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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antigen CD10 (common acute lymphoblastic leukaemia antigen), which is the zinc metalloprotease, neutral endopeptidase 24.11 (also known as NEP or 'enkephalinase'), is expressed by acute lymphoblastic leukaemias, normal lymphoid progenitors, mature polymorphonuclear leukocytes and certain nonhaematopoietic cells. CD10/NEP hydrolyses several naturally occurring peptides, including the endogenous opioid pentapeptides Met- and Leu-enkephalin. In invertebrate organisms such as the mollusc Mytilus edulis, Met-enkephalin triggers inflammatory responses by inducing morphological changes, directed migration and aggregation of haemocytes. We report here that a structure related to CD10/NEP is expressed by M. edulis haemocytes and that abrogation of CD10/NEP enzymatic activity reduces the amount of Met-enkephalin required for haemocyte activation by five orders of magnitude. Similar results are obtained with CD10+ human polymorphonuclear leukocytes, indicating that CD10/NEP related structures regulate enkephalin-mediated inflammatory responses in organisms whose ancestors diverged approximately 500 million years ago.
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PMID:Downregulation of enkephalin-mediated inflammatory responses by CD10/neutral endopeptidase 24.11. 169 30

The common acute lymphoblastic leukemia antigen (CALLA, CD10), which is expressed on early lymphoid progenitors and neutrophils, is the zinc metalloprotease, neutral endopeptidase 24.11 (NEP, "enkephalinase"). The CD10 cell surface enzyme is known to hydrolyze a variety of biologically active peptides including met-enkephalin, formyl-met-leu-phe (f-MLP), and substance P. These three CD10/NEP substrates induce the migration and aggregation of neutrophils, suggesting that each of the peptides can function as a mediator of neutrophil inflammatory responses. Recently, inhibition of CD10/NEP was found to reduce the concentration of metenkephalin needed to activate human and invertebrate granulocytes by several orders of magnitude. Herein we show that f-MLP and substance P induce rapid changes in neutrophil morphology, migration, and adhesion molecule expression, including upregulation of Mo1 (CD11b/CD18) and shedding of LAM-1 (also known as LECAM-1, Leu8, or TQ-1, the human homologue of murine gp100MEL14). Importantly, these coordinated changes are potentiated by inhibition of cell surface CD10/NEP enzymatic activity. Neutrophil cell surface CD10/NEP enzymatic activity is also shown to be regulated by the activation state of the cell during the time period in which the enzyme has its most pronounced effects. These results suggest that in neutrophils, CD10/NEP functions to control responsiveness to multiple inflammatory peptides.
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PMID:CD10 (CALLA)/neutral endopeptidase 24.11 modulates inflammatory peptide-induced changes in neutrophil morphology, migration, and adhesion proteins and is itself regulated by neutrophil activation. 171 72

The activation or interruption of the responses induced by regulatory peptides are ensured by ectoenzymes, the most important of them belonging to the group of zinc metallopeptidases. Thus angiotensin converting enzyme (ACE) forms the hypertensive peptide angiotensin II from its inactive precursor AI. This also the case for aminopeptidase N (APN) and neutral endopeptidase 24.11 (NEP, CALLA) which together inactivate the endogenous opioid peptides, enkephalins, whereas only NEP is involved in the metabolism of the atrial natriuretic factor (ANP) at the kidney and vascular levels. The pharmacological effects resulting from the inhibition of these enzymatic processes will appear only in tissues where the peptide substrate is tonically or phasically released. This promising approach is expected to avoid, or at least to minimize, the side effects resulting from excessive and ubiquitous stimulation of peptide receptors by exogenously administered agonists or antagonists. The essential amino acids known to be present in the active site of the bacterial endopeptidase thermolysin from crystallographic studies, have also been found in NEP by using a new program of sequence comparison associated with mutagenesis experiments. Several classes of selective inhibitors of NEP, APN and ACE have been rationally designed by taking into account the structural differences in the active site of these peptidases. Thus, the retro-inversion of the amide bond of the NEP inhibitor thiorphan resulted in the elimination of a residual interaction with ACE. Moreover, we have proposed to associate inhibitory potencies towards two peptidases in the same compound. Thus kelatorphan HONH-CO-CH2-CH(CH2 phi)-CONH-CH(CH3)-COOH and other systemically-active mixed NEP/APN inhibitors were shown capable of completely blocking enkephalin metabolism in vivo. This concept has been extended to mixed NEP/ACE inhibitors with compounds such as HS-CH2-CH(CH2 phi)-CONH-CH(CH2R)-COOH where R = CH-(CH3)2 (ES 34) or -OCH2 phi (ES 37). Only mixed inhibitors of NEP and APN are able to produce potent analgesia after intracerebroventricular or systemic administration without the major side effects of morphine (tolerance and dependence). Thiorphan or its prodrugs acetorphan or sinorphan lead to a increase in natriuresis and diuresis by protection of ANP degradation, but without any significant antihypertensive effect. Contrastingly mixed NEP/ACE inhibitors such as ES34 induce decreases in blood pressure higher than those that produced by the association of selective NEP and ACE inhibitors.
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PMID:[New approach in the research of analgesics and antihypertensive agents]. 184 70

