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)

The metalloendopeptidase EC (EP24.15) is a neuropeptide-metabolizing enzyme expressed predominantly in brain, pituitary, and testis, and is implicated in several physiological processes and diseases. Multiple putative phosphorylation sites in the primary sequence led us to investigate whether phosphorylation effects the specificity and/or the kinetics of substrate cleavage. Only protein kinase A (PKA) treatment resulted in serine phosphorylation with a stoichiometry of 1.11 +/- 0.12 mol of phosphate/mol of recombinant rat EP24.15. Mutation analysis of each putative PKA site, in vitro phosphorylation, and phosphopeptide mapping indicated serine 644 as the phosphorylation site. Phosphorylation effects on catalytic activity were assessed using physiological (GnRH, GnRH(1-9), bradykinin, and neurotensin) and fluorimetric (MCA-PLGPDL-Dnp and orthoaminobenzoyl-GGFLRRV-Dnp-edn) substrates. The most dramatic change upon PKA phosphorylation was a substrate-specific, 7-fold increase in both K(m) and k(cat) for GnRH. In both rat PC12 and mouse AtT-20 cells, EP24.15 was serine-phosphorylated, and EP24.15 phosphate incorporation was enhanced by forskolin treatment, and attenuated by H89, consistent with PKA-mediated phosphorylation. Cloning of the full-length mouse EP24.15 cDNA revealed 96.7% amino acid identity to the rat sequence, and conservation at serine 644, consistent with its putative functional role. Therefore, PKA phosphorylation is suggested to play a regulatory role in EP24.15 enzyme activity.
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PMID:The neuropeptide processing enzyme EC 3.4.24.15 is modulated by protein kinase A phosphorylation. 1096 67

Neuropeptides and their corresponding G protein-coupled receptors (GPCRs) are increasingly implicated in the autocrine/paracrine stimulation of growth of human cancers. We report that neurotensin induced rapid Ca2+ mobilization from intracellular stores followed by Ca2+ influx in five human ductal pancreatic cancer cell lines: HPAF-II, Capan-1, Capan-2, PANC-1, and MIA PaCa-2. In addition, most cell lines exhibited Ca2+ responses to multiple neuropeptides including bombesin, bradykinin, cholecystokinin, and vasopressin and to bioactive lipids, including lysophosphatidic acid (LPA), that also act via GPCRs. The well-differentiated line HPAF-II responded to at least seven independent GPCR agonists. The concentrations of neurotensin required to induce half-maximal effects (EC50) in HPAF-II and PANC-1 cells were 5 and 8nM, respectively. Digital fluorescence image analysis to measure Ca2+ responses in single cells revealed that 90% or more of HPAF-II and PANC-1 cells responded to 10nM neurotensin. Addition of neurotensin to PANC-1 cells also induced rapid and dose-dependent extracellular-regulated protein kinase (ERK-1 and ERK-2) activation and subsequently, stimulated DNA synthesis. The signaling complexity of GPCRs uncovered by these studies reveals a new aspect in the biology of human pancreatic cancer and could offer the basis for new approaches to the treatment of this disease.
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PMID:G protein-coupled receptor signaling in human ductal pancreatic cancer cells: neurotensin responsiveness and mitogenic stimulation. 1114 14

