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

Wnt proteins are secreted, cysteine-rich glycoprotein ligands with numerous roles during animal development. Recent studies of endoderm induction during embryogenesis in the nematode Caenorhabditis elegans challenge the prevailing view that Wnt signalling specifies cell fate by converting transcriptional repressors into activators. Instead, a mitogen-activated protein kinase (MAPK)-related pathway converges with Wnt signalling in C. elegans to relieve transcriptional repression. Furthermore, Wnt signalling induces endoderm in part by aligning the mitotic spindle in a responding cell along the anterior-posterior body axis. To orient mitotic spindles, Wnt signalling might directly target the cytoskeleton, prior to any regulation of gene transcription in responding cells.
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PMID:Wnt signalling in Caenorhabditis elegans: regulating repressors and polarizing the cytoskeleton. 1060 71

CXCR4 is the Gi protein-linked seven-transmembrane receptor for the alpha chemokine stromal cell-derived factor 1 (SDF-1), a chemoattractant for lymphocytes. This receptor is highly conserved between human and rodent. CXCR4 is also a coreceptor for entry of human immunodeficiency virus (HIV) in T cells and is expressed in the CNS. To investigate how these CXCR4 ligands influence CNS development and/or function, we have examined the expression and signalling of this chemokine receptor in rat neurons and astrocytes in vitro. CXCR4 transcripts and protein are synthesized by both cell types and in E15 brain neuronal progenitors. In these progenitors, SDF-1, but not gp120 (the HIV glycoprotein), induced activation of extracellular signal regulated kinases (ERKs) 1/2 and a dose-dependent chemotactic response. This chemotaxis was inhibited by Pertussis toxin, which uncouples Gi proteins and the bicyclam AMD3100, a highly selective CXCR4 antagonist, as well as by an inhibitor of the MAP kinase pathway. In differentiated neurons, both SDF-1 and the glycoprotein of HIV, gp120, triggered activation of ERKs with similar kinetics. These effects were significantly inhibited by Pertussis toxin and the CXCR4 antagonist. Rat astrocytes also responded to SDF-1 signalling by phosphorylation of ERKs but, in contrast to cortical neurons, no kinase activation was induced by gp120. Thus neurons and astrocytes can respond differently to signalling by SDF-1 and/or gp120. As SDF-1 triggers directed migration of neuronal progenitors, this alpha chemokine may play a role in cortex development. In differentiated neurons, both natural and viral ligands of CXCR4 activate ERKs and may therefore influence neuronal function.
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PMID:Differential signalling of the chemokine receptor CXCR4 by stromal cell-derived factor 1 and the HIV glycoprotein in rat neurons and astrocytes. 1065 66

Mitogen-activated protein (MAP) kinases stimulated by phorbol 13-myristate 12-acetate (PMA) have been shown to inhibit interleukin-6-induced activation of STAT3 (Sengupta, T. K., Talbot, E. S., Scherle, P. A., and Ivashkiv, L. B. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 11107-11112). In the present study we demonstrate that in addition to STAT3, also tyrosine phosphorylation of STAT1, signal transducer gp130, and phosphotyrosine-phosphatase SHP2 underlies negative regulation by MAP kinases. Stimulation of Erks by basic fibroblast growth factor or a constitutively active mutant of Raf also led to down-regulation of STAT activity. Using chimeric receptor mutants we show that tyrosine 759 of glycoprotein 130 is crucial for the inhibitory effect of MAP kinases. Inhibition is also dependent on gene transcription and translation indicating that newly synthesized proteins are involved. Both PMA and basic fibroblast growth factor rapidly stimulate mRNA expression of the suppressor of cytokine signaling-3 (SOCS-3) and this induction is strongly reduced by an inhibitor of MAP kinase activation. Together with recent results demonstrating that SOCS-3 can bind in vitro to a phosphorylated tyrosine 759 peptide of glycoprotein 130 these data suggest SOCS-3 to be instrumental in the inhibition of the Janus kinase/STAT pathway by MAP kinases.
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PMID:The inhibition of interleukin-6-dependent STAT activation by mitogen-activated protein kinases depends on tyrosine 759 in the cytoplasmic tail of glycoprotein 130. 1076 98

