 3T3-F442A fibroblasts into adipocytes, thus confirming that the expression of the three subtypes may each be regulated independently to exert a specific physiologic role in different tissues or at different stages of development.
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PMID:Structure, function, and regulation of the three beta-adrenergic receptors. 869 50

The adhesion of different epidermal growth factor (EGF) receptor (EGFR) expressing cell lines to various extracellular matrix (ECM) proteins is influenced by EGF. To investigate a putative receptor crosstalk between EGFR and integrins we chose two cell lines for a more detailed analysis: the highly metastatic rat mammary carcinoma clone MTLn3 that showed increased adhesion to a panel of ECM proteins in the presence of 10 ng/ml EGF and the nonmetastatic human vulva carcinoma cell line A431 which showed a decreased adhesion under the same conditions. These EGF-mediated stimulatory or inhibitory effects on adhesion were observed within a few minutes. On human A431 cells the inhibitory effect was blocked by an EGFR specific antibody that interferes with ligand binding. In cell adhesion assays performed in the presence of divalent cations MTLn3 and A431 cells exhibited the typical behavior described for integrin-dependent matrix adhesion: Mn2+ enhanced binding to collagen IV and fibronectin whereas Ca2+ inhibited adhesion to collagen IV but not to fibronectin. Adhesion-inhibition assays with anti-human integrin antibodies revealed that A431 cells adhere to collagen via alpha 1 beta 1 and alpha 2 beta 1, and that adhesion to fibronectin is mediated predominantly through alpha 5 beta 1. The interaction of MTLn3 cells with fibronectin was in part RGD dependent, indicating the involvement of either alpha 3 beta 1 or alpha 5 beta 1. Addition of EGF in these assays showed that affecting the integrin extracellular domains by addition of either bivalent cations, RGD peptides, or function-blocking integrin antibodies did not prevent the effects mediated by EGF. We conclude that signals downstream of EGFR can modulate integrin-mediated adhesion to ECM proteins in both an inhibitory and a stimulatory manner.
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PMID:Signaling by epidermal growth factor differentially affects integrin-mediated adhesion of tumor cells to extracellular matrix proteins. 891 81

Integrins can trigger signals by activation of cytoplasmic tyrosine kinases, including pp125FAK. Preliminary evidence suggests that serine/threonine kinases such as ERKs may also be activated via integrins. Thus, there seems to be at least partial overlap between RTK signaling pathways and integrin signaling. In tumor cells, ectopic expression or over-expression of certain integrins such as alpha 5/beta 1 can result in reduced tumorigenesis. Presumably the effects of integrins on tumor growth are mediated by the integrin signaling pathway(s) involving FAK and ERKs. However, the precise mechanisms involved have not yet been elucidated.
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PMID:Integrin signals and tumor growth control. 898 69

The process of corneal wound healing involves the transformation of adjacent corneal keratocytes to myofibroblast-like cells characterized by the development of prominent microfilament bundles containing alpha-smooth muscle-specific actin (alpha-SM), a contractile protein thought to be important in mediating wound contraction. Recent studies have shown that the expression of alpha-SM in cultured corneal keratocytes can be induced by serum and TGF beta 1. To study the cellular and molecular mechanisms underlying this transformation process and to begin to identify the role of alpha-SM in wound contractile events, we generated immortalized rabbit corneal cell strains with extended life by using SV40 transfection. Two unique strains were isolated (TRK-36 and TRK-43). TRK-36, which appears similar to normal corneal keratocytes, maintains a stellate, keratocyte morphology when grown in the absence of serum and transforms to a myofibroblast-like cell when treated with TGF beta 1 (1 ng/ml), as indicated by the induced expression of alpha-SM actin. TRK-43 exhibits features characteristic of myofibroblasts in that it constitutively expresses alpha-SM actin under serum-free conditions. Both strains show in vitro contraction of collagen gels < or = 80% in 24 h in serum-containing medium. Interestingly, under serum-free conditions, TRK-43 cells showed significantly greater contraction of collagen gels compared with those of TRK-36. Overall, the establishment and further study of these cell strains may provide important insights into the molecular mechanisms underlying myofibroblast transformation.
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PMID:Characterization of SV40-transfected cell strains from rabbit keratocytes. 898 37

