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)

Attachment of circulating tumor cells to endothelial cell adhesion molecules restricted to select vascular compartments is thought to be responsible for site-specific metastasis. Lung-metastatic rat R3230AC-MET breast and RPC-2 prostate carcinoma cells bound outside-out endothelial cell membrane vesicles, prepared by perfusion of the rat lung vasculature with a low-strength formaldehyde solution, in significantly higher numbers than their nonmetastatic counterparts R3230AC-LR and RPC-LR. In contrast, vesicles derived from the vasculature of a nonmetastasized organ (e.g., hind leg muscle) showed no binding preference for either of the four tumor cell lines. Lung-derived endothelial vesicles were used here to generate mAbs against lung endothelial cell adhesion molecules. The first group of mice were actively immunized against lung endothelial vesicles, whereas the second group was injected with syngeneic mouse antiserum against leg endothelial vesicles before active immunization with lung endothelial vesicles. 17 hybridoma supernatants obtained from the two fusions bound lung vesicles with at least a 10-fold higher affinity than leg vesicles. Seven (four obtained by a passive/active immunization protocol) stained rat capillary endothelia. One mAb, mAb 8.6A3, inhibited specific adhesion of lung-derived vesicles to lung-metastatic breast and prostate carcinoma cells. Purification of the antigen (endothelial cell adhesion molecule) from rat lung extracts revealed a protein with a 110-kD mol wt. NH2-terminal sequencing established identity with dipeptidyl peptidase IV which had been reported to serve as a fibronectin-binding protein. These results indicate that vesicles obtained from in situ perfused organs are a convenient immunogen for the production of antibodies to compartment-specific endothelial cell surface molecules, and reinforce the concept that endothelial cell surface components are selectively recognized by circulating cancer cells during metastasis formation.
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PMID:Lung endothelial dipeptidyl peptidase IV is an adhesion molecule for lung-metastatic rat breast and prostate carcinoma cells. 809 89

The effects of cholecystokinin (CCK) fragments and Asp-Tyr-D-Phe-Gly-Trp-[N-Me]Nle-Asp-Phe-NH2 1(SNF 9007), a synthetic CCK analog which binds with high affinity to CCKB and opioid delta receptors, were evaluated in isolated sheets of mouse ileum mounted in Ussing flux chambers. Serosal, but not mucosal, administration of cholecystokinin octapeptide-sulfated [CCK8(s)] and cholecystokinin tetrapeptide (30-33) [CCK4(30-33)] produced a brief, concentration-related increase in short circuit current (Isc) without changing tissue conductance. Serosal, but not mucosal, SNF 9007 produced a similar concentration-related increase in Isc which was followed by an immediate concentration-related and sustained decrease in Isc; no decrease in Isc was observed for either CCK8 or CCK4(30-33). The increase and subsequent decrease in the SNF 9007 Isc response were respectively classified as phase I (i.e., CCK-like) and phase II (opioid-like) activity. CCK8(s) and SNF 9007 (phase I) were active at low nanomolar concentrations, whereas CCK4(30-33) was active only at high nanomolar concentrations: the rank order of potencies to increase Isc was CCK8(s) > SNF 9007 > CCK4(30-33). Devazepide (L364,718), a selective antagonist of CCKA receptors, effectively blocked the action of CCK8(s), but not that of CCK4(30-33) or SNF 9007 (phase I). In contrast, 3R[+]-N-[2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-benzodiazepin-3-yl ]-N'- [3-methyl-phenyl]urea (L365,260), a selective CCKB receptor antagonist, blocked the action of CCK4(30-33) and SNF 9007 (phase I), and also antagonized CCK8(s), though to a lesser degree.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of SNF 9007, a novel cholecystokinin/opoid ligand in mouse ileum in vitro: evidence for involvement of cholecystokininA and cholecystokininB receptors in regulation of ion transport. 811 56

