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)

Serum erythropoietic activity and reticulocyte response to anemia were investigated using a rabbit model. In hemolytic anemia, induced by injections of phenylhydrazine on Day 0 the hemoglobin reached a nadir (mean, 6.23 g/dl) on Day 4 when SEA was maximal (mean, 765 mU/ml). In animals venesected on Day 0 and Day 1 to produce anemia of equal severity, the SEA was maximal (mean 235 mU/ml) on Day 2. In both groups the reticulocyte response peaked on Day 7--at 34% for the hemolytic group and 21% for the venesected group. The 2,3-diphosphoglycerate, measured on Day 4, was significantly reduced in the PHZ-treated group. In the venesected group the 2,3-DPG increased between Day 0 and Day 4. There were no concurrent changes in acid-base balance. These results imply that the degree of anemia is only one of the factors which influence the level of circulating SEA.
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PMID:Serum erythropoietic activity in acute anemia--an animal model. 271 49

Fetal oxygen supply depends on the one hand on placental perfusion and on the other on maternal and fetal oxygen transport parameters. In the study reported here the maternal oxygen transport parameters, such as the O2 half-saturation pressure P50 (mmHg) and the factors influencing it (2, 3-DPG, ATP, pH) were studied in high-risk pregnancies in comparison with a control group of normal pregnancies. A total of 112 patients at the Department of Gynecology and Obstetrics of the Rhine-Westphalian Technical University in Aachen were examined. All calculations were done with the BMDP static analysis system. Using the Mann-Whitney test, no location differences in the various parameters were detected at the level alpha = 0,05 between to group of patients with EPH gestosis and the control group. The same results were obtained when patients with placental insufficiency were compared with the control group. In contrast, a significant shift in location in oxygen transport was detectable in patients in whom there was an imminent danger of premature birth. In such cases it must be assumed that the fetus is at risk. After at least two days' intravenous administration of Fenoterol the possibility of a transient deficiency of fetal oxygen supply due to the change in the maternal oxygen transport parameters must be considered, since it cannot be assumed that there will be a compensatory increase in placental perfusion under Fenoterol. With peroral tokolysis the oxygen supply to the fetus is not impaired as far as maternal oxygen transport parameters are concerned.
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PMID:[Parameters of maternal oxygen transport in risk pregnancies]. 368 51

In a screen for receptor protein-tyrosine kinase (RTK) genes expressed during gametogenesis in the cnidarian Hydra vulgaris, we isolated a cDNA encoding Lemon, an RTK with unusual features. Lemon is orthologous to Drosophila Dtrk, chicken Klg, and human colon carcinoma kinase-4. These genes constitute an RTK class characterized by a conserved transmembrane sequence, the presence of extracellular immunoglobulin-like repeats, and the absence of the DFG motif in the kinase domain. We provide evidence that Lemon is a component of an unusual RTK signal transduction mechanism that may involve transmembrane domain-mediated interactions and may not be dependent on its own catalytic activity. Lemon transcription is dynamically regulated in interstitial cells during asexual budding and gametogenesis. Transcriptional up-regulation occurs early in spermatogenesis and oogenesis concurrent with the local accumulation of interstitial cells in the body column of sexual polyps.
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PMID:Lemon encodes an unusual receptor protein-tyrosine kinase expressed during gametogenesis in Hydra. 1092 67

Complement receptors (CRs), along with Fc receptors, play a primary role in the removal of bacterial pathogens in poultry. The binding of serum-opsonized bacteria to CR results in the secretion of both toxic oxygen metabolites and antibacterial granules. We have previously shown that the stimulation of chicken heterophils with serum-opsonized Salmonella enteritidis induced tyrosine kinase-dependent phosphorylation regulated degranulation. In the present studies, we used selective pharmacological inhibitors to investigate the roles of protein tyrosine kinases, phospholipases C and D (PLC and PLD), phosphatidylinositol 3'-kinase (PI3-K), and the super family of mitogen-activated protein kinases (MAPKs) on CR-mediated heterophil degranulation. Inhibitors of receptor-linked tyrosine kinases (the tryphostins AG1478 and AG1296) had no attenuating effects on CR-mediated degranulation. However, PP2, a selective inhibitor of the src family of protein tyrosine kinases, and piceatannol, an inhibitor of Syk tyrosine kinases, both significantly attenuated the CR-mediated degranulation. Additionally, the specific inhibitors of PLC, U73122, and PI3-K, LY294002, significantly decreased CR-mediated heterophil degranulation. Two inhibitors of PLD-mediated signaling, 2,3-diphosphoglycerate (2,3-DPG) and 1-butanol, hindered degranulation. Addition of purified PLD restored control levels of degranulation in heterophils in which PLD was inhibited. Lastly, SP600125, a selective inhibitor of c-Jun N-terminal kinase (JNK), inhibited degranulation; whereas neither PD98059, the inhibitor of p38 MAPK, nor SB203580, the inhibitor of extracellular signal-regulated kinase, had any effect on CR-mediated heterophil degranulation. These studies demonstrate that CRs on chicken heterophils lack intrinsic tyrosine kinase activity, but that binding of serum-opsonized bacteria activates both proximal tyrosine kinases (src and Syk kinases), but differentially activates downstream tyrosine kinases (JNK, but not p38 nor ERK). Activation of src and Syk kinases plays a significant role in signal transduction of heterophil degranulation probably by stimulating downstream phosphorylation of PLC, PLD, and PI3-K. PI3-K has also been recently shown to be an upstream mediator of JNK activation, suggesting that this enzyme can induce signaling as both a lipid kinase and protein kinase. Engaging CRs on chicken heterophils activates a proximal tyrosine kinase (src and Syk kinases)-->PLC (PLD)-->PI3-K-->JNK signal transduction pathway that induces degranulation.
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PMID:The use of selective pharmacological inhibitors to delineate signal transduction pathways activated during complement receptor-mediated degranulation in chicken heterophils. 1275 38

