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

---

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

The >30 known members of the Ets multigene family of transcriptional regulators are increasingly being recognized for their involvement in early embryonic development and late tissue maturation, directing stage-specific and tissue-restricted programs of target gene expression. Identifiable primarily by their 85 amino acid ETS DNA-binding domain and dispersed across all metazoan lineages into distinct subfamilies, Ets genes also produce malignancies in humans and other vertebrates when overexpressed or rearranged into chimeras retaining the ETS domain, suggesting that their oncogenic potential is determined by the program of target genes they regulate. Searching for Ets factors that regulate expression of the HER2/neu (c-erbB2) oncogene in human breast cancer, we identified a new epithelium-restricted Ets encoding an ETS domain homologous to the Drosophila E74/human Elf-1 subfamily, an amino-terminal region (A-region or Pointed domain) homologous to the distantly related Ets-1 subfamily, and a serine-rich box homologous to the transactivating domain of the lymphocyte-restricted High Mobility Group (HMG) protein, SOX4. Recombinant protein encoded by ESX (for epithelial-restricted with serine box) exhibits Ets-like DNA binding specificity in electrophoretic mobility shift assays and, in transient transfection assays, transactivates Ets-responsive promoter elements including that found in the HER2/neu oncogene. ESX is located at chromosome 1q32 in a region known to be amplified in 50% of early breast cancers, is heregulin-inducible and overexpressed in HER2/neu activated breast cancer cells. Tissue hybridization suggests that ESX becomes overexpressed at an early stage of human breast cancer development known as ductal carcinoma in situ (DCIS).
...
PMID:ESX: a structurally unique Ets overexpressed early during human breast tumorigenesis. 912 54

The staphylococcal enterotoxins, SEA and SEE, bind one zinc atom per molecule of protein. The presence of this metal atom enhances the binding of the toxins to MHC class II molecules, presumably through an interaction with histidine 81 of the beta chain. L cell transfectants expressing HLA-DR1 and HLA-DR7 molecules, with mutations in either the alpha1 or beta1 domains, were tested for their ability to bind SEA and present it to T cells. Cells expressing DR1 molecules with alanine at positions 77, 78, 80, 83, 84 and 85, or serine at position 79 could all bind SEA and present it to either polyclonal or monoclonal T cells. Most point mutations within the alpha-helical portion of the DR7 beta chain had no effect on binding and presentation. However, substitution of histidine 81 with alanine, glutamate, or aspartate, abrogated SEA binding as well as T cell stimulation by the superantigen. This effect was also observed when the non-polymorphic aspartate, at position 76 was changed to alanine. Mutation of the asparagine at position 82 had an intermediate effect. Point mutations of the DR alpha chain had little effect on binding of SEA as determined by a flow cytometric assay. However, mutation of lysine at position 39 of the alpha chain and, to a lesser extent methionine at position 36, markedly decreased the ability of SEA to stimulate toxin-responsive mouse T cell hybridomas. Finally, the monoclonal antibody, L243 binds to the alpha chain of HLA-DR, and was able to block T cell activation by SEA without blocking SEA binding. These data support the model whereby HLA-DR has two binding sites for SEA. A low affinity site, present on the alpha chain, is required for T cell stimulation by the superantigen, but is insufficient to mediate toxin binding. High affinity binding of HLA-DR to SEA occurs solely through residues on the beta chain, including both histidine 81 and aspartate 76.
...
PMID:Functional activity of staphylococcal enterotoxin A requires interactions with both the alpha and beta chains of HLA-DR. 912 63

We have investigated a phosphatase-sensitive sequential epitope of the nucleoprotein (N), one of the phosphoproteins of rabies virus, which is recognized by the monoclonal antibody (MAb) #5-2-26. The epitope was shared in common by all of the rabies virus strains we tested, including the HEP, ERA, CVS and Japanese strains (Nishigahara and Komatsukawa). Thin layer chromatography of the acid hydrolyzates of 32P-labeled N protein showed that the protein contained phosphoserine and phosphothreonine at a molar ratio of about 4 to 1, while no phosphotyrosine was detected. Immunoprecipitation studies with several deletion mutants of the N protein showed that the epitope is located in a region spanning from amino acid 344 to 415. If the phosphatase-sensitive epitope is located at or near the phosphoamino acid, the location of the latter could be narrowed further to a region from amino acid 354 to 389 by comparing the amino-acid sequences among the viral strains. To examine this assumption, point mutation was introduced by amino-acid substitution with alanine at either of five potential phosphorylation sites (i.e., positions 354, 375, 377, 386 and 389) in the 354-389 region. Among those, only one substitution, at position 389, greatly affected the antigenicity. Substitution of serine-389 by threonine also reduced the antigenicity. These results strongly suggest that serine-389 is a phosphorylation site and essential for constructing or stabilizing the antigenic structure for MAb 5-2-26.
...
PMID:Identification of a phosphatase-sensitive epitope of rabies virus nucleoprotein which is recognized by a monoclonal antibody 5-2-26. 913 Feb 35