Neurotensin modulates dopaminergic transmission in the nigrostriatal system. DARPP-32, a dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa, is phosphorylated on Thr34 by cAMP-dependent protein kinase, resulting in its conversion into a potent inhibitor of protein phosphatase-1 (PP 1). Here, we examined the effect of neurotensin on DARPP-32 Thr34 phosphorylation using mouse neostriatal slices. Neurotensin stimulated DARPP-32 Thr34 phosphorylation by 4-7-fold with a K(0.5) of approximately 50 nM. The effect of neurotensin was antagonized by a combined neurotensin receptor type-1 (NTR1)/type-2 (NTR2) antagonist, SR142948. It was not antagonized by a NTR1 antagonist, SR48692 or by a NTR2 antagonist, levocabastine; neither was it antagonized by the two combined. Pretreatment with TTX or cobalt abolished the effect of neurotensin. The effect of neurotensin was antagonized by a dopamine D1 antagonist, SCH23390, and by ionotropic glutamate receptor antagonists, MK801 and CNQX. These results indicate that neurotensin stimulates the release of dopamine from nigrostriatal presynaptic terminals in an NMDA receptor- and AMPA receptor-dependent manner, leading to the increase in DARPP-32 Thr34 phosphorylation. Neurotensin stimulated the phosphorylation of Ser845 of the AMPA receptor GluR1 subunit in wild-type mice but not in DARPP-32 knockout mice. Thus, neurotensin, by stimulating the release of dopamine, activates the dopamine D1-receptor/cAMP/PKA/DARPP-32/PP 1 cascade.
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PMID:Neurotensin regulates DARPP-32 thr34 phosphorylation in neostriatal neurons by activation of dopamine D1-type receptors. 1206 80

The suprachiasmatic nuclei (SCN) of the hypothalamus house the main mammalian circadian pacemaker. Cell bodies in the rat SCN contain the neuropeptide neurotensin (NT), and two NT receptor types, NTS1 and nts2. Because the role of NT in the circadian rhythm processes is unknown, we studied the phase-shifting effects of NT on the firing rate rhythm of rat SCN neurons in vitro. Additionally, the NT receptor antagonists SR142948a and SR48692 were used to try and block any NT-induced phase shifts. To elucidate the second messenger pathway responsible for mediating the phase-resetting actions of NT, we utilized the phospholipase C (PLC) and protein kinase A (PKA) inhibitors U-73122 and KT5720, respectively. Application of NT during the projected day resulted in a large advance in the time of peak in FRR, whereas treatments during the projected night had no effect. Both NT receptor antagonists blocked the NT-induced phase shifts, as did the PLC inhibitor U-73122. The PKA inhibitor KT5720 had no influence on the magnitude of the phase shift caused by NT during the middle of the projected day. These results provide the first evidence that NT may play a role in regulating the rat circadian pacemaker, using NTS1 and nts2 receptors presumably coupled to PLC.
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PMID:Neurotensin phase-shifts the firing rate rhythm of neurons in the rat suprachiasmatic nuclei in vitro. 1216 14

Neuropeptides can function as autocrine growth factors in cancer cells. High levels of bombesin (BB) and neurotensin (NT)-like immunoreactivity are present in small cell lung cancer (SCLC), a neuroendocrine tumor. Vasoactive intestinal peptide (VIP) stimulates and somatostatin (SST) inhibits the release of BB-like peptides from SCLC cells. BB-like peptides bind to BB(2) receptors, which are present on the cell surface. BB-like peptides stimulate the mitogen activated protein kinase (MAPK) cascade leading to increased expression of nuclear oncogenes and growth factors in SCLC cells. Due to the high density of neuropeptide receptors present on the cell surface, SST analogs have been radiolabeled to image neuroendocrine tumors. VIP receptors are present in many epithelial cancers including breast, colon, non-small cell lung cancer (NSCLC), pancreatic and prostate cancers. Due to the high density of VIP receptors on lung cancer cells, radiolabeled VIP agonists may be used to image these tumors. VIP receptor antagonists, such as VIPhybrid, inhibit the growth of cancer cell lines in vitro and in vivo. VIPhybrid and SR48692, a NT receptor antagonist, potentiate the cytotoxicity of chemotherapeutic drugs. These results suggest that neuropeptide receptor antagonists may be useful in the treatment of cancer.
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PMID:Neuropeptides as autocrine growth factors in cancer cells. 1257 Aug 13

