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

---

Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD38, a surface glycoprotein of unrestricted lineage, is an ectoenzyme (adenosine diphosphate [ADP] ribosyl cyclase/cyclic ADP-ribose hydrolase) that regulates cytoplasmic calcium. The molecule also performs as a receptor, modulating cell-cell interactions and delivering transmembrane signals, despite showing a structural ineptitude to the scope. CD38 ligation by agonistic monoclonal antibodies induced signals leading to activation of the lytic machinery of natural killer (NK) cells from adults; similar signals could not be reproduced in YT and NKL, 2 CD16(-) human NK-like lines. It was hypothesized that CD38 establishes a functional cooperation with professional signaling molecules of the NK cell surface. The present work answers the question about the molecule exploited by CD38 for signaling in NK cells, using as a model CD16(-) NK lines genetically corrected for CD16 expression. Our results indicate that a functional CD16 molecule is a necessary and sufficient requisite for CD38 to control an activation pathway, which includes calcium fluxes, tyrosine phosphorylation of ZAP70 and mitogen-activated protein kinase, secretion of interferon-gamma, and cytotoxic responses. Fluorescence resonance energy transfer and cocapping experiments also showed a surface proximity between CD38 and CD16. These results were confirmed by using the NKL cell line, in which CD16(+) and CD16(-) variants were obtained without genetic manipulation. Together, our findings show CD38 to be a unique receptor molecule that cannot signal by itself but whose receptor function is rescued by functional and physical associations with a professional signaling structure that varies according to lineage and environment. This molecule is CD16 in NK cells.
...
PMID:Human CD38 and CD16 are functionally dependent and physically associated in natural killer cells. 1189 84

The gonadotropic hormones, FSH and LH exert a major effect on ovarian and testicular function through interaction with specific seven-transmembrane domain glycoprotein receptors. Desensitization to the hormones, which can occur both in vivo and in vitro, is essential for prevention of overstimulation of the gonadal cells. The long-term process of desensitization to the gonadotropic hormones is probably mediated, in part, by extensive clustering and internalization of the hormone-receptor complex. Short-term desensitization may occur as a result of phosphorylation of serine or threonine residues on the receptor molecules, although a specific receptor kinase has not yet been identified. Recently, we have discovered a novel mechanism of gonadotropin desensitization, which is exerted by down-regulation of StAR expression and steroidogenesis mediated by MAPK activation as a result of hormone-receptor interaction, cAMP accumulation and PKA activation. Thus, PKA not only mediates gonadotropin-induced steroidogenesis, it also activates the down-regulation mechanism that can silence steroidogenesis under certain conditions. Moreover, our findings raise the possibility that activation or inhibition of ERK by other pathways could be an important mechanism for diminution or amplification of gonadotropin-stimulated steroidogenesis. This could contribute to functional luteolysis, a process in which luteinized granulosa cells show reduced sensitivity to LH despite maintenance of LH receptors, or to up-regulation of the steroidogenic machinery during luteinization of granulosa cells.
...
PMID:Mechanisms of gonadotropin desensitization. 1198 13

Human cartilage glycoprotein 39 (HC-gp39) is a glycoprotein secreted by articular chondrocytes, synoviocytes and macrophages. Increased levels of HC-gp39 have been demonstrated in synovial fluids of patients with rheumatoid or osteoarthritis. The increased secretion of HC-gp39 under physiological and pathological conditions with elevated connective-tissue turnover suggests its involvement in the homoeostasis of these tissues. We report here that HC-gp39 promotes the growth of human synovial cells as well as skin and fetal lung fibroblasts. A dose-dependent growth stimulation was observed when each of the fibroblastic cell lines was exposed to HC-gp39 in a concentration range from 0.1 to 2 nM, which is similar to the effective dose of the well-characterized mitogen, insulin-like growth factor-1. At suboptimal concentrations, the two growth factors work in a synergistic fashion. The use of selective inhibitors of the mitogen-activated protein kinase and the protein kinase B (AKT) signalling pathways indicates that both are involved in mediating the mitogenic response to HC-gp39. Phosphorylation of both extracellular signal-regulated kinases 1/2 and AKT occurred in a dose- and time-dependent fashion upon addition of HC-gp39. Activation of these signalling pathways could also be demonstrated in human chondrocytes. Thus HC-gp39 initiates a signalling cascade in connective-tissue cells which leads to increased cell proliferation, suggesting that this protein could play a major role in the pathological conditions leading to tissue fibrosis.
...
PMID:The chitinase 3-like protein human cartilage glycoprotein 39 (HC-gp39) stimulates proliferation of human connective-tissue cells and activates both extracellular signal-regulated kinase- and protein kinase B-mediated signalling pathways. 1207 45

