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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic and pharmacological experiments have recently implicated several protein kinase cascades in LTP and memory formation. The small GTPases of the Ras subfamily are activated by multiple extracellular stimuli and, via a complex array of downstream effectors, they control a variety of cellular events that culminate in gene transcription. In the well-characterized Aplysia gill-withdrawal reflex, activation of the Ras-dependent mitogen-activated protein kinase (MAPK) cascade is essential for the long-term, but not the short-term, facilitation process. In addition, in the rodent hippocampus, specific inhibition of the MAPK pathway significantly impairs the induction of LTP, which implicates this signalling cascade in hippocampal-dependent behaviour. Mice that lack the neuronal-specific Ras regulator, Ras-GRF (guanine-releasing factor), have severely impaired LTP in the amygdala and a corresponding deficit in long-term memory for aversive events. The results obtained from these different systems demonstrate the involvement of Ras-dependent signalling in neuronal plasticity and behaviour and raise a number of intriguing questions.
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PMID:Is the Ras-MAPK signalling pathway necessary for long-term memory formation? 1052 15

Ionic mechanisms play an important role in the regulation of hormone secretion. The GHRH-induced GH release by human GH-secreting cells is transmitted through protein kinase A (PKA), which activates nonselective cation current (NSCC) and induces membrane depolarization, intracellular Ca2+ increase, and GH secretion. To evaluate whether ionic mechanisms have pathophysiological significance in GH oversecretion of GH-secreting pituitary adenomas, we examined four adenomas with constitutively active Gs alpha mutation (gsp mutation) and compared with three gsp-negative adenomas. In primary-cultured cells of gsp-positive adenomas, GHRH did not increase the NSCC under voltage-clamp experiments. Detailed examination showed that NSCC was maximally activated at the basal level and application of GHRH did not increase the current in these adenomas. Furthermore, by using single-cell RT-PCR method, we demonstrated for the first time at the single cell level that gsp mutation is heterozygous in GH-secreting pituitary adenomas. These indicate that heterozygous gsp mutation fully activates NSCC at the basal level, which may account for the GH oversecretion in gsp-positive GH-secreting pituitary adenomas.
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PMID:Heterozygous gsp mutation renders ion channels of human somatotroph adenoma cells unresponsive to growth hormone-releasing hormone. 1021 50

The full-length versions of the Ras-specific exchange factors Ras-GRF1 (GRF1) and Ras-GRF2 (GRF2), which are expressed in brain and a restricted number of other organs, possess an ionomycin-dependent activation of Erk mitogen-activated protein kinase activity in 293T cells (C. L. Farnsworth et al., Nature 376:524-527, 1995; N. P. Fam et al., Mol. Cell. Biol. 17:1396-1406, 1996). Each GRF protein contains a Dbl homology (DH) domain. A yeast two-hybrid screen was used to identify polypeptides that associate with the DH domain of GRF1. In this screen, a positive cDNA clone from a human brain cDNA library was isolated which consisted of the GRF2 DH domain and its adjacent ilimaquinone domain. Deletion analysis verified that the two-hybrid interaction required only the DH domains, and mutation of Leu-263 to Gln (L263Q) in the N terminus of the GRF1 DH domain abolished the two-hybrid interaction, while a cluster of more C-terminally located mutations in the DH domain did not eliminate the interaction. Oligomers between GRF1 and GRF2 were detected in a rat brain extract, and forced expression of GRF1 and GRF2 in cultured mammalian cells formed homo- and hetero-oligomers. Introduction of the L263Q mutation in GRF1 led to a protein that was deficient in oligomer formation, while GRF1 containing the DH cluster mutations formed homo-oligomers with an efficiency similar to that of wild type. Compared to wild-type GRF1, the focus-forming activity on NIH 3T3 cells of the GRF1 DH cluster mutant was reduced, while the L263Q mutant was inactive. Both mutants were impaired in their ability to mediate ionomycin-dependent Erk activity in 293T cells. In the absence of ionomycin, 293T cells expressing wild-type GRF1 contained much higher levels of Ras-GTP than control cells; the increase in Erk activity induced by ionomycin in the GRF1-expressing cells also induced a concomitant increase in Raf kinase activity, but without a further increase in the level Ras-GTP. We conclude that GRF1 and GRF2 can form homo- and hetero-oligomers via their DH domains, that mutational inactivation of oligomer formation by GRF1 is associated with impaired biological and signaling activities, and that in 293T cells GRF1 mediates at least two pathways for Raf activation: one a constitutive signal that is mainly Ras-dependent, and one an ionomycin-induced signal that cooperates with the constitutive signal without further augmenting the level of GTP-Ras.
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PMID:Ras-specific exchange factor GRF: oligomerization through its Dbl homology domain and calcium-dependent activation of Raf. 1037 10