Impaired vascular beta-adrenergic responsiveness may play an important role in the development and/or maintenance of hypertension. This defect has been associated with an alteration in receptor/guanine nucleotide regulatory protein (G-protein) interactions. However, the locus of this defect remains unclear. G-Protein-coupled receptor kinases (GRKs) phosphorylate serine/threonine residues on G-protein-linked receptors in an agonist-dependent manner. GRK activation mediates reduced receptor responsiveness and impaired receptor/G-protein coupling. To determine whether the impairment in beta-adrenergic response in human hypertension might be associated with altered GRK activity, we studied lymphocytes from younger hypertensive subjects as compared with older and younger normotensive subjects. We assessed GRK activity by rhodopsin phosphorylation and GRK expression by immunoblot. GRK activity was significantly increased in lymphocytes from younger hypertensive subjects and paralleled an increase in GRK-2 (beta ARK-1) protein expression. In contrast, no alterations in cAMP-dependent kinase (A-kinase) activity or GRK-5/6 expression were noted. GRK activity was not increased in lymphocytes from older normotensive subjects who demonstrated a similar impairment in beta-adrenergic-mediated adenylyl cyclase activation. These studies indicate that GRK activity is selectively increased in lymphocytes from hypertensive subjects. The increase in GRK activity may underlie the reduction in beta-adrenergic responsiveness characteristic of the hypertensive state.
...
PMID:G-protein-coupled receptor kinase activity is increased in hypertension. 915 75

In contrast to the 52-kDa Shc isoform, insulin stimulation caused a quantitative, time-dependent decrease in the SDS-PAGE mobility of 66-kDa Shc in both Chinese hamster ovary/IR cells and 3T3L1 adipocytes. Alkaline phosphatase treatment and direct phosphoamino acid analysis demonstrated that insulin stimulated an increase in serine phosphorylation of the 66-kDa isoform but not 52-kDa Shc, although the latter displayed a marked increase in tyrosine phosphorylation. To identify the responsible kinase pathway, we compared the effects on 66-kDa Shc serine phosphorylation by insulin, anisomycin, and osmotic shock, agents that specifically activate the ERK, JNK, or both pathways, respectively. Insulin and osmotic shock both stimulated a decrease in 66-kDa Shc mobility, whereas anisomycin had no effect. Furthermore, expression of a dominant-interfering Ras mutant (N17Ras) prevented the insulin-stimulated, but not the osmotic shock-induced serine phosphorylation of 66-kDa Shc. Consistent with a MEK-dependent pathway mediating 66-kDa Shc serine phosphorylation, the specific MEK inhibitor (PD98059) and expression of a dominant-interfering MEK mutant partially inhibited both the insulin and osmotic shock-induced reduction in 66-kDa Shc mobility. In contrast, expression of the MAP kinase phosphatase (MKP-1) completely prevented ERK activation but did not inhibit the serine phosphorylation of 66-kDa Shc. These data demonstrate that insulin stimulates the serine phosphorylation of the 66-kDa Shc isoform through a MEK-dependent mechanism.
...
PMID:Insulin stimulates the phosphorylation of the 66- and 52-kilodalton Shc isoforms by distinct pathways. 916 38