Our objective was to evaluate the effects of substituting feather meal (FM) for soybean meal (SBM) on ruminal fiber fermentation, lamb gain, blood metabolite profiles, and wool growth. A SBM supplement was formulated, and FM replaced either 33% (33FM), 66% (66FM), or 100% (FMS) of the SBM protein. Four ruminally cannulated wethers were used in a 4 x 4 Latin square design to study in situ ruminal digestion. Wethers were limit-fed barley straw and fed the supplements once daily. Ruminal NH3 N concentrations reflected a sampling time x protein source interaction (P < .01). Within sampling times, ruminal NH3 N concentrations decreased linearly (P < .05) as FM replaced soybean meal. Cubic (0 h; P < .10) and quadratic (24 h; P < .05) responses also were noted for ruminal NH3 N concentration. Substitution of FM for SBM had no effect (P > .10) on rate and extent of straw NDF disappearance. A 56-d feeding trial was conducted using 28 wether lambs (n = 7 per treatment; initial BW 32.3 kg). Wethers were individually fed chopped barley straw and one of the four supplements described previously. Linear increases (P < .05) in BW gain and serum total protein concentration were observed as FM replaced SBM. Wool fiber diameter and sulfur content did not differ (P > .10) among treatments. These data suggest that FM can be substituted for SBM in protein supplements fed to sheep consuming low-quality roughages at a maintenance level of ME intake.
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PMID:Effects of substituting feather meal for soybean meal on ruminal fiber fermentation and lamb and wool growth. 815 38

Keratinocyte growth factor (KGF) is a fibroblast growth factor (FGF) family member that acts specifically on cells of epithelial origin. Its receptor (KGFR) is a membrane-spanning tyrosine kinase, which also binds acidic FGF (aFGF) with equally high affinity, and basic FGF (bFGF) with much lower affinity. The KGFR is encoded by the bek/FGFR-2 gene, whose alternative transcript specifies a receptor with high affinity for aFGF and bFGF, but no detectable binding of KGF. The only structural difference between these two receptors is a 49-amino acid segment in the extracellular domain that is determined by single alternative exons. We report that a synthetic peptide (NH2-His199...Tyr223-COOH) corresponding to part of the predicted sequence of the KGFR alternative exon blocks KGF mitogenic activity and the interaction between KGF and its receptor. The peptide also blocks the interaction between KGF and a neutralizing monoclonal antibody raised against this growth factor. These results demonstrate that the peptide binds directly and specifically to KGF and argue that this region of the receptor constitutes part or all of the KGF binding site.
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PMID:A keratinocyte growth factor receptor-derived peptide antagonist identifies part of the ligand binding site. 838 85

Replacement of Met31 by (N-Me)Nle in CCK8 or CCK4 has been shown to improve the affinity and selectivity for CCK-B receptors. In order to obtain molecules with enhanced bioavailability, two novel series of protected tetrapeptides of the general formula Boc-Trp30-X-Asp-Y33 have been developed. Introduction of (N-Me)Nle and the bulky, aromatic naphthylalaninamide (Nal-NH2) in positions X and Y, respectively, does not greatly modify the affinity for guinea pig brain CCK-B receptors. In contrast, incorporation of hindering N-methyl amino acids such as (N-Me)Phe, (N-Me)Phg, or (N-Me)Chg, but not their non-methylated counterparts, in position X induced a large decrease in affinity for the CCK-B binding sites. Among the various peptides synthesized, Boc-[(N-Me)Nle31,1Nal-NH2(33)]CCK4 (2) (KI = 2.8 nM), Boc-[Phg31,1Nal-NH2(33)]CCK4 (15) (KI = 14 nM), and Boc-[Phg31,1Nal-N(CH3)2(33)]CCK4 (17) (KI = 39 nM) displayed good affinities for brain CCK-B receptors and had good selectivity ratios. These pseudopeptides, in which the presence of unnatural and hydrophobic residues is expected to improve their penetration of the central nervous system, were shown to be very resistant to brain peptidases. Interestingly, whereas compounds 2 and 15 proved to be full agonists for rat hippocampal CCK-B receptors when measured in an electrophysiological assay, compound 17 behaved as a potent antagonist in the same test and displayed a good affinity in rat brain KI(CCK-B) = 51 nM as compared to the Merck antagonist L365,260,KI(CCK-B) = 12 nM. This illustrates a simple means to obtain CCK-B antagonists and suggests that the free, CONH2 group plays a critical role in the recognition of the agonist state of brain CCK-B receptors.
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PMID:CCK-B agonist or antagonist activities of structurally hindered and peptidase-resistant Boc-CCK4 derivatives. 842 Dec 83