Saccharomyces cerevisiae Cdc25 is the prototype Ras GDP/GTP exchange protein. Its C-terminal catalytic domain was found to be highly conserved in the homologues p140(ras-GRF) and Sos. The regulatory domains in each Ras exchanger mediate the signals arriving from upstream elements such as tyrosine kinases for Sos, or Ca2+ and G proteins for p140.(Ras-GRF) In this study, we show that the N-terminal half (NTH) of S. cerevisiae Cdc25, as well as the C-terminal 37 amino acids, is essential for processing the elevation of cAMP in response to glucose. The mammalian p140(ras-GRF) catalytic domain (CGRF) restores glucose signaling in S. cerevisiae only if tethered between the N-terminal half (NTH) of S. cerevisiae Cdc25 and the C-terminal 37 amino acids. The glucose-induced transient elevation in cAMP is nullified or severely hampered by the deletion of domains within the NTH of Cdc25. These deletions, however, do not modify the intrinsic GDP/GTP exchange activity of mutant proteins as compared to native Cdc25. We also show that 7 Ser to Ala mutations at the cAMP-dependent protein kinase putative phosphorylation sites within the NTH of Cdc25 eliminate the descending portion of the glucose response curve, responsible for signal termination. These findings support a dual role of the NTH of Cdc25 in both enabling the glucose signal and being responsible for its attenuation.
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PMID:The N-terminal half of Cdc25 is essential for processing glucose signaling in Saccharomyces cerevisiae. 1052 98

The prepro-GH-releasing hormone (prepro-GHRH; 12.3 kDa) precursor, like other neuropeptide precursors, undergoes proteolytic cleavage to give rise to mature GHRH, which is the primary stimulatory regulator of pituitary GH secretion. In this study we present the first model of in vitro pro-GHRH processing. Using pulse-chase analysis, we demonstrate that at least five peptide forms in addition to GHRH are produced. The pro-GHRH (after removal of its signal peptide, 10.5 kDa) is first processed to an 8.8-kDa intermediate form that is cleaved to yield two products: the 5.2-kDa GHRH and GHRH-related peptide (GHRH-RP; 3.6 kDa). GHRH-RP is a recently described peptide derived from proteolytic processing of pro-GHRH that activates stem cell factor, a factor known to be essential for hemopoiesis, spermatogenesis, and melanocyte function. Further cleavage results in a 3.5-kDa GHRH and a 2.2-kDa product of GHRH-RP. Like GHRH, there is GHRH-RP immunostaining in hypothalamic neurons in the median eminence as detected by immunohistochemistry and immunoelectron microscopy. Based on deduced amino acid sequences of the pro-GHRH processing products, several peptides were synthesized and tested for their ability to stimulate the cAMP second messenger system. GHRH, GHRH-RP, and one of these peptides [prepro-GHRH-(75-92)-NH2] all significantly stimulated the PKA pathway. This work delineates a new model of pro-GHRH processing and demonstrates that novel peptides derived from this processing may have biological action.
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PMID:Posttranslational processing of progrowth hormone-releasing hormone. 1057 48

The highly conserved neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) has been implicated in a broad variety of physiological processes. The PACAP precursor protein gives rise to three different peptides, the cryptic peptide, GHRH, and PACAP, respectively, and here we dissect their functional properties using Xenopus as model system. PACAP and GHRH but not the cryptic peptide directly neuralize animal caps. In contrast to GHRH, the neuralizing effect mediated by PACAP is independent of the PKA pathway. Moreover, PACAP but not GHRH behaves like a BMP-4 antagonist. Blastocoel injection of PACAP-38 but not of the closely related peptides PACAP-27 and VIP leads to strong anteriorization of the injected embryos suggesting the possible involvement of a novel PACAP-preferring receptor.
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PMID:Dissecting GHRH- and pituitary adenylate cyclase activating polypeptide-mediated signalling in Xenopus. 1084 63

Influx of Ca2+ via Ca2+ channels is the major step triggering exocytosis of pituitary somatotropes to release growth hormone (GH). Voltage-gated Ca2+ and K+ channels, the primary determinants of the influx of Ca2+, are regulated by GH-releasing hormone (GHRH) through G-protein-coupled intracellular signalling systems. Using whole-cell patch-clamp techniques, the changes of the Ca2+ and K+ currents in primary cultured ovine and human somatotropes were recorded. Growth hormone-releasing hormone (10 nmol/L) increased both L- and T-type voltage-gated Ca2+ currents. Inhibition of the cAMP/protein kinase A (PKA) pathway by either Rp-cAMP or H89 blocked this increase in both L- and T-type Ca2+ currents. Growth hormone-releasing hormone also decreased voltage-gated transient (IA) and delayed rectified (IK) K+ currents. Protein kinase C (PKC) inhibitors, such as calphostin C, chelerythrine or downregulation of PKC, blocked the effect of GHRH on K+ currents, whereas an acute activation of PKC by phorbol 12, 13-dibutyrate (1 micromol/L) mimicked the effect of GHRH. Intracellular dialysis of a specific PKC inhibitor (PKC19-36) also prevented the reduction in K+ currents by GHRH. It is therefore concluded that GHRH increases voltage-gated Ca2+ currents via cAMP/PKA, but decreases voltage-gated K+ currents via the PKC signalling system. The GHRH-induced alteration of Ca2+ and K+ currents augments the influx of Ca2+, leading to an increase in [Ca2+]i and the GH secretion.
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PMID:Diverse intracellular signalling systems used by growth hormone-releasing hormone in regulating voltage-gated Ca2+ or K channels in pituitary somatotropes. 1094 60