After insulin receptor activation, many cytoplasmic enzymes, including mitogen-activated protein (MAP) kinase, MAP kinase kinase (MEK) and casein kinase II (CKII) are activated, but exactly how insulin signalling progresses to the nucleus remains poorly understood. In Chinese hamster ovary cells overexpressing human insulin receptors [CHO(Hirc)], MEK, CKII and the MAP kinases ERK I and ERK II can be detected by immunoblotting in the nucleus, as well as in the cytoplasm, in the unstimulated state. Nuclear localization of MAP kinase is also observed in 3T3-F442A adipocytes, NIH-3T3 cells and Fao hepatoma cells, whereas MEK is found in the nucleus only in Fao and CHO cells. Insulin treatment for 5-30 min induces a translocation of MEK from the cytoplasm to the nucleus, whereas the MAP kinases and CKII are not translocated into the nucleus in response to insulin during this period. However, nuclear MAP kinase and CKII activities increase by 2-3-fold within 1-10 min after stimulation with insulin. By using gel-shift assays, it has been shown that insulin also stimulates nuclear protein binding to an AP-1 site with kinetics similar to MEK translocation and MAP kinase and CKII activation. Treatment of the extracts in vitro with protein phosphatase 2A or treatment of the intact cells with 5, 6-dichloro-1-beta-d-ribofuranosylbenzimidazole, a cell-permeable inhibitor of CKII, almost completely blocks the insulin-induced DNA-binding activity, whereas incubation of cells with a MEK inhibitor produces only a slight decrease. These results suggest that insulin signalling results in the activation of serine kinases in the nucleus via two pathways: (1) insulin stimulates the nuclear translocation of some kinases, such as MEK, which might directly phosphorylate nuclear protein substrates or activate other nuclear kinases, and (2) insulin activates nuclear kinases without translocation. The latter is true of CKII, which seems to regulate the binding of nuclear proteins to the AP-1 site, possibly by phosphorylation of AP-1 transcription factors.
...
PMID:Insulin regulation of mitogen-activated protein kinase kinase (MEK), mitogen-activated protein kinase and casein kinase in the cell nucleus: a possible role in the regulation of gene expression. 916 93

Rat C6 glioma cells have been used to characterize molecular events involved in the regulation of inducible nitric oxide synthase (iNOS) gene expression stimulated by interferon-gamma (IFN-gamma) plus lipopolysaccharide (LPS). IFNs induce a signaling event which involves activation of Stat1 transcription factor. Previous studies have shown that IFNs also induce extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) activation. However, the mechanisms by which IFNs stimulate MAPK activation remain elusive. Here we show that in C6 glioma cells, transiently expressing the dominant-negative form of c-Ha-Ras (Asn-17) abrogated IFN-gamma-induced ERK1 and ERK2 activation. Furthermore, PD98059, a specific MEK1 inhibitor, also blocked this activation. These results indicate that p21ras and MEK1 are required for IFN-gamma-induced ERK1 and ERK2 activation. Recent studies have reported that MAPK is responsible for serine phosphorylation of Stat1 which is required for Stat1's DNA binding and maximal transcriptional activity. Thus, we examined the role of the Ras-MAPK pathway in Stat1 activation and subsequent iNOS induction in C6 glioma cells. Further experiments showed that neither Asn-17 Ras expression nor concentrations of PD98059, which completely abrogated IFN-gamma-induced ERK1 and ERK2 activation, affected Stat1 DNA binding activity or iNOS induction, indicating that the Ras-MAPK pathway does not appear to be involved in the activation of Stat1 and subsequent iNOS induction in C6 glioma cells.
...
PMID:Activation of Stat1 and subsequent transcription of inducible nitric oxide synthase gene in C6 glioma cells is independent of interferon-gamma-induced MAPK activation that is mediated by p21ras. 918 Feb 63

One of the most promising targets for the rational design of anti-cancer drugs is the family of the EGF-receptor protein tyrosine kinases. Despite the high sequence homology within the ATP-binding region of protein tyrosine and/or serine threonine kinases, ATP-competitive compounds have the potential to be selective inhibitors of protein kinases. Dianilino-phthalimides CGP 52 411 and CGP 53,353 have been identified as potent and ATP-competitive inhibitors of the EGF-R tyrosine kinase with no or only minor activity against a panel of tyrosine and serine/threonine kinases. Using a calculated 3-D computer model of the catalytic domain of the EGF-R-tyrosine kinase together with CGP 52 411 as example of an ATP-competitive inhibitor, a pharmacophore model for ATP-competitive inhibitors in the active site of the EGF-R PTK was developed. With the help of this model, 4-phenylamino-7H-pyrrolo[2,3-d]pyrimidines were then identified as new potent EGF-R PTK inhibitors. In an interactive process, the class of the 4-phenylamino-pyrrolo-pyrimidines was optimized and structure-activity-relationship of a series of derivatives thereof are discussed. In vitro, the most active compounds (CGP 59 326, CGP 60 261, CGP 62 706) inhibited the EGF-R tyrosine kinase with IC50 value between 6-30 nM. High selectivity towards a panel of non-receptor tyrosine kinases (c-SRC, v-Abl) and serine/threonine kinases (PKC alpha, PKA) was observed. Kinetic analysis revealed competitive type kinetics relative to ATP. In cells, EGF-stimulated cellular tyrosine phosphorylation was inhibited by these compounds at IC50 values between 0.1-0.3 microM, whereas the ligand-induced receptor autophosphorylation of the PDGR-R was not effected by concentrations up to 100 microM. Furthermore, CGP 59 326, CGP 60 261, CGP 62 706 were able to selectively inhibit c-fos mRNA expression in EGF-dependent cell lines with (IC50) approx. 0.1-1 microM) but not in EGF-independent cell systems (IC50 > 100 microM). Proliferation of the EGF-dependent MK cell line was inhibited with similar IC50 values. In addition, CGP 59 326 and CGP 62 706 showed good in vivo efficacy at low doses after oral or subcutaneous administration in nude mice tumor models using xenografts of the EGF-dependent A431 cell lines. The ED50 values were between 1.5-2 mg/kg. Phenylamino-pyrrolo-pyrimidines therefore represent a new series of tyrosine kinase inhibitors which preferentially inhibit the EGF-mediated signal transduction pathway and have the characteristics for further evaluation as anticancer agents.
...
PMID:Design and synthesis of novel tyrosine kinase inhibitors using a pharmacophore model of the ATP-binding site of the EGF-R. 919 32

