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:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Desensitization and internalization of G-protein-coupled receptors can reflect receptor phosphorylation-dependent binding of beta-arrestin, which prevents G-protein activation and targets receptors for internalization via clathrin-coated vesicles. These can be pinched off by a dynamin collar, and proteins controlling receptor internalization can also mediate mitogen-activated protein kinase signaling. Gonadotropin-releasing hormone (GnRH) stimulates internalization of its receptors via clathrin-coated vesicles. Mammalian GnRH receptors (GnRH-Rs) are unique in that they lack C-terminal tails and do not rapidly desensitize, whereas non-mammalian GnRH-R have C-terminal tails and, where investigated, do rapidly desensitize and internalize. Using recombinant adenovirus expressing human and Xenopus GnRH-Rs we have explored the relationship between receptor internalization and mitogen-activated protein kinase signaling in HeLa cells with regulated tetracycline-controlled expression of wild-type or a dominant negative mutant (K44A) of dynamin. These receptors were phospholipase C-coupled and had appropriate ligand affinity and specificity. K44A dynamin expression did not alter human GnRH-R internalization but dramatically reduced internalization of Xenopus GnRH-R (and epidermal growth factor (EGF) receptor). Blockade of clathrin-mediated internalization (sucrose) abolished internalization of all three receptors. Both GnRH-Rs also mediated phosphorylation of ERK 2 and for both receptors, this was inhibited by K44A dynamin. The same was true for EGF- and protein kinase C-mediated ERK 2 phosphorylation. ERK 2 phosphorylation was also inhibited by a protein kinase C inhibitor but not affected by an EGF receptor tyrosine kinase inhibitor. We conclude that a) desensitizing and non-desensitizing GnRH-Rs are targeted for clathrin-coated vesicle-mediated internalization by functionally distinct mechanisms, b) GnRH-R signaling to ERK 2 is dynamin-dependent and c) this does not reflect a dependence on dynamin-dependent GnRH-R internalization.
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PMID:Differential internalization of mammalian and non-mammalian gonadotropin-releasing hormone receptors. Uncoupling of dynamin-dependent internalization from mitogen-activated protein kinase signaling. 1149 5

The hypothalamic gonadotropin-releasing hormone (GnRH) is a key regulator of the reproductive system, triggering the synthesis and release of LH and FSH in the pituitary. GnRH transmits its signal via two specific serpentine receptors that belong to the large group of G-protein coupled receptors (GPCRs). Here we review the intracellular signaling pathways mediated by the GnRH receptor (GnRHR). In pituitary-derived alpha T3-1 cells, a widely used model for GnRH action, GnRHR signaling includes activation of mitogen-activated protein kinase (MAPK) cascades, which provide an important link for the transmission of signals from the cell surface to the nucleus and play a role in the regulation of gonadotropin transcription. Activation of ERK--one of the MAPK cascades--by GnRH in these cells depends mainly on the phosphorylation of Raf1 by PKC, supported by a pathway involving c-Src, dynamin, and Ras. On the other hand, the activation of JNK, another MAPK cascade, involves PKC, c-Src, CDC42/Rac1, and probably MEKK1. The GnRHR is also expressed in non-pituitary cells and was found to be involved in the inhibition of cell proliferation in certain cells. Therefore, GnRHR represents a potential target for GnRH-analogs used for cancer treatment. Interestingly, the signaling mechanism of the GnRHR in other cell types significantly differs from that in pituitary cells. Studies conducted in GnRHR-expressing COS7 cells have shown that GnRHR transmits its signals mainly via Gi, EGF receptor, c-Src, and is not dependent on PKC. Understanding the signaling mechanisms elicited by GnRHR can shed light on the mechanism of action of GnRH in pituitary and extra-pituitary tissues.
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PMID:Intracellular signaling pathways mediated by the gonadotropin-releasing hormone (GnRH) receptor. 1175 Jul 25