Pituitary adenylate cyclase activating polypeptide (PACAP) is a novel member of the secretin-glucagon peptide family. In mammals, this peptide has been located in a wide range of tissues and is involved in a variety of biological functions. In lower vertebrates, especially fish, increasing evidence suggests that PACAP may function as a hypophysiotropic factor regulating pituitary hormone secretion. PACAP has been identified in the brain-pituitary axis of representative fish species. The molecular structure of fish PACAP is highly homologous to mammalian PACAP. The prepro-PACAP in fish, however, is distinct from that of mammals as it also contains the sequence of fish GHRH. In teleosts, the anterior pituitary is under direct innervation of the hypothalamus and PACAP nerve fibers have been identified in the pars distalis. Using the goldfish as a fish model, mRNA transcripts of PACAP receptors, namely the PAC1 and VPACI receptors, have been identified in the pituitary as well as in various brain areas. Consistent with the pituitary expression of PACAP receptors, PACAP analogs are effective in stimulating growth hormone (GH) and gonadotropin (GTH)-II secretion in the goldfish both in vivo and in vitro. The GH-releasing action of PACAP is mediated via pituitary PAC1 receptors coupled to the adenylate cyclase-cAMP-protein kinase A and phospholipase C-IP3-protein kinase C pathways. Subsequent stimulation of Ca2+ entry through voltage-sensitive Ca2+ channels followed by activation of Ca2+-calmodulin protein kinase II is likely the downstream mechanism mediating PACAP-stimulated GH release in goldfish. Although the PACAP receptor subtype(s) and the associated post-receptor signaling events responsible for PACAP-stimulated GTH-II release have not been characterized in goldfish, these findings support the hypothesis that PACAP is produced in the hypothalamus and delivered to the anterior pituitary to regulate GH and GTH-II release in fish.
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PMID:Pituitary adenylate cyclase activating polypeptide as a novel hypophysiotropic factor in fish. 1094 84

Three classes of mammalian phosphoinositide-specific phospholipase C (PLC) have been characterized, PLCbeta, PLCgamma and PLCdelta, that are differentially regulated by heterotrimeric G-proteins, tyrosine kinases and calcium. Here we describe a fourth class, PLCepsilon, that in addition to conserved PLC domains, contains a GTP exchange factor (GRF CDC25) domain and two C-terminal Ras-binding (RA) domains, RA1 and RA2. The RA2 domain binds H-Ras in a GTP-dependent manner, comparable with the Ras-binding domain of Raf-1; however, the RA1 domain binds H-Ras with a low affinity in a GTP-independent manner. While G(alpha)q, Gbetagamma or, surprisingly, H-Ras do not activate recombinant purified protein in vitro, constitutively active Q61L H-Ras stimulates PLC(epsilon) co-expressed in COS-7 cells in parallel with Ras binding. Deletion of either the RA1 or RA2 domain inhibits this activation. Site-directed mutagenesis of the RA2 domain or Ras demonstrates a conserved Ras-effector interaction and a unique profile of activation by Ras effector domain mutants. These studies identify a novel fourth class of mammalian PLC that is directly regulated by Ras and links two critical signaling pathways.
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PMID:Phospholipase C(epsilon): a novel Ras effector. 1117 19

In order to investigate the relationship between abnormal intracellular signal transduction and tumorgenesis of human pituitary somatotrophinomas, the effects of protein kinase A (PKA)-dependent growth hormone (GH) releasing hormone (GHRH) and protein kinase C (PKC)-dependent GH-releasing peptide (GHRP-6) on cAMP production were observed by using cell culture and biochemical methods, and the expression of the gsp oncogene was detected by using PCR and direct sequence assay methods in 11 patients with human pituitary somatotrophinomas. It was found that GHRP-6 exerted significant stimulatory effect on cAMP production by 2 gsp-positive tumors and no effect on the gsp-negative tumors. GHRP-6 could enhance the stimulation of cAMP production induced by GHRH in tumor without gsp oncogenes. It was suggested that both GHRH and GHRP-6 exert identical effects on human pituitary soamtotrophinomas, which was contributed to the cross-talk between the two intracellular signal transduction pathways in pituitary cells.
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PMID:Preliminary study on the relationship between cAMP level and gsp expression in cultured human pituitary somatotrophinomas. 1121 52


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