Kidney transplant rejection is an inflammatory process characterized by lymphocyte infiltration. Our earlier observations have shown that peritubular capillary endothelium (PTCE) is the site of lymphocyte entry into the rejecting renal allograft. During rejection, PTCE begins to express sialyl Lewis x de novo, and binds lymphocytes by a mechanism largely dependent on L-selectin. Hence, inhibiting the lymphocyte-endothelial interaction with oligosaccharide ligands of L-selectin offers an attractive possibility to prevent the inflammation and rejection. Here, we report enzyme-assisted synthesis of N-acetyllactosamine-based tetra-, deca-, and docosameric saccharides carrying one, two or four distally located sialyl Lewis x groups [Neu-NAc alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc] (sLex), respectively. When tested for their ability to inhibit lymphocyte-endothelial interaction during rat kidney transplant rejection, all sLex-saccharides were inhibitors in the Stamper-Woodruff binding assays; the analogues lacking fucose showed no inhibitory potency. The tetravalent sLex glycan proved to be a high-affinity adhesion inhibitor with an IC50 < 50 nM. While less powerful than the tetravalent glycan, also the divalent sLex saccharide was a much better inhibitor than the monovalent glycan. Hence, increasing multivalency and, possibly, increasing chain length of the polylactosamine backbone, enhances the inhibitory potency of sLex bearing glycans in the lymphocyte-endothelial adhesion assay. This suggests that L-selectin behaves as a "functional oligomer" on lymphocyte surfaces.
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PMID:Synthesis of a tetravalent sialyl Lewis x glycan, a high-affinity inhibitor of L-selectin-mediated lymphocyte binding to endothelium. 899 11

Hepatocyte growth factor (HGF)/scatter factor (SF) is the ligand for a tyrosine kinase cell surface receptor encoded by the MET protooncogene (c-MET). HGF/SF can induce proliferation and motility in epithelial cells and promotes invasion of carcinoma cells and NIH3T3 fibroblasts transfected with both HGF/SF and c-MET genes. Our results show that HGF/ SF and c-MET also play a role in adhesion and invasion of human lymphoma cells. c-MET mRNA is expressed in hemopoietic cells, such as hemopoietic progenitor cells (CD34+ cells) in bone marrow (BM) and mobilized peripheral blood, immature B cells in cord blood and BM, and germinal center B-centroblasts. In normal peripheral blood B cells, which are c-MET-, c-MET expression was induced by PMA, ConA, HGF/ SF, and Epstein-Barr virus (EBV) infection. Using immunohistochemistry, we detected c-MET on the cell surface of large activated centroblasts in lymph nodes from patients with B-non-Hodgkin's lymphoma and Hodgkin's disease. In the latter group, c-MET expression correlated well with the presence of EBV. Because HGF/SF and c-MET promote metastasis of carcinoma cells, we studied the effects of c-MET stimulation by HGF/SF of B-lymphoma cells on properties relevant for metastasis, ie, adhesion, migration, and invasion. HGF/SF stimulated adhesion of the c-MET+ B-cell lines to the extracellular matrix molecules fibronectin (FN) and collagen (CN) in a dose dependent manner. However, adhesion to laminin was not affected by HGF/SF. Adhesion to FN was mediated by beta 1-integrins alpha 4 beta 1 (VLA4) and alpha 5 beta 1 (VLA5) since blocking antibodies against beta 1- (CD29), alpha 4-(CD49d), or alpha 5- (CD49e) integrin subunits, completely reversed the effect of HGF/SF. Furthermore, HGF/SF induced adhesion was abrogated by addition of genistein, which blocks protein tyrosine kinases, including c-MET. Addition of HGF/SF resulted in a sixfold increase in migration of c-MET B-lymphoma cells through Matrigel, compared to medium alone. In rat fibroblast cultures, HGF/SF doubled the number of c-MET+ B-lymphoma cells that invaded the fibroblast monolayer. In these adhesion, migration and invasion assays HGF/SF had no effect on c-MET- cell lines. In conclusion, c-MET is expressed or can be induced on immature, activated, and certain malignant B cells. HGF/SF increased adhesion of c-MET+ B-lymphoma cells to FN and CN, mediated via beta 1-integrins alpha 4 beta 1 and alpha 5 beta 1, and furthermore promoted migration and invasion.
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PMID:Hepatocyte growth factor/scatter factor promotes adhesion of lymphoma cells to extracellular matrix molecules via alpha 4 beta 1 and alpha 5 beta 1 integrins. 902 31