The aim of these studies was to elucidate a role for epidermal growth factor (EGF) signaling in the transcriptional regulation of the glycoprotein hormone alpha subunit gene, a subunit of chorionic gonadotropin. Studies examined the effects of EGF and the adenylate cyclase activator forskolin on the expression of a transfected alpha subunit reporter gene in a human choriocarcinoma cell line (JEG3). At maximal doses, administration of EGF resulted in a 50% increase in a subunit reporter activity; forskolin administration induced a fivefold activation; the combined actions of EGF and forskolin resulted in synergistic activation (greater than eightfold) of the alpha subunit reporter. Mutagenesis studies revealed that the cyclic AMP response elements (CRE) were required and sufficient to mediate EGF-forskolin-induced synergistic activation. The combined actions of EGF and forskolin resulted in potentiated activation of extracellular signal-regulated kinase (ERK) enzyme activity compared with EGF alone. Specific blockade of ERK activation was sufficient to block EGF-forskolin-induced synergistic activation of the alpha subunit reporter. Pretreatment of JEG3 cells with a p38 mitogen-activated protein kinase inhibitor did not influence activation of the alpha reporter. However, overexpression of c-Jun N-terminal kinase (JNK)-interacting protein 1 as a dominant interfering molecule abolished the synergistic effects of EGF and forskolin on the alpha subunit reporter. CRE binding studies suggested that the CRE complex consisted of CRE binding protein and EGF-ERK-dependent recruitment of c-Jun-c-Fos (AP-1) to the CRE. A dominant negative form of c-Fos (A-Fos) that specifically disrupts c-Jun-c-Fos DNA binding inhibited synergistic activation of the alpha subunit. Thus, synergistic activation of the alpha subunit gene induced by EGF-forskolin requires the ERK and JNK cascades and the recruitment of AP-1 to the CRE binding complex.
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PMID:Role of the cyclic AMP response element binding complex and activation of mitogen-activated protein kinases in synergistic activation of the glycoprotein hormone alpha subunit gene by epidermal growth factor and forskolin. 1077 23

Follicle-stimulating hormone (FSH) regulated growth and function of the ovarian follicle was previously thought to be mediated solely through activation of G(s)-coupled receptors. In this study, we show for the first time that this function is predominantly mediated through the alternatively spliced and novel growth factor type 1 receptor (oFSH-R3) that is also present in the ovary. Immortalized granulosa cells lacking endogenous FSH receptors, when transfected with either oFSH-R3 cDNA (JC-R3) or the G(s)-coupled oFSH-R1 (JC-R1), expressed the corresponding glycosylated receptor. In JC-R3 or JC-R1 cells labeled with bromodeoxyuridine or [(3)H]thymidine, FSH stimulated the cells to progress through S-phase and divide. The growth promoting effect of recombinant FSH in JC-R3 cells was preceded by the rapid activation of ERK1 and ERK2. This effect was hormone-specific and transient. In JC-R3 cells inhibitors like calphostin C, PD98059, Ag 18, or calcium chelators EGTA or 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/AM inhibited both mitogen-activated protein kinase activation and bromodeoxyuridine incorporation. FSH induced phosphorylation of the FSH-R3 receptor was blocked by pretreating cells with calphostin C. There was no cAMP induction by FSH in JC-R3 cells. The cAMP independent growth promoting effect of FSH is mediated by activation of Ca(2+) and mitogen-activated protein kinase-dependent pathways. Thus, alternative splicing of a G-protein coupled receptor creates the expression of a novel receptor motif that can mediate a widely recognized function of the glycoprotein hormone.
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PMID:Activation of extracellular-regulated kinase pathways in ovarian granulosa cells by the novel growth factor type 1 follicle-stimulating hormone receptor. Role in hormone signaling and cell proliferation. 1086 52