A growing body of evidence suggests that muscle cell caveolae may function as specialized membrane micro-domains in which the dystrophin-glycoprotein complex and cellular signaling molecules reside. Caveolin-3 (Cav-3) is the only caveolin family member expressed in striated muscle cell types (cardiac and skeletal). Interestingly, skeletal muscle fibers from Cav-3 (-/-) knock-out mice show a number of myopathic changes, consistent with a mild-to-moderate muscular dystrophy phenotype. However, it remains unknown whether a loss of Cav-3 affects the phenotypic behavior cardiac myocytes in vivo. Here, we present a detailed characterization of the hearts of Cav-3 knock-out mice. We show that these mice develop a progressive cardiomyopathic phenotype. At four months of age, Cav-3 knock-out hearts display significant hypertrophy, dilation, and reduced fractional shortening, as revealed by gated cardiac MRI and transthoracic echocardiography. Histological analysis reveals marked cardiac myocyte hypertrophy, with accompanying cellular infiltrates and progressive interstitial/peri-vascular fibrosis. Interestingly, loss of Cav-3 expression in the heart does not change the expression or the membrane association of the dystrophin-glycoprotein (DG) complex. However, a marker of the DG complex, alpha-sarcoglycan, was specifically excluded from lipid raft domains in the absence of Cav-3. Because activation of the Ras-p42/44 MAPK pathway in cardiac myocytes can drive cardiac hypertrophy, we next assessed the activation state of this pathway using a phospho-specific antibody probe. We show that p42/44 MAPK (ERK1/2) is hyperactivated in hearts derived from Cav-3 knock-out mice. These results are consistent with previous in vitro data demonstrating that caveolins may function as negative regulators of the p42/44 MAPK cascade. Taken together, our data argue that loss of Cav-3 expression is sufficient to induce a molecular program leading to cardiac myocyte hypertrophy and cardiomyopathy.
...
PMID:Caveolin-3 knock-out mice develop a progressive cardiomyopathy and show hyperactivation of the p42/44 MAPK cascade. 1213 67

Despite sharing more than 91% sequence identity, the tomato Cf-4 and Cf-9 proteins discriminate between two Cladosporium-encoded avirulence determinants, Avr4 and Avr9. Comparative studies between Cf-4 and Cf-9 are thus of particular interest. To investigate Cf-4 protein function in initiating defence signalling, we established transgenic tobacco lines and derived cell suspension cultures expressing c-myc-tagged Cf-4. Cf-4:myc encodes a membrane-localized glycoprotein of approximately 145 kDa, which confers recognition of Avr4. Elicitation of Cf-4:myc and Cf-9:myc tobacco cell cultures with Avr4 and Avr9, respectively, triggered the synthesis of active oxygen species and MAP kinase activation. Additionally, an Agrobacterium-mediated transient assay was used to express Cf-4:myc and a newly engineered fusion protein Cf-4:TAP. Both transiently expressed proteins were found to be functional in an in vivo assay, conferring a hypersensitive response (HR) to Avr4. Consistent with previous observations that Cf-9 is present in a protein complex, gel filtration analysis of microsomal fractions solubilized with octylglucoside revealed that epitope-tagged Cf-4 proteins migrated at a molecular mass of 350-475 kDa. Using blue native gel electrophoresis, the molecular size was confirmed to be approximately 400 kDa. Significantly, this complex appeared to contain only one Cf-4 molecule, supporting the idea that, as previously described for Cf-9, additional glycoprotein partners participate with Cf-4 in the perception of the Avr4 protein. Intriguingly, Cf proteins and Clavata2 (CLV2) of Arabidopsis are highly similar in structure, and the molecular mass of Cf-4 and CLV complexes is also very similar (400 and 450 kDa, respectively). However, extensive characterization of the Cf-4 complex revealed essentially identical characteristics to the Cf-9 complex and significant differences from the CLV2 complex.
...
PMID:An approximately 400 kDa membrane-associated complex that contains one molecule of the resistance protein Cf-4. 2859 25