A digestibility trial involving 20 Hampshire ram lambs and a 2-yr grazing study using 103 mature crossbred cows were conducted to determine the effects of methionine addition to a urea-grain supplement on intake and digestibility of dormant range grasses and on cow performance. In each trial, four treatment groups were supplemented with either a urea-grain control (CON), urea-grain plus methionine (MET, 3.3% DL-methionine), urea-grain plus inorganic sulfur (SUL, 3.0% sodium sulfate), or soybean meal (SBM). Supplements were designed to provide 45 and 360 g of CP.animal-1.d-1 (lambs and cows, respectively) and were balanced for ME, Ca, P, and K. Lambs had ad libitum access to mature prairie hay, whereas cows grazed dormant winter range from mid-November until mid-February. For the grazing study, forage OM intake (OMI) was determined in late November and in late January by the fecal output/indigestibility ratio technique. Controlled-release chromic oxide boluses were used as an external marker to estimate fecal output, and acid insoluble ash was used as an internal marker to predict OM digestibility (OMD). Mean daily DMI of mature prairie hay was 1,057 g/lamb and was not affected by supplementation. Apparent DM, NDF, and ADF digestibilities and N biological value did not differ (P > .10) among treatments. Nitrogen digestibility was increased (P = .06) for lambs fed the MET or SUL compared with CON.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of methionine addition to a urea-grain supplement on intake and digestibility of mature, dormant grasses and performance of cows grazing winter range. 844 Jun 72

TGF alpha-PE40, a recombinant toxin in which transforming growth factor alpha (TGF alpha) is fused to a mutant form of Pseudomonas exotoxin, is selectively cytotoxic to cells bearing epidermal growth factor (EGF) receptors. Heparin binding EGF-like growth factor is a potent mitogen for smooth muscle cells capable of binding to both the EGF receptor and to immobilized heparin (Higashiyama, S., Abraham, J., Miller, J., Fiddes, J., and Klagsbrun, M. (1991) Science 251, 936-938). To study the effect of the heparin-binding domain in a chimeric toxin targeted to the EGF receptor, we fused the DNA sequence corresponding to the putative NH2-terminal heparin-binding (HB) domain of HB-EGF to chimeric toxins composed of TGF alpha and two different recombinant forms of Pseudomonas exotoxin (PE). One of these is a truncated form of PE devoid of the binding domain (TGF alpha-PE38); another is a mutant form of full-length toxin containing inactivating mutations in the binding domain and an altered carboxyl terminus (TGF alpha-PE4EKDEL). The resulting chimeric toxins HB-TGF alpha-PE38 and HB-TGF alpha-PE4EKDEL were expressed in Escherichia coli as inclusion bodies, refolded, and purified by heparin affinity chromatography. Both of the toxins were eluted from heparin at 0.8 M NaCl, in contrast to their respective TGF alpha toxins which were eluted at 0.15 M. Binding studies on A431 cells showed that the HB-TGF alpha toxins bound to the EGF receptor with an affinity similar to that of the TGF alpha toxins. However, cell killing studies on a panel of malignant cell lines showed that cytotoxicity was strongly affected by the presence of the HB domain. Cell lines expressing high numbers of EGF receptors such as A431 and KB were less sensitive to toxins containing the HB domain. Cells with low number of EGF receptors had similar responses to both types of toxins (MCF-7 and LNCaP) or were more sensitive to the toxin with the added HB domain (HEP-G2). HB-TGF alpha-PE4EKDEL was over 10-fold more cytotoxic against proliferating vascular smooth muscle cells (VSMC) than to quiescent VSMC. Moreover, HB-TGF alpha-PE4EKDEL was 6-fold more potent than TGF alpha-PE4EKDEL to proliferating VSMC. Competition studies with EGF and/or heparin showed that heparin blocks the cytotoxicity of HB-TGF toxins and the inhibitory action of heparin is stronger in cells expressing lower number of EGF receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Heparin-binding transforming growth factor alpha-Pseudomonas exotoxin A. A heparan sulfate-modulated recombinant toxin cytotoxic to cancer cells and proliferating smooth muscle cells. 844 64

Mammalian CDK7 is a protein kinase identified as the catalytic subunit of cyclin-dependent kinase (CDK)-activating kinase and as an essential component of the transcription factor TFIIH that is involved in transcription initiation and DNA repair. We have identified in human cells a number of CDK7-associated cellular proteins that appear to fall into two classes based on their relative [35S] metabolic labeling intensity. One class of proteins present in CDK7 immunocomplexes as a minor fraction contains components of the TFIIH transcription complex such as p62 and p89ERCC3, whereas the other fraction contains four polypeptides (p35, p37Cyclin H, p75, and p95) that are stoichiometrically associated with CDK7. Whereas the levels of association of p35, p37Cyclin H, and p75 with CDK7 remain unchanged between density-arrested and proliferating Ewing sarcoma EW-1 cells, the association of p95 with CDK7 was significantly decreased as cells reached confluency. Through a large-scale immunopurification of CDK7 complexes and protein microsequencing, we have isolated a cDNA that encodes p35 and have shown that it is the human homologue of Mat1 that is involved in the assembly of CAK. MAT1 contains a highly conserved C3HC4 motif at its NH2 terminus, a characteristic feature shared among RING finger proteins. The human MAT1 gene expresses a single 1.6-kb transcript, the steady-state level of which, like CDK7 and cyclin H, varies significantly in different cell lines and in different terminally differentiated tissues.
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PMID:Molecular cloning of CDK7-associated human MAT1, a cyclin-dependent kinase-activating kinase (CAK) assembly factor. 852 93