Interleukin 1beta (IL-1beta) is a multifunctional polypeptide considered a key cytokine during inflammation. Fibronectin (FN), a matrix glycoprotein highly expressed in injured tissues, can induce expression of IL-1beta in human blood monocytic cells. Herein, we explore the intracellular signals and transcriptional mechanisms responsible for IL-1beta induction by FN using human promonocytic U937 cells transfected with the human IL-1beta promoter connected to a reporter gene. Exposure of transfected U937s to FN resulted in increased expression of the full-length IL-1beta promoter. This effect, mediated via the alpha5beta1 integrin, was associated with activation of mitogen-activated protein kinases (MAPKs) and was abolished by pre-treatment of cells with Calphostin C, a specific inhibitor of protein kinase C (PKC) activation. Deletion analysis and co-transfection studies using consensus activator protein 1 (AP-1) oligonucleotides suggested that an AP-1 site present in the 5' end of the IL-1beta promoter was involved in the FN-induced response. Finally, electrophoretic mobility shift assays showed that FN induced binding of AP-1, but not NF-kappaB. Together, these experiments demonstrate that FN binding to the alpha5beta1 integrin activates MAPK-dependent signal pathways, and results in the transcription of the IL-1beta promoter in U937 cells by activating PKC and inducing AP-1.
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PMID:Transcriptional regulation of the human interleukin 1beta gene by fibronectin: role of protein kinase C and activator protein 1 (AP-1). 1105 9

PC-cell-derived growth factor (PCDGF) is an 88-kDa glycoprotein corresponding to the granulin precursor. We have reported that PCDGF was expressed in human breast cancer cells. In estrogen-receptor positive cells, 17-beta-estradiol (E(2)) transcriptionally stimulated PCDGF expression in a dose- and time-dependent fashion. We demonstrate here that PCDGF mediates the mitogenic effect of E(2) in MCF-7 cells. PCDGF substituted for E(2) to stimulate DNA synthesis. The E(2) mitogenic effect was inhibited in a dose-dependent fashion by anti-PCDGF neutralizing antibody. Inhibition of PCDGF expression by antisense transfection also inhibited the E(2) mitogenic effect. In contrast, overexpression of PCDGF in MCF-7 cells resulted in cells that were able to proliferate in the absence of estrogen and were tamoxifen resistant. The PCDGF signaling pathway was examined. Like E(2), PCDGF stimulated mitogen-activated protein kinase activity. PCDGF could substitute for E(2) in stimulating cyclin D1 expression. The cyclin D1 stimulation by E(2) was 50% inhibited by anti-PCDGF antibody. In contrast, PCDGF did not stimulate c-myc expression, another molecular target of E(2). We conclude that autocrine PCDGF mediates the E(2) mitogenic effect via stimulation of cyclin D1. These studies provide information on estrogen action and identify an autocrine molecular target in human breast cancer cells.
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PMID:Mediation of estrogen mitogenic effect in human breast cancer MCF-7 cells by PC-cell-derived growth factor (PCDGF/granulin precursor). 1113 21