IGF-IR (Insulin-like growth factor receptor 1) is a tetrameric glycoprotein composed of two alpha and two beta subunits. The alpha subunit localizes extra-cellularly for ligand binding, whereas the beta subunit consists of transmembrane chains and a cytoplasmic tyrosine kinase domain for enzymatic activity. IGF-IR ligands, IGF-I and IGF-II, are mitogens and survival factors for many cancer cells. Binding of ligands to the IGF-IR initiates a cascade of events leading to activation of signal transduction pathways, mainly MAPK and PI-3K pathways, to stimulate proliferation/mitogenesis, to induce neoplastic transformation, to inhibit apoptosis, and to promote angiogenesis and metastasis. It has been shown that the presence of IGF-IR was required for transformation induced by many oncogenes and over-expression or constitutive activation of IGF-IR gave rise to transformed phenotypes. Significantly, over-expression of IGF-IR was observed in multiple human cancers including carcinomas of breast, lung, colon, and prostate. Patients with IGF-IR positive cancers had a worse prognosis in some cases. Furthermore, down-regulation or functional inactivation of IGF-IR sensitized tumor cells to apoptosis and reversed tumor cell phenotype. Thus, IGF-IR appears to be a promising cancer target. Indeed, a variety of approaches aimed at targeting IGF-IR have been utilized to prove the concept, or are being developed for potential anticancer therapies. These include targeting functional IGF-IR on cell surface, targeting ligand/receptor interaction, targeting receptor expression and functions, and targeting receptor kinase activity. Cancer patients could eventually benefit from the development of these specific IGF-IR antagonists.
...
PMID:Insulin-like growth factor receptor-1 as an anti-cancer target: blocking transformation and inducing apoptosis. 1218 7

Transcriptional activation of the human glycoprotein hormone alpha-subunit (alphaGSU) promoter in response to GnRH and phorbol-12-myristate-13-acetate (PMA) has been well characterized in alphaT3-1 gonadotropes but not investigated in the more differentiated LbetaT2 clonal gonadotrope. We have evaluated alphaGSU transcription in the more mature LbetaT2 cell line, using deletion and heterologous constructs of the alphaGSU promoter linked to a luciferase reporter gene. Basal alphaGSU-promoter activity was significantly less in LbetaT2 cells than in alphaT3-1 cells, but stimulation of transfected cells with GnRH and PMA resulted in similar increases in alphaGSU-promoter activity. Deletional analysis of the human alphaGSU promoter in LbetaT2 cells indicated that sequences between -398 and -244 and between -244 and -195 base pairs (bp) were involved in regulating basal alphaGSU-promoter transcription, whereas the region between -244 and -195 bp regulated PMA-stimulated promoter activity. Deletion of this promoter region containing a steroidogenic factor-1 (SF-1) binding site abolished basal and PMA-stimulated transcription. Site-directed mutagenesis of the SF-1 binding site resulted in a significant attenuation of basal and PMA-stimulated alphaGSU transcription. Pretreatment of LbetaT2 cells with a mitogen-activated protein kinase kinase-specific inhibitor, U0126, abolished the PMA-stimulated increase in MAPK activity and significantly reduced basal and PMA-stimulated promoter activity. Electrophoretic mobility shift assays for SF-1 and GATA revealed that PMA failed to affect SF-1 binding but enhanced GATA binding to a consensus GATA oligonucleotide, an effect that was blocked with U0126 pretreatment, suggesting that GATA may mediate ERK activation of alphaGSU transcription. Our data suggests that, in the mature LbetaT2 gonadotrope cell line, two regions of the human alphaGSU promoter regulate basal transcription and that SF-1 is involved in mediating basal and PMA-stimulated promoter activity. Furthermore, PKC-stimulated transcription partially relies on ERK acting on elements downstream of -244 bp of the human alphaGSU promoter.
...
PMID:Regulation of human glycoprotein hormone alpha-subunit gene transcription in LbetaT2 gonadotropes by protein kinase C and extracellular signal-regulated kinase 1/2. 1219 78