Neutral endopeptidase (NEP, also known as enkephalinase, CALLA, or EC 3.4.24.11) is a membrane-bound peptidase present in many different cell types. Previous studies have shown that it modulates the actions of a variety of biologically active peptides on several airway responses. More recent studies have demonstrated that reductions in neutral endopeptidase activity in animal airways is associated with increased responses to exogenously applied and endogenously released peptides. To study the regulation of NEP expression, we used human airway epithelial cells transformed in vitro with an origin-defective SV40 plasmid. Enzymatic activity, measured using [3H-Tyr,D-Ala2]leucine enkephalin, increased with cell density (1.4 ng/10(6) cells at 530 cells/cm2 and 21 ng/10(6) cells at confluence, 400 X 10(3) cells/cm2). In both confluent and nonconfluent cultures, the glucocorticoid budesonide increased neutral endopeptidase activity in time- and concentration-dependent fashions. Maximal increases of 10 ng/10(6) cells greater than control were observed after 6 days of incubation at 10(-7) M budesonide. Dexamethasone also increased NEP, suggesting that the effect is due to glucocorticoid receptor effects. Transcription, as assessed by Northern blot analysis of total cellular RNA, showed that NEP-specific RNAs also increased with increasing concentration of glucocorticoid. We conclude that neutral endopeptidase can be increased by cell growth or density and by glucocorticoids and that the effects of glucocorticoids are mediated by increased NEP gene expression.
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PMID:Glucocorticoids induce neutral endopeptidase in transformed human tracheal epithelial cells. 184 94

Opioid peptides and their analogs have been shown to stimulate adherence, conformational changes and locomotory activity in human as well as invertebrate granulocytes. The present study demonstrates that [Met]-enkephalin-Arg6-Phe7, an opioid substance thus far not included in these immunological tests, exhibits stimulatory effects comparable to those of [Met]-enkephalin in this regard. Furthermore, since neutral endopeptidase 24.11 (enkephalinase; CD10/NEP) exists in invertebrate immunocyte membranes, we demonstrate that its specific inhibitor, phosphoramidon, potentiates the effects of the heptapeptide in inducing conformational change in both human and invertebrate granulocytes. Additionally, the major metabolic products of NEP activity, Phe-Met-Arg-Phe and Tyr-Gly-Gly, appear to be potent antagonists of this enzyme activity, especially the tetrapeptide. The effects of heptapeptide stimulation showed a major difference between vertebrate and invertebrate immunocytes with respect to their time course, namely, the speed of their onset. [Met]-enkephalin-Arg6-Phe7 markedly stimulated the locomotory activity of these cells which becomes most noticeable within 15-45 min for Mytilus cells and in a 5-15 min period for human cells. It also enhanced the mobility and velocity of the responsive human (5 microns/min) and invertebrate cells (2.1 microns/min).
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PMID:A possible immunoregulatory function for [Met]-enkephalin-Arg6-Phe7 involving human and invertebrate granulocytes. 199 23

We have previously reported that the amino acid sequence of the common acute lymphoblastic leukemia antigen (CALLA, CD10) translated from a normal human kidney cDNA clone is identical to that of neutral endopeptidase (NEP, EC 3.4.24.11). In this study, we show that by flow cytometry, a monoclonal antibody (135A3) produced against rabbit NEP reacted selectively with leukemia and melanoma cell lines expressing CALLA on their surface. A glycoprotein of apparent Mr 100,000 was immunoprecipitated from surface labeled NALM-1 leukemia or Mel-1477 melanoma cells with monoclonal antibodies to NEP (135A3) or CALLA (44C10). mRNAs hybridizing to a NEP-specific probe were present in CALLA+ leukemia and melanoma cell lines, but absent from CALLA- lines. NEP enzymatic activity was detected on intact cells from CALLA+ lines, but not CALLA- lines. The activity was blocked by two selective inhibitors of NEP, thiorphan and phosphoramidon. CALLA antigen purified from the NALM-6 leukemic cell line by affinity to 44C10-IgG Sepharose retained a peptidase activity that was completely blocked by thiorphan and phosphoramidon. Thus the CALLA antigen present at the surface of leukemia and melanoma cell lines is an enzymatically active neutral endopeptidase.
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PMID:Common acute lymphoblastic leukemia antigen expressed on leukemia and melanoma cell lines has neutral endopeptidase activity. 252 92