Among early-passage, near-diploid gliomas in vitro, transforming growth factor type beta (TGF beta) has been previously shown to be an autocrine growth inhibitor. In contrast, hyperdiploid (> or = 57 chromosomes/metaphase) glioblastoma multiforme (HD-GM) cultures were autocrinely stimulated by the TGF beta. The mechanism of this 'conversion' from autocrine inhibitor to mitogen is not understood; previous studies have suggested that platelet-derived growth factor (PDGF) might be modulated by TGF beta. The similar expression of TGF beta types 1-3, PDGF-AA; -BB, as well as the PDGF receptor alpha and beta subunits (a/beta PDGFR) between biopsies of the HD-GM and near-diploid, TGF beta-inhibited glioblastomas (GM) by immunohistochemistry did not explain the discrepancy in their regulatory responses. Flow cytometry demonstrated that TGF beta's mitogenic effect was selective for the aneuploid subpopulations of two of three selected HD-GM cultures, while the diploid cells were inhibited. Among the HD-GM, TGF beta 1 induced the RNA of PDGF-A, c-sis and TGF beta 1. The amount of PDGF-AA secreted following TGF beta treatment was sufficient to stimulate the proliferation of a HD-GM culture. Antibodies against PDGF-AA, -BB, -AB, alpha PDGFR and/or beta PDGFR subunits effectively neutralized TGF beta's induction of DNA synthesis among the HD-GM cell lines, indicating that PDGF served as the principal mediator of TGF beta's growth stimulatory effect. By comparison, TGF beta induced only the RNA of PDGF-A and TGF beta 1 among the near-diploid GM, c-sis was not expressed at all. However, the amount of PDGF-A which was secreted in response to TGF beta 1 was insufficient to prevent TGF beta's arrest of the near-diploid cultures in G1 phase. Thus, the emergence of hyperdiploidy was associated with qualitative and quantitative differences in TGF beta's modulation of PDGF-A and c-sis, which provided a mechanism by which the aneuploid glioma cells might achieve 'clonal dominance'. We hypothesize that TGF beta may serve as an autocrine promoter of GM progression by providing a selective advantage to the hyperdiploid subpopulation through the loss of a tumor suppressor gene which mediates TGF beta's inhibitory effect.
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PMID:Transforming growth factor beta as a potential tumor progression factor among hyperdiploid glioblastoma cultures: evidence for the role of platelet-derived growth factor. 904 53

Smooth muscle cell (SMC) proliferation is dependent on both anchorage to the extracellular matrix by integrins and the presence of growth factors. Integrins and growth factor receptors transduce signals that seem to converge on the extracellular signal-regulated (ERK) pathway, but the molecular basis for this interaction is not known. SMC proliferation has previously been shown to be supported by culture on fibronectin (FN), whereas cells cultured on laminin (LN) are growth inhibited. In the present study, we examined the mitogenic response to platelet-derived growth factor BB (PDGF-BB) in baboon SMCs cultured on FN vs. LN. Induction of DNA synthesis and the activity of ERK and the ERK activating kinase MKK-1 were reduced only slightly after stimulation with PDGF-BB in cells cultured on LN vs. those cultured on FN. We tested the possibility that endogenous FN secretion contributes to the ability of the cells to respond to PDGF stimulation during culture on LN. Inhibition of interactions between FN and integrin alpha 5 beta 1 by the competitive GRGDSP-peptide or anti-alpha 5 integrin antibody restricted cell spreading, reduced cell-surface staining for alpha 5 beta 1 and FN fibrils, and inhibited PDGF-BB-induced DNA synthesis. These results showed that SMC growth on LN required a provisional FN matrix. Although disruption of interactions between alpha 5 beta 1 and FN by the GRGDSP-peptide prevented PDGF-BB-induced DNA synthesis, neither ERK activity nor translocation of ERKs into the nucleus was inhibited. These results show that integrins regulate SMC growth through pathways that function in parallel with, but distinct from, growth factor-mediated ERK signaling.
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PMID:Disruption of integrin alpha 5 beta 1 signaling does not impair PDGF-BB-mediated stimulation of the extracellular signal-regulated kinase pathway in smooth muscle cells. 920 31


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