Detailed studies have been focused on the mechanisms by which the rat alpha and LHbeta genes are differentially regulated by GnRH and indicate that differential sensitivity to the second messenger exists in a physiological context. Differential signaling from the GnRH receptor may be a mechanism for preferential regulation of luteinizing hormone subunit gene transcription; however which of these genes are specifically regulated by PKC or calcium and how GnRH pulsatility could preferentially activate individual pathways of second messengers within gonadotrope cells remain unclear. Several transcription factors that have profound effects on basal and/or GnRH-stimulated LHbeta gene promoter activity have been identified: SF-1, Egr-1, Sp-1. A model explaining possible interactions among them in mediating GnRH responsiveness of the LHbeta gene has been proposed: Sp1, SF-1 and Egr-1 form a tripartite GnRH response element which is sensitive to the spacing changes between the upstream Sp1 binding sites and the downstream SF-1/Egr-1 binding elements and SF-1 plays a critical role in integrating the effects of Sp1 and Egr-1. GnRH responsive element located on LHbeta gene promoter in position between -495 to -342 has been identified. At 3'-end of the promoter three Sp-1 binding sites have been identified: position -416, sequence: GGGGGCTGGG and two sites almost completely overlapping, position -403, sequence; GGGGCGGCGCCCA while at the 5'region of the promoter one Sp-1 binding site exists: position -450, sequence: ACCACACCCATTTTTGG. The 5'Sp1 site overlaps a CArG box (at -443 to -434, sequence: CCATTTTTGG) which seems to be essential in LHbeta gene sensitivity for pulsatile GnRH stimulation.
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PMID:GnRH pulsality and the differential activation of the rat luteinizing hormone subunit genes in the anterior pituitary gland. 1178 41

GnRH acts on pituitary gonadotropes to stimulate the synthesis and release of LH and FSH. However, the signaling pathways downstream of the GnRH receptor that mediate these effects are not fully understood. In this paper, we demonstrate that GnRH activates ERK, c-Jun N-terminal kinase, and p38MAPK in the LbetaT2 gonadotrope cell line. Phosphorylation of both ERK and p38MAPK are stimulated rapidly, 30- to 50-fold in 5 min, but activation of c-Jun N-terminal kinase has slower kinetics, reaching only 10-fold after 30 min. Activation of ERK by GnRH is blocked by inhibition of MAPK kinase (MEK) and partially blocked by inhibition of PKC and calcium, but not PI3K or p38MAPK signaling. We demonstrate that phosphorylated ERK accumulates in the nucleus in a PKC-dependent manner. We also show that GnRH induces c-fos and LHbeta subunit protein expression in LbetaT2 cells via MEK. Experiments with EGTA or calcium channel antagonists indicated that calcium influx is important for the induction of both genes by GnRH. In conclusion, these results show that GnRH activates all three MAPK subfamilies in LbetaT2 cells and induces c-fos and LHbeta protein expression through calcium and MEK-dependent mechanisms. These results also demonstrate that the nuclear translocation of ERK by GnRH requires PKC signaling.
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PMID:GnRH activates ERK1/2 leading to the induction of c-fos and LHbeta protein expression in LbetaT2 cells. 1187 99

GnRH regulates gonadotrope cells through GnRH receptor activation of the PKC-, MAPK-, and calcium-activated signaling cascades. Due to the paucity of homologous model systems expressing FSHbeta, little is known about the specific mechanisms involved in transcriptional regulation of this gene by GnRH. Previous studies from our laboratory demonstrated that the gonadotrope-derived LbetaT2 cell line expresses FSHbeta mRNA. In the present study we characterized the mechanisms involved in GnRH regulation of the FSHbeta promoter using this cell model. Using transfection assays, we show that GnRH regulation of the ovine FSHbeta promoter involves at least two elements, present between -4152/-2878 and -2550/-1089 bp, in association with one or several elements within the proximal region of the promoter. Surprisingly, the two activating protein-1 sites previously shown to be involved in the FSHbeta response to GnRH in heterologous cells do not play a role in GnRH responsiveness in the gonadotrope cell model. Here we demonstrate that calcium influx itself is not sufficient to confer the response, but it is necessary for both 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and GnRH induction of the FSHbeta gene. Moreover, we show that GnRH regulation of FSHbeta gene expression is mediated by PKC and establish the presence of multiple PKC isozymes in LbetaT2 cells. Interestingly, GnRH and TPA induce activity of the FSHbeta promoter through different, although possibly overlapping, pools of PKC isoforms. This is further supported by the use of a MAPK inhibitor, which abolishes the induction of FSHbeta by GnRH, but not by TPA. In conclusion, we have demonstrated that calcium, PKC, and MAPK signaling systems are all involved in the induction of FSHbeta gene expression by GnRH in the LbetaT2 mouse gonadotrope cell model.
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PMID:Transcriptional activation of the ovine follicle-stimulating hormone-beta gene by gonadotropin-releasing hormone involves multiple signal transduction pathways. 1195 46