We purified CALLA from human kidney and isolated a cDNA clone reactive with two oligonucleotide probes corresponding to two distinct peptides. The amino acid sequence translated from the CALLA cDNA revealed 100% identity with that of human neutral endopeptidase (NEP, enkephalinase). The distribution of CALLA antigen and NEP in normal tissues are similar.
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PMID:Common acute lymphocytic leukemia antigen is identical to neutral endopeptidase. 297 56

The purpose of this study was to identify the presence of placental neutral metalloendopeptidase (NEP; enkephalinase; EC 3.4.24.11) in human normotensive and pre-eclamptic pregnancy. The localization of NEP in placentae from normotensive, chronic hypertensive and pre-eclamptic pregnancies was carried out on fresh frozen tissues by using a monoclonal primary antibody developed against human common acute lymphoblastic leukaemia antigen (CD10) together with the avidin-biotin-peroxidase method. In placentae from normotensive, chronic hypertensive and superimposed pre-eclamptic pregnancies, intense staining was found in the extravillous trophoblast, and also in fibroblasts of the chorionic plate and stem villi. Light to moderate staining was noted in the villous-associated trophoblast and in some cells from the villous core. In cases of pre-eclampsia, very intense staining was detected not only on the surface, but also in the cytoplasm of the villous-associated trophoblast. The increased expression of placental NEP in pre-eclampsia suggests that this enzyme may be involved in the regulation of the local concentration of circulating biologically active peptides at the fetomaternal interface, and thus could be implicated in the pathophysiological changes of this syndrome.
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PMID:Increased immunohistochemical expression of neutral metalloendopeptidase (enkephalinase; EC 3.4.24.11) in villi of the human placenta with pre-eclampsia. 747 14

The effects of retinoic acid (RA) on the expression of osteoblastic-related cell markers was examined. A marrow stromal osteogenic cell line, MBA-15, was analyzed by Northern blotting for the expression of bone matrix proteins. These cells constitutively express mRNA encoding for procollagen alpha 2 (I), osteonectin, osteopontin, biglycan, and alkaline phosphatase (ALK-P). Gene expression was unchanged in response to RA triggering for 24 hr. Furthermore, cell growth and enzymatic activities of ALK-P and neutral endopeptidase (CD10/NEP) were studied. These parameters were examined in MBA-15 and clonal populations representing different stages of differentiation. The cell's growth rate was unchanged, while ALK-P activity was greatly increased during the culture period under RA treatment in MBA-15 and in the clonal cell lines examined while CD10/NEP activity displayed a different pattern. MBA-15.4, a preosteoblast cell line, exhibited an inhibition in CD10/NEP activity at the beginning of the culture period, reaching basal level with time. This activity was greatly increased over control level in MBA-15.6, a mature stage of osteoblasts. Furthermore, the response of cell lines to various growth factors was tested subsequent to priming the cultures with RA. A synergistic effect was monitored for ALK-P activity in MBA-15.4 and MBA-15.6 cells under rh-bone morphogenic protein (BMP-2) and purified osteogenin (BMP-3), and an antagonist effect was measured when cells were exposed to transforming growth factor beta (TGF beta). Contrarily, BMP-2 and BMP-3 inhibited the CD10/NEP activity that had remained unchanged following priming of the cell with RA. Insulin-like growth factor I (IGF-I) and basic fibroblast growth factors (bFGF) did not affect either ALK-P nor CD10/NEP activities in both cloned cells. Cellular response to bone-seeking hormone, parathyroid hormone (PTH), and prostaglandin E2 (PGE2) was monitored by activation of intracellular cAMP. Treatment with RA caused a dramatic decrease in MBA-15.6 cell responses to PTH and PGE2, but no significant effects could be observed in other clonal lines.
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PMID:Differential effects of retinoic acid and growth factors on osteoblastic markers and CD10/NEP activity in stromal-derived osteoblasts. 752 53

The functional modulation of enzymatic activities of alkaline phosphatase (ALK-P) and neutral endopeptidase (CD10/NEP) in MBA-15.4 and MBA-15.6 marrow stromal osteoblastic cells was studied. The hormonal effects of parathyroid hormone (PTH) and 1,25 (OH)2D3 combined with various growth factors (bone morphogenic protein [BMP-2 and BMP-3], TGF beta and IGF-I) on these cells were monitored. The cell responses of MBA-15.4, a preosteoblastic cell, and MBA-15.6, a more mature osteoblastic cell, to the growth factors and the hormonal challenge were measured by changes of the enzymatic activities (ALK-P and CD10/NEP). The cellular response was not uniform and revealed a differential pattern.
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PMID:PTH and 1,25(OH)2 vitamin D priming to growth factors differentially regulates the osteoblastic markers in MBA-15 clonal subpopulations. 774 41


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