Mice heterozygous for the N-ethyl-N-nitrosourea-induced Waved-5 (Wa5) mutation, isolated in a screen for dominant, visible mutations, exhibit a wavy coat similar to mice homozygous for the recessive Tgfa wa1 or Egfr wa2 alleles. In this study, we show that Wa5 is a new allele of Egfr (Egfr Wa5) containing a missense mutation within the coding region for the highly conserved DFG motif of the tyrosine kinase domain. In vivo analysis of placental development, modification of Apc Min tumorigenesis, and levels of EGF-dependent EGFR phosphorylation demonstrates that Egfr Wa5 functions as an antimorphic allele, recapitulating many abnormalities associated with reduced EGFR activity. Furthermore, Egfr wa5 enhances Egfr Wa2 compound or Tgfa tm1Dcl double mutants exposing additional EGFR-dependent phenotypes. In vitro characterization shows that the antimorphic property of Egfr Wa5 is caused by a kinase-dead receptor acting as a dominant negative.
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PMID:Wa5 is a novel ENU-induced antimorphic allele of the epidermal growth factor receptor. 1536 72

ERK2 is a proline-directed protein kinase that displays a high specificity for a single threonine (Thr-38) on the substrate Ets-1, which lies within the consensus sequence 36phi-chi-Thr-Pro39 (where phi is typically a small hydrophobic residue and chi appears to be unrestricted). Thr-38 lies in a long flexible N-terminal tail (residues 1-52), which also contains a second potential phosphorylation site, Ser-26. How Ets-1 binds ERK2 to promote the phosphorylation of Thr-38 while simultaneously discriminating against the phosphorylation of Ser-26 is unclear. To delineate the details of the molecular recognition of Ets-1 by ERK2, the binding of various mutants and truncations of Ets-1 were analyzed by fluorescence anisotropy. The data that were obtained support the notion that the N-terminal tail contains a previously unrecognized docking site that promotes the phosphorylation of Thr-38. This new docking site helps assemble the complex of Ets-1 and ERK2 and makes a similar contribution to the stabilization of the complex as does the pointed domain of Ets-1. The in vitro activation of ERK2 by MKK1 induces a large conformational transition of the activation segment (DFG-APE), but neither induces self-association of ERK2 nor destabilizes the stability of the ERK2.Ets-1 complex. This latter observation suggests that interactions intrinsic to the active site are not important for complex assembly, a notion further supported by the observation that the substitution of a number of different amino acids for Pro-39 does not destabilize the complex. Mutagenesis of ERK2 within loop 13 suggests that Ets-1 binds the substrate-binding groove. These data suggest that ERK2 uses two weak docking interactions to specifically assemble the complex, perhaps in doing so denying Ser-26 access to the active site. Displacement of residues 1-138 of Ets-1 (EtsDelta138) from ERK2 by the peptide N-QKGKPRDLELPLSPSL-C, derived from Elk-1, suggests that Ets-1 engages the D-recruitment site (beta7-beta8 reverse turn and the alphaD-alphaE helix) of ERK2. Displacement of EtsDelta138 from ERK2 by the peptide N-AKLSFQFPS-C derived from Elk-1 shows that EtsDelta138 communicates with the F-recruitment site of ERK2 also.
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PMID:Properties and regulation of a transiently assembled ERK2.Ets-1 signaling complex. 1710 91