GnRH regulates pituitary gonadotropin gene expression through GnRH receptor activation of the protein kinase C (PKC) and calcium signaling cascades. The pulsatile pattern of GnRH release is crucial for induction of LHbeta-subunit (LHbeta) gene expression; however, continuous prolonged GnRH exposure leads to repression of LHbeta gene transcription. Although in part, long-term repression may be due to receptor down-regulation, the molecular mechanisms of this differential regulation of LHbeta transcription are unknown. Using transfection into the LH-secreting immortalized mouse gonadotrope cell line (LbetaT4), we have demonstrated that LHbeta gene transcription is increased by acute activation (6 h) of GnRH receptor or PKC but not calcium influx; in contrast long-term activation (24 h) of GnRH receptor, PKC, or calcium influx each repress LHbeta transcription. Whereas blockade of PKC prevented the acute action of GnRH and unmasked an acute repression of LHbeta transcription by calcium, it did not prevent long-term repression by GnRH or calcium. Removal of calcium resulted in potentiation of acute GnRH and PKC induction of LHbeta gene expression but prevented long-term repression by GnRH and reduced long-term repression by either calcium or 12-O-tetradecanoyl-phorbol-13-acetate (TPA). We conclude that GnRH uses PKC for acute induction, and calcium signaling is responsible for long-term repression of LHbeta gene expression by GnRH. Furthermore, analysis of the responsiveness of truncated and mutated LHbeta promoter regions demonstrated that not only do acute induction and long-term repression use different signaling systems, but they also use different target sequences for regulating the LHbeta gene.
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PMID:Different signaling pathways control acute induction versus long-term repression of LHbeta transcription by GnRH. 1219 54

Gonadotrophin-releasing hormone (GnRH) plays a pivotal role in the endocrine control of both reproduction and embryonic development. This first study of the marsupial GnRH receptor (GnRH-R) gene in the tammar wallaby provides information on the complex molecular events that regulate hypothalamic-pituitary-gonadal function in marsupials, and allows a comparison with eutherian mammals. Two identical wallaby GnRH-R cDNA clones were obtained, one isolated from cDNA generated from the testis of a 79-day-old pouch young and the other from the pituitary of an adult. Wallaby GnRH-R is composed of 328 amino acid residues. Sequence analysis showed that wallaby GnRH-R contains 7 transmembrane domains and is a member of the G protein-coupled receptor family. A putative protein kinase A phosphorylation site and a putative protein kinase C (PKC) phosphorylation site were found in the first intracellular loop, and an additional PKC phosphorylation site was located in the third intracellular loop. Comparisons with the eutherian GnRH-Rs show a greater diversity in the N-terminal extracellular domain. Wallaby GnRH-R has approximately 80% amino acid sequence homology with eutherian GnRH-Rs and 93% homology with the brush-tail possum, another member of the Diprotodontia semiorder.
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PMID:Molecular cloning and tissue expression of the gonadotrophin-releasing hormone receptor in the tammar wallaby (Macropus eugenii). 1221 37