Germ-like and somatic mutations in the RET proto-oncogene are associated with inherited and sporadic medullary thyroid carcinoma (MTC). The majority of patients with multiple endocrine neoplasia type 2A (MEN2A) and familial medullary thyroid carcinoma (FMTC) carry germ-line point mutations that result in the substitution of one of five cysteine residues. We investigated exons 10, 11, 13, 14 and 16 of the RET proto-oncogene in 33 unrelated Japanese patients with MTC. Eleven of the 33 cases (33%) were found to have germ-line mutations. Three previously unreported mutations in exon 10 and 11 were identified: one in codon 620, (TGC-->GGC), resulting in a cysteine to glycine substitution, and two in codon 630, (TGC-->TCC) and (TGC-->TAC), resulting in cysteine to serine and cysteine to tyrosine changes, respectively. The new mutations were present in the germ-line DNA of four unrelated patients for whom a family history of MTC had not been documented. Because the new RET alleles described here involve cysteine residues in a region of protein previously associated with FMTC and MEN2A, it is very likely that they represent mutations that predispose to the development of MTC.
...
PMID:Novel germline RET proto-oncogene mutations associated with medullary thyroid carcinoma (MTC): mutation analysis in Japanese patients with MTC. 922 75

Calcium deposition diseases caused by calcium pyrophosphate dihydrate (CPPD) and basic calcium phosphate (BCP) crystals are a significant source of morbidity in the elderly. We have shown previously that both types of crystals can induce mitogenesis, as well as metalloproteinase synthesis and secretion by fibroblasts and chondrocytes. These responses may promote degradation of articular tissues. We have also shown previously that both CPPD and BCP crystals activate expression of the c-fos and c-jun proto-oncogenes. Phosphocitrate (PC) can specifically block mitogenesis and proto-oncogene expression induced by either BCP or CPPD crystals in 3T3 cells and human fibroblasts, suggesting that PC may be an effective therapy for calcium deposition diseases. To understand how PC inhibits BCP and CPPD-mediated cellular effects, we have investigated the mechanism by which BCP and CPPD transduce signals to the nucleus. Here we demonstrate that BCP and CPPD crystals activate a protein kinase signal transduction pathway involving p42 and p44 mitogen-activated protein (MAP) kinases (ERK 2 and ERK 1). BCP and CPPD also cause phosphorylation of a nuclear transcription factor, cyclic AMP response element-binding protein (CREB), on serine 133, a residue essential for CREB's ability to transactivate. Treatment of cells with PC at concentrations of 10(-3) to 10(-5) M blocked both the activation of p42/p44 MAP kinases, and CREB serine 133 phosphorylation, in a dose-dependent fashion. At 10(-3) M, a PC analogue, n-sulfo-2-aminotricarballylate and citrate also modulate this signal transduction pathway. Inhibition by PC is specific for BCP- and CPPD-mediated signaling, since all three compounds had no effect on serum-induced p42/P44 or interleukin-1beta induced p38 MAP kinase activities. Treatment of cells with an inhibitor of MEK1, an upstream activator of MAPKs, significantly inhibited crystal-induced cell proliferation, suggesting that the MAPK pathway is a significant mediator of crystal-induced signals.
...
PMID:Phosphocitrate inhibits a basic calcium phosphate and calcium pyrophosphate dihydrate crystal-induced mitogen-activated protein kinase cascade signal transduction pathway. 922 71


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---