Neurotensin (NT), a neuropeptide highly expressed in the gastrointestinal tract, participates in the pathophysiology of intestinal inflammation. We recently showed that NT stimulates interleukin-8 (IL-8) expression in NCM460 nontransformed human colonic epithelial cells via both mitogen-activating protein kinase (MAPK)- and NF-kappaB-dependent pathways. However, the molecular mechanism by which NT induces expression of proinflammatory cytokines such as IL-8 has not been investigated. In this study we show that inhibition of endogenous Rho family proteins (RhoA, Rac1, and Cdc42) by their respective dominant negative mutants inhibits NT-induced IL-8 protein production and promoter activity. Western blot experiments demonstrated that NT strongly activated RhoA, Rac1, and Cdc42. Overexpression of the dominant negative mutants of RhoA, Rac1, and Cdc42 significantly inhibited NT-induced NF-kappaB-dependent reporter gene expression and NF-kappaB DNA binding activity. NT also stimulated p38 MAPK phosphorylation, and overexpression of dominant negative mutants of RhoA, Rac1, and Cdc42 did not significantly alter p38 and ERK1/2 phosphorylation in response to NT. Together, our findings indicate that NT-stimulated IL-8 expression is mediated via a Rho-dependent NF-kappaB-mediated pathway.
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PMID:Neurotensin stimulates IL-8 expression in human colonic epithelial cells through Rho GTPase-mediated NF-kappa B pathways. 1258 13

Neurotensin is a neuropeptide involved in dopaminergic signalling. We have recently reported that neurotensin stimulates the phosphorylation of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa) at Thr34 (PKA-site) by activating dopamine D1-type receptors in neostriatal neurons. DARPP-32 is also phosphorylated by cyclin-dependent kinase 5 on Thr75, and the phosphorylated form of DARPP-32 at Thr75 inhibits protein kinase (PKA) activity. In this study, we examined the effect of neurotensin on DARPP-32 Thr75 phosphorylation using mouse neostriatal slices. Neurotensin decreased the level of phospho-Thr75 DARPP-32 at 2 min of incubation, maximally to about 50% of control at a concentration of 1 micro m. Pretreatment with a combined neurotensin receptor type 1 (NTR1)/type 2 (NTR2) antagonist, SR142948, reduced the basal level of phospho-Thr75 DARPP-32 and abolished the ability of neurotensin to decrease DARPP-32 Thr75 phosphorylation. However, neither an NTR1 antagonist, SR48692, an NTR2 antagonist, levocabastine, nor the two combined affected the basal level and the neurotensin-mediated decrease in DARPP-32 Thr75 phosphorylation. The effect of neurotensin was abolished by tetrodotoxin (TTX) or MK801 plus CNQX, but not by SCH23390 or raclopride. These results indicate that neurotensin stimulates the release of glutamate by activating a hypothesized unidentified neurotensin receptor, resulting in the dephosphorylation of DARPP-32 at Thr75 by activating NMDA and AMPA receptors expressed at medium spiny neurons. Thus, neurotensin, by removing the inhibition of PKA by phospho-Thr75 DARPP-32, potentiates its signalling via the dopamine/D1 receptor/PKA/phospho-Thr34 DARPP-32/PP-1 cascade.
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PMID:Regulation of DARPP-32 Thr75 phosphorylation by neurotensin in neostriatal neurons: involvement of glutamate signalling. 1295 23