The hypothalamic decapeptide, gonadotropin-releasing hormone (GnRH), utilizes multiple signaling pathways to activate extracellularly regulated mitogen-activated protein kinases (ERK1/2) in normal and immortalized pituitary gonadotrophs and transfected cells expressing the GnRH receptor. In immortalized hypothalamic GnRH neurons (GT1-7 cells), which also express GnRH receptors, GnRH, epidermal growth factor (EGF), and phorbol 12-myristate 13-acetate (PMA) caused marked phosphorylation of ERK1/2. This action of GnRH and PMA, but not that of EGF, was primarily dependent on activation of protein kinase C (PKC), and the ERK1/2 responses to all three agents were abolished by the selective EGF receptor kinase inhibitor, AG1478. Consistent with this, both GnRH and EGF increased tyrosine phosphorylation of the EGF receptor. GnRH and PMA, but not EGF, caused rapid phosphorylation of the proline-rich tyrosine kinase, Pyk2, at Tyr(402). This was reduced by Ca(2+) chelation and inhibition of PKC, but not by AG1478. GnRH stimulation caused translocation of PKC alpha and -epsilon to the cell membrane and enhanced the association of Src with PKC alpha and PKC epsilon, Pyk2, and the EGF receptor. The Src inhibitor, PP2, the C-terminal Src kinase (Csk), and dominant-negative Pyk2 attenuated ERK1/2 activation by GnRH and PMA but not by EGF. These findings indicate that Src and Pyk2 act upstream of the EGF receptor to mediate its transactivation, which is essential for GnRH-induced ERK1/2 phosphorylation in hypothalamic GnRH neurons.
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PMID:Dependence of gonadotropin-releasing hormone-induced neuronal MAPK signaling on epidermal growth factor receptor transactivation. 1244 5

GnRH regulation of GtH synthesis and release involves PKC- and Ca(2+)-dependent pathways. There are differential signaling mechanisms in different cells, tissues and species. Signaling mechanisms involved in GnRH-mediated GtH release appear to be more conserved compared to that of GnRH-induced GtH gene expression. This may in part be due to different 5' regulatory regions on the GtH-subunit genes. Cell type specific expression of various signaling and/or exocytotic components may also be responsible for the observed differences in signaling between gonadotropes and somatotropes in the goldfish and tilapia pituitaries. However, this can not explain the observed differences in post receptor mechanisms for sGnRH and cGnRH-II in gonadotropes which is more likely to result from the existence of GnRH receptor subtypes. Support for this hypothesis is also provided by observations on mechanisms of autocrine/paracrine regulation of ovarian function by sGnRH and cGnRH-II in the goldfish ovary in which GnRH antagonists only block GnRH stimulation of oocyte meiosis and do not affect inhibitory effects of sGnRH. It should be easier to explain observed variations concerning GnRH-induced responses as more information becomes available on different types of GnRH receptors, and their distribution and function in mammals and non-mammalian vertebrates.
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PMID:Multiplicity of gonadotropin-releasing hormone signaling: a comparative perspective. 1250 65

Reproductive function is dependent on the interaction between GnRH and its cognate receptor found on gonadotrope cells of the anterior pituitary gland. GnRH activation of the GnRH receptor (GnRHR) is a potent stimulus for increased expression of multiple genes including the gene encoding the GnRHR itself. Thus, homologous regulation of the GnRHR is an important mechanism underlying gonadotrope sensitivity to GnRH. Previously, we have found that GnRH induction of GnRHR gene expression in alpha T3-1 cells is partially mediated by protein kinase C activation of a canonical activator protein-1 (AP-1) element. In contrast, protein kinase A and a cAMP response element-like element have been implicated in mediating the GnRH response of the GnRHR gene using a heterologous cell model (GGH(3)). Herein we find that selective removal of the canonical AP-1 site leads to a loss of GnRH regulation of the GnRHR promoter in transgenic mice. Thus, an intact AP-1 element is necessary for GnRH responsiveness of the GnRHR gene both in vitro and in vivo. Based on in vitro analyses, GnRH appeared to enhance the interaction of JunD, FosB, and c-Fos at the GnRHR AP-1 element. Although enhanced binding of cFos reflected an increase in gene expression, GnRH appeared to regulate both FosB and JunD at a posttranslational level. Neither overexpression of a constitutively active Raf-kinase nor pharmacological blockade of GnRH-induced ERK activation eliminated the GnRH response of the GnRHR promoter. GnRH responsiveness was, however, lost in alpha T3-1 cells that stably express a dominant-negative c-Jun N-terminal kinase (JNK) kinase, suggesting a critical role for JNK in mediating GnRH regulation of the GnRHR gene. Consistent with this possibility, we find that the ability of forskolin and membrane-permeable forms of cAMP to inhibit the GnRH response of the GnRHR promoter is associated with a loss of both JNK activation and GnRH-mediated recruitment of the primary AP-1-binding components.
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PMID:c-Jun N-terminal kinase activation of activator protein-1 underlies homologous regulation of the gonadotropin-releasing hormone receptor gene in alpha T3-1 cells. 1258 60


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