Focal glomerulosclerosis (FGS) is the predominant glomerular lesion in patients with human immunodeficiency virus (HIV)-associated nephropathy. Initial mesangial cell hyperplasia and subsequent hypoplasia are common features of FGS. In the present study we evaluated the effect of HIV-1 glycoprotein (gp) 120 on human mesangial cell (HMC) growth. HIV-1 gp 120 stimulated HMC proliferation at lower concentrations, whereas it suppressed cell proliferation at higher concentrations. In parallel to the modulation of cell growth, gp 120 at low concentrations resulted in an increase in the expression of c-Myc, Max, and 14-3-3epsilon proteins and phosphorylation of ATP-dependent tyrosine kinases (Akt) at Ser(473). However, the expression of these proteins decreased with increasing concentrations of gp 120. Furthermore, gp 120 also exhibited a dose-dependent inhibition of Akt phosphorylation at Ser-473 without any significant alteration of Akt expression. Little or no effects of gp 120 were observed on the expression of extracellular signal-regulated kinase (ERK), phospho-ERK, Bcl-2, and Bax proteins. At a higher concentration, gp 120 not only promoted HMC apoptosis but also enhanced expression of Fas and FasL. These results suggest that HIV-1 gp 120 induces alterations in conflicting survival signaling pathways that contribute to the potential dual effects of gp 120 in promoting or inhibiting HMC proliferation.
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PMID:Role of 14-3-3epsilon, c-Myc/Max, and Akt phosphorylation in HIV-1 gp 120-induced mesangial cell proliferation. 1120 9

On endothelial cells, thrombin binds to thrombomodulin (TM), an integral membrane-bound glycoprotein, and to protease-activated receptors (PARs). Thrombin binding to TM modulates endothelial cell and smooth muscle cell proliferation mediated through PAR1. We studied the phosphorylation and nuclear translocation of extracellular signal-regulated kinases (ERKs) 1 and 2 in human umbilical vein endothelial cells activated by thrombin. Thrombin and thrombin receptor-activating peptide (TRAP)-induced DNA synthesis were significantly inhibited by PD98059, an inhibitor of ERK phosphorylation. Immunoblots of phosphorylated ERKs (pERKs) and immunocytochemical studies of pERK localization revealed differences in the signal generated by thrombin and TRAP. After a short activation (15 minutes), the phosphorylation and the intracellular localization of pERKs were the same with the 2 agonists. After 4 hours, however, pERKs were visualized in the nuclei of thrombin-activated cells but barely detectable in TRAP-activated cells. Moreover, after 4 hours, the pERKs were visualized in the nuclei of cells stimulated by TRAP in the presence of a thrombin mutant that bound to TM, whereas they were around the nuclei in cells stimulated by thrombin in the presence of a monoclonal antibody preventing thrombin binding to TM. The results demonstrate that ERKs are involved in human umbilical vein endothelial cell DNA synthesis mediated by PAR agonists, that the duration of pERK nuclear retention is in inverse ratio to the mitogenic response, and that in addition to its role in the regulation of blood coagulation, TM acts as a thrombin receptor that modulates the duration of pERK nuclear retention and cell proliferation in response to thrombin.
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PMID:Thrombomodulin prolongs thrombin-induced extracellular signal-regulated kinase phosphorylation and nuclear retention in endothelial cells. 1130 85

Gonadotropin releasing hormone (GnRH), the first key hormone of reproduction, is synthesized and secreted from the hypothalamus in a pulsatile manner and stimulates pituitary gonadotrophs (5-10% of the pituitary cells) to synthesize and release gonadotropin luteinizing hormone (LH) and follicle stimulating hormone (FSH). Gonadotrophs consist of 60% multihormonal cells (LH+FSH) and 18% LH- and 22% FSH-containing cells. LH and FSH, members of the glycoprotein hormone family, stimulate spermatogenesis, folliculogenesis, and ovulation. Although GnRH plays a pivotal role in gonadotropin synthesis and release, other factors such as gonadal steroids and gonadal peptides exert positive and negative feedback mechanisms, which affect GnRH actions. GnRH actions include activation of phosphoinositide turnover as well as phospholipase D and A2, mobilization and influx of Ca2+, activation of protein kinase C (PKC) and mitogen-activated protein kinase (MAPK). A complex crosstalk between the above messenger molecules mediates the diverse actions of GnRH. Understanding the signaling mechanisms involved in GnRH actions is the basis for our understanding of basic reproductive functions in general and gonadotropin synthesis and release in particular.
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PMID:Mechanism of GnRH receptor signaling on gonadotropin release and gene expression in pituitary gonadotrophs. 1135 18


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