Neurotensin (NT) and epidermal growth factor (EGF) induced rapid extracellular-regulated protein kinase (ERK) activation through different signaling pathways in the K-Ras mutated human pancreatic carcinoma cell lines PANC-1 and MIA PaCa-2. NT stimulated ERK activation via a protein kinase C (PKC)-dependent (but EGF receptor-independent) pathway in PANC-1 and MIA PaCa-2 cells, whereas EGF promoted ERK activation through a PKC-independent pathway in these cells. Concomitant stimulation of these cells with NT and EGF induced a striking increase in the duration of ERK pathway activation as compared with that obtained in cells treated with each agonist alone. Stimulation with NT + EGF promoted synergistic stimulation of DNA synthesis and anchorage-independent growth. Addition of the MEK inhibitor U0126, either prior to stimulation with NT + EGF or 2 h after stimulation with NT + EGF prevented the synergistic increase in DNA synthesis and suppressed the sustained phase of ERK activation. Furthermore, treatment with the selective PKC inhibitor GF-1 converted the sustained ERK activation in response to NT and EGF into a transient signal and also abrogated the synergistic increase in DNA synthesis. Collectively, our results suggest that the sustained phase of ERK signaling mediates the synergistic effects of NT and EGF on DNA synthesis in pancreatic cancer cells.
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PMID:Neurotensin and EGF induce synergistic stimulation of DNA synthesis by increasing the duration of ERK signaling in ductal pancreatic cancer cells. 1538 44

Neuroendocrine (NE) cells are found in prostate tumors, and their incidence is considered a promising prognostic indicator for the development of androgen-independent disease. NE cells are derived from non-NE prostate cancer cells and secrete factors that can act in a paracrine manner to stimulate the survival, growth, motility, and metastatic potential of prostatic carcinoma cells. Factors such as IL-6, epinephrine, and forskolin induce NE differentiation in prostate cancer cells; the mechanisms involve increases in intracellular cAMP, protein kinase A (PKA) activation and reduced intracellular calcium levels. Transcription factors implicated in the acquisition of NE characteristics by prostate cancer cells include STAT3, CREB, EGR1, c-fos, and NF-kappaB. Expression of Chromogranin A, neuron-specific enolase, bcl-2, and the androgen receptor are modulated during NE differentiation and serve as molecular markers for NE cells. Most importantly, NE cells secrete neuropeptides, such as bombesin, neurotensin, PTHrP, serotonin, and calcitonin, which trigger growth and survival responses in androgen-independent prostate cancer cells. Prostate cancer cell receptors that play a role in these processes include the gastrin-releasing peptide (GRP) receptor, neurotensin receptors, and the epidermal growth-factor receptor (EGFR). Signal-transduction molecules activated by these neuropeptides include Src, focal adhesion kinase (FAK), ERK, and PI3K/Akt, with subsequent activation of Elk-1, NF-kappaB, and c-myc transcription factors. A multitude of genes are then expressed by prostate cancer cells, which are involved in proliferation, anti-apoptosis, migration, metastasis, and angiogenesis. Targeting of these pathways at multiple levels can be exploited to inhibit the process by which NE cells contribute to the progression of androgen-independent, treatment-refractory prostate cancer.
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PMID:Neuroendocrine cells in prostate cancer. 1566 58

The pars intermedia of the frog (Rana esculenta) pituitary, which is composed of a single population of endocrine cells, the melanotrophs, is a very suitable model to study the mode of action of hypophysiotropic neuropeptides. We have recently characterized neurotensin (NT) in Rana esculenta and found that synthetic frog NT (fNT) stimulates the electrical and secretory activities of melanotrophs. By combining biochemical, pharmacological, microfluorimetric, and electrophysiological approaches, we observed that NT stimulates inositol-trisphosphate production that provokes Ca(2+) release from intracellular stores. The resulting increase in cytosolic Ca(2+) concentration ([Ca(2+)](c)) activates the secretion of alpha-melanocyte-stimulating hormone (alpha-MSH), stimulates Ca(2+)-dependent protein kinase (PKC) activity, and provokes a depolarizing chloride efflux. PKC reduces the amplitude, whereas membrane depolarization increases the frequency of L- and N-type Ca(2+) currents underlain by the action potential discharge. The complex regulatory processes exerted by NT on Ca(2+) signaling likely generate discrete variations in the [Ca(2+)](c) at various distances from secretory vesicles, contributing to the fine-tuning of alpha-MSH secretion.
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PMID:Signal transduction in Rana melanotrope cells: mechanism of action of neurotensin on secretory and electrical activities. 1589 Oct 16


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