Lysosomal cathepsin B but not L degraded rAPP751 to yield C-terminal 19-25 kDa fragments containing beta A4, reinforcing the view that acidic proteases participate in endosomal-lysosomal processing to yield amyloidogenic fragments in situ. This mechanism is consistent with fragmentation of endogenous APPs within clathrin-coated vesicles (CVs) by vesicular hydrolases, with the appearance of C-terminal amyloidogenic fragments following incubation at pH 6.5. A neutral endopeptidase resembling NEP 24.11 (PS-NEP) purified from detergent extracts of human brain degraded rAPP751; however, breakdown was not blocked robustly by metal chelators or phosphoramidon, suggesting the presence of an alternative processing enzyme. Effects of other inhibitors showed that breakdown was mediated by serine-protease-like component(s). A phosphoramidon-insensitive metalloendopeptidase (PI-NEP) partially purified from rat brain P2 using detergents, and resembling NEP 24.15, showed no activity towards rAPP751. Peptides containing putative beta- or gamma-secretase sites were synthesized for purposes of examining their metabolism by the brain enzymes. Those containing beta-secretase sites were hydrolysed at one or more sites by the four enzymes, but only PI- and PS-NEP acted at the Met-Asp site of Ac-Val-Lys-Met-Asp-Ala-Glu-Phe-Arg.NH2. In the case of substrates containing the gamma-site, these two categories of enzymes were the only ones degrading N-Ac-Ile-Ala.NH2. These data imply that the brain metalloendopeptidases, while inactive towards intact precursors, may be involved in turnover of intermediates containing beta- or gamma-sites.
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PMID:Brain cathepsin B but not metalloendopeptidases degrade rAPP751 with production of amyloidogenic fragments. Comparison with synthetic peptides emulating beta- and gamma-secretase sites. 853 84

Tyrosine kinase growth factor receptors activate MAP kinase by a complex mechanism involving the SH2/3 protein Grb2, the exchange protein Sos, and Ras. The GTP-bound Ras protein binds to the Raf kinase and initiates a protein kinase cascade that leads to MAP kinase activation. Three MAP kinase kinase kinases have been described--c-Raf, c-Mos, and Mekk--that phosphorylate and activate Mek, the MAP kinase kinase. Activated Mek phosphorylates and activates MAP kinase. Subsequently, the activated MAP kinase translocates into the nucleus where many of the physiological targets of the MAP kinase signal transduction pathway are located. These substrates include transcription factors that are regulated by MAP kinase phosphorylation (e.g., Elk-1, c-Myc, c-Jun, c-Fos, and C/EBP beta). Thus the MAP kinase pathway represents a significant mechanism of signal transduction by growth factor receptors from the cell surface to the nucleus that results in the regulation of gene expression. Three MAP kinase homologs have been identified in the rat: Erk1, Erk2, and Erk3. Human MAP kinases that are similar to the rat Erk kinases have also been identified by molecular cloning. The human Erk1 protein kinase has been shown to be widely expressed as a 44-kDa protein in many tissues. The human Erk2 protein kinase is a 41-kDa protein that is expressed ubiquitously. In contrast, a human Erk3-related protein kinase has been found to be expressed at a high level only in heart muscle and brain. The loci of these MAP kinase genes are widely distributed within the human genome: erk2 at 22q11.2; erk1 at 16p11.2; and ek3-related at 18q12-21. In the yeast Saccharomyces cerevisiae, five MAP kinase gene homologs have been described: smkl, mpk1, hog1, fus3, and kss1. Together, these kinases are a more diverse group than the human erks that have been identified. Thus the erks are likely to represent only one subgroup of a larger human MAP kinase gene family. A candidate for this extended family of MAP kinases is the c-Jun NH2-terminal kinase (Jnk), which binds to and phosphorylates the transcription factor c-Jun at the activating sites Ser-63 and Ser-73. Evidence is presented here to demonstrate that Jnk is a distant relative of the MAP kinase group that is activated by dual phosphorylation at Tyr and Thr.
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PMID:Transcriptional regulation by MAP kinases. 860 77


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