Germ line missense mutations in the RET (rearranged during transfection) oncogene are the cause of multiple endocrine neoplasia, type 2 (MEN2), but at present surgery is the only treatment available for MEN2 patients. In this study, the ability of Sorafenib (BAY 43-9006) to act as a RET inhibitor was investigated. Sorafenib inhibited the activity of purified recombinant kinase domain of wild type RET and RET(V804M) with IC(50) values of 5.9 and 7.9 nm, respectively. Interestingly, these values were 6-7-fold lower than the IC(50) for the inhibition of B-RAF(V600E). In cell-based assays, Sorafenib inhibited the kinase activity and signaling of wild type and oncogenic RET in MEN2 tumor and established cell lines at a concentration between 15 and 150 nm. In contrast, inhibition of oncogenic B-RAF- or epidermal growth factor-induced ERK1/2 phosphorylation required micromolar concentrations of Sorafenib demonstrating the high specificity of this drug in targeting RET. Moreover, prolonged exposure to Sorafenib resulted in inhibition of cell proliferation and RET protein degradation. Using lysosomal and proteasomal inhibitors, we demonstrate that Sorafenib induces RET lysosomal degradation independent of proteasomal targeting. Furthermore, we provide a structural model of the Sorafenib.RET complex in which Sorafenib binds to and induces the DFG(out) conformation of the RET kinase domain. These results strengthen the argument that Sorafenib may be effective in the treatment of MEN2 patients. In addition, because inhibition of RET is not impaired by mutation of the Val(804) gatekeeper residue, MEN2 tumors may be less susceptible to acquired Sorafenib resistance.
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PMID:Sorafenib functions to potently suppress RET tyrosine kinase activity by direct enzymatic inhibition and promoting RET lysosomal degradation independent of proteasomal targeting. 1766 73

The p90 ribosomal S6 kinases (RSKs) also known as MAPKAP-Ks are serine/threonine protein kinases that are activated by ERK or PDK1 and act as downstream effectors of mitogen-activated protein kinase (MAPK). RSK1, a member of the RSK family, contains two distinct kinase domains in a single polypeptide chain, the regulatory C-terminal kinase domain (CTKD) and the catalytic N-terminal kinase domain (NTKD). Autophosphorylation of the CTKD leads to activation of the NTKD that subsequently phosphorylates downstream substrates. Here we report the crystal structures of the unactivated RSK1 NTKD bound to different ligands at 2.0 A resolution. The activation loop and helix alphaC, key regulatory elements of kinase function, are disordered. The DFG motif of the inactive RSK1 adopts an "active-like" conformation. The beta-PO(4) group in the AMP-PCP complex adopts a unique conformation that may contribute to inactivity of the enzyme. Structures of RSK1 ligand complexes offer insights into the design of novel anticancer agents and into the regulation of the catalytic activity of RSKs.
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PMID:Crystal structures of the N-terminal kinase domain of human RSK1 bound to three different ligands: Implications for the design of RSK1 specific inhibitors. 1796 87

The mammalian ortholog of the retroviral oncogene v-Eyk, and a receptor tyrosine kinase upstream of antiapoptotic and transforming signals, Mer (MerTK) is a mediator of the phagocytic process, being involved in retinal and immune cell clearance and platelet aggregation. Mer knockout mice are viable and are protected from epinephrine-induced pulmonary thromboembolism and ferric chloride-induced thrombosis. Mer overexpression, on the other hand, is associated with numerous carcinomas. Although Mer adaptor proteins and signaling pathways have been identified, it remains unclear how Mer initiates phagocytosis. When bound to its nucleotide cofactor, the high-resolution structure of Mer shows an autoinhibited alphaC-Glu-out conformation with insertion of an activation loop residue into the active site. Mer complexed with compound-52 (C52: 2-(2-hydroxyethylamino)-6-(3-chloroanilino)-9-isopropylpurine), a ligand identified from a focused library, retains its DFG-Asp-in and alphaC-Glu-out conformation, but acquires other conformational changes. The alphaC helix and DFGL region is closer to the hinge region and the ethanolamine moiety of C52 binds in the groove formed between Leu593 and Val601 of the P-loop, causing a compression of the active site pocket. These conformational states reveal the mechanisms of autoinhibition, the pathophysiological basis of disease-causing mutations, and a platform for the development of chemical probes.
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PMID:Structural insights into the inhibited states of the Mer receptor tyrosine kinase. 1902 87

B-Raf protein kinase, which is a key signaling molecule in the RAS-RAF-MEK-ERK signaling pathway, plays an important role in many cancers. The B-Raf V600E mutation represents the most frequent oncogenic kinase mutation known and is responsible for increased kinase activity in approximately 7% of all human cancers, establishing B-Raf as an important therapeutic target for inhibition. Through the use of an iterative program that utilized a chemocentric approach and a rational structure based design, we have developed novel, potent, and specific DFG-out allosteric inhibitors of B-Raf kinase. Here, we present efficient and versatile chemistry that utilizes a key one pot, [3+2] cycloaddition reaction to obtain highly substituted imidazoles and their application in the design of allosteric B-Raf inhibitors. Inhibitors based on this scaffold display subnanomolar potency and a favorable kinase profile.
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PMID:Application of a novel [3+2] cycloaddition reaction to prepare substituted imidazoles and their use in the design of potent DFG-out allosteric B-Raf inhibitors. 1996 19


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