Equids and primates are the only species known to express the placental hormone chorionic gonadotropin (CG). CG is a member of the heterodimeric glycoprotein family and is composed of an alpha subunit linked to a hormone-specific beta subunit. Previously, we have reported that epidermal growth factor (EGF) regulates the equine glycoprotein hormone alpha subunit promoter through a protein kinase C (PKC)/mitogen-activated protein kinase (MAPK) signal transduction pathway in trophoblasts. The current study investigates the regulatory element/factors involved in the induction of equine glycoprotein alpha subunit gene expression by EGF. Using 5' deletion mutagenesis, we have delineated the primary EGF/PKC responsive region of the equine alpha subunit gene to be located between -2039 to -2032 base pairs upstream of the transcriptional start site. The sequence within this region contains an activator protein 1 (AP-1)-like response element (TGAATCA) and is similar to a consensus AP-1 (TGAC/GTCA) response element. This element appeared to preferentially interact with a c-fos/JunD heterodimer. Stimulation by EGF induced the binding of c-fos and JunD to this element and subsequently elevated promoter activity. In conclusion, an EGF/PKC/MAPK signal transduction pathway regulates equine glycoprotein alpha subunit gene expression through a distinct regulatory element(s) that lies between -2039 to -2032 of the equine glycoprotein alpha subunit promoter in trophoblasts and involves an AP-1 complex.
...
PMID:An activator protein-1 complex mediates epidermal growth factor regulation of equine glycoprotein alpha subunit expression in trophoblast cells. 1219 10

Overexpression of gp120, the major coat protein of the HIV-1 virus, in central glial cells, or treatment of neurons with gp120 in culture, produces apoptotic neuronal death. Here we demonstrate that CEP-1347 (KT7515), an inhibitor of mixed lineage kinase 3 (MLK3), an upstream activator of JNK, inhibits gp120IIIB-induced apoptosis of hippocampal neurons. Furthermore, expression of wild type MLK3 in hippocampal pyramidal neurons enhanced gp120IIIB-induced neurotoxicity, whereas expression of a dominant negative MLK3 protected neurons from the toxic effects of the glycoprotein. These results indicate a role for MLK3 signaling in gp120IIIB-induced neuronal death, and suggest potential clinical utility of CEP-1347 in inhibiting the progression of AIDS dementia.
...
PMID:Mixed lineage kinase 3 mediates gp120IIIB-induced neurotoxicity. 1235 90

The hepatic drug-metabolizing cytochrome P-450 (CYP) enzymes are down-regulated during inflammation. In vitro studies with hepatocytes have shown that the cytokines released during inflammatory responses are largely responsible for this CYP repression. However, the signaling pathways and the cytokine-activated factors involved remain to be properly identified. Our research has focused on the negative regulation of CYP3A4 (the major drug-metabolizing human CYP) by interleukin 6 (IL-6) (the principal regulator of the hepatic acute-phase response). CYP3A4 down-regulation by IL-6 requires activation of the glycoprotein receptor gp130; however, it does not proceed through the JAK/STAT pathway, as demonstrated by the overexpression of a dominant-negative STAT3 factor by means of an adenoviral vector. The involvement of IL-6-activated kinases such as extracellular signal-regulated kinase ERK1/2 or p38 is also unlikely, as evidenced by the use of specific chemical inhibitors. It is noteworthy that IL-6 caused a moderated induction in the mRNA of the transcription factor C/EBPbeta (CCAAT-enhancer binding protein beta) and a marked increase in the translation of C/EBPbeta-LIP, a 20-kDa C/EBPbeta isoform lacking a transactivation domain. Adenovirus-mediated expression of C/EBPbeta-LIP caused a dose-dependent repression of CYP3A4 mRNA, whereas overexpression C/EBPalpha and C/EBPb-LAP (35 kDa) caused a significant induction. Our results support the idea that IL-6 down-regulates CYP3A4 through translational induction of C/EBPbeta-LIP, which competes with and antagonizes constitutive C/EBP transactivators. From a clinical point of view, these findings could be relevant in the development of therapeutic cytokines with a less repressive effect on hepatic drug-metabolizing enzymes.
...
PMID:Down-regulation of human CYP3A4 by the inflammatory signal interleukin-6: molecular mechanism and transcription factors involved. 1235 97


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---