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)

PC12-E2 cells, a stable variant subcloned from native cell populations, produce neurites in a rapid, transcription-independent manner upon exposure to nerve growth factor (NGF) or basic fibroblast growth factor (bFGF). They also give a similar morphological response to interleukin-6 (IL-6), which is, however, transcription-dependent and with a slower onset, a phenomenon basically not observed in native PC12 cells. The response profile of PC12-E2 cells to NGF and bFGF is similar to that observed for native PC12 cells pre-exposed (primed) to NGF, and such cells also respond to IL-6 in a fashion indistinguishable from PC12-E2 cells. Mechanistically, NGF and bFGF induce a sustained phosphorylation and activation of ERK1 and ERK2 in both cells, while IL-6 produces only a transient and weak tyrosine phosphorylation. However, it does stimulate a prolonged and biphasic tyrosine phosphorylation and nuclear translocation of Stat3 (signal transducers and activators of transcription 3; at least 24 h) and, to a lesser extent, Stat1. Gel shift and supershift analyses confirm that IL-6 predominantly activates Stat3 (and some Stat1) and stimulates sis-inducible element binding activity. Other members of the same cytokine subfamily, including ciliary neurotrophic factor and leukemia inhibitory factor, also cause a transient initial phase of tyrosine phosphorylation and activation of Stat1 and Stat3 (up to 1 h) but fail to stimulate a second phase of response and do not produce significant neurites. These results suggest that sustained signaling of either STAT or ERK pathways in PC12-E2 cells leads to induction of neuronal differentiation. However, only the latter is effective in native PC12 cells as the activation of Stat3 and Stat1 in native PC12 cells by IL-6 fails to induce neuronal differentiation. Thus, the response of PC12-E2 cells to IL-6 suggests the constitutive expression of a required factor(s) for differentiation, that is induced in native PC12 cells by NGF or bFGF (possibly by ERK activation), but not by IL-6 via Janus kinase/STAT activation. This factor(s), which has a sufficient half-life to allow primed cells to remain responsive to IL-6 for several days, is necessary but not sufficient for differentiation (as measured by neurite proliferation) to occur.
...
PMID:Induction of neurite outgrowth by interleukin-6 is accompanied by activation of Stat3 signaling pathway in a variant PC12 cell (E2) line. 866 45

Interleukin-5 (IL-5) is one of the major regulators of eosinophilic granulocytes in vivo. IL-5 exerts its pleiotropic effects by binding to the IL-5 receptor, which is composed of an IL-5-specific alpha chain and a common betac chain shared with the receptors for IL-3 and granulocyte-macrophage colony-stimulating factor. Previous studies have shown that binding of IL-5 to its receptor triggers the activation of multiple signaling cascades, including the Ras/mitogen-activated protein kinase, the phosphatidyl -3'-kinase, and the Janus kinase/signal transducer and activator of transcription pathways. Here we describe that IL-5 activates the serine/threonine protein kinase Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) pathway. We show that IL-5 activates TPA response element (TRE)-dependent transcription in transfection experiments. TRE activation by IL-5 is mediated by a region of the betac (577-581) that is also responsible for activation of JNK/SAPK and for activation of dyad symmetry element (DSE)-dependent transcription. Dominant-negative SAPK or ERK kinase-1 was used to demonstrate that JNK/SAPK activation is necessary for induction of DSE- and TRE-dependent transcription by IL-5, whereas extracellular signal-regulated kinase 2 was not essential for TRE- and DSE-dependent transcription. By contrast, IL-5-induced activation of the tyrosine kinase Janus kinase 2 seems to be a prerequisite for TRE- and DSE-dependent transcription. Taken together, we show for the first time that IL-5 activates kinases of the JNK/SAPK family, and that this activation is linked to IL-5-induced TRE- and DSE-dependent transcription.
...
PMID:Activation of 12-O-tetradecanoylphorbol-13-acetate response element- and dyad symmetry element-dependent transcription by interleukin-5 is mediated by Jun N-terminal kinase/stress-activated protein kinase kinases. 899 40

Stem Cell Factor (SCF), the ligand for the c-kit proto-oncogene, has been shown to synergistically interact with other cytokines, enhancing the responsiveness of haemopoietic precursors. In this study we have examined the effects of SCF, in combination with interleukin-3 (IL-3), on FDCP-Mix A4 cells, a murine, multipotent, haemopoietic progenitor cell line. Low concentration of IL-3 act to enhance cell survival but do not stimulate proliferation in A4 cells. Similarly, SCF when added alone, acts as a good survival stimulus, but is a poor proliferative stimulus. However, in combination with low concentrations of IL-3, SCF stimulates a synergistic enhancement of proliferation leading to a large increase in cell number after seven days. The synergy observed was not due to SCF stimulated alterations in the mRNA, protein levels or affinity of the IL-3 receptors. Therefore, interactions between cytokines at the level of cytoplasmic signalling pathways were investigated. IL-3 stimulated the rapid and transient tyrosine phosphorylation of several proteins (including those of molecular weights 130, 110, 100, 95, 80, 65, 50 and 45 kDa). Some of these proteins were identified as the Src Homology Collagen (SHC) protein, Janus kinase (JAK-2) and the Mitogen Activated Protein Kinase isoforms ERK 1 and ERK 2. IL-3 also stimulated a transient increase in the activity of both ERK 1 and 2. SCF stimulated a rapid and transient increase in the tyrosine phosphorylation of ERK 1 and ERK 2 although, coaddition of SCF with IL-3, caused no gross differences in the phosphorylation of SHC, JAK-2 or ERKs compared to those observed with IL-3 alone. Coaddition of SCF and low concentration of IL-3 stimulated a reproducible synergistic increase in the activity of ERK 2, whereas only an additive increase in the activity of ERK 1 was observed. These results suggest that ERK 2 activation represents a point at which the two pathways, stimulated by IL-3 and SCF, interact synergistically.
...
PMID:Investigation of the molecular mechanisms underlying growth factor synergy: the role of ERK 2 activation in synergy. 971 13

The signal transducer and activator of transcription (STAT) proteins deliver signals from the cell membrane to the nucleus. An N-terminally truncated fragment of murine Stat3beta, Stat3betatc (127-722), was produced in bacteria. STAT proteins must be specifically phosphorylated at a single tyrosine residue for dimerization and DNA binding. Therefore, Stat3betatc was coexpressed with the catalytic domain of the Elk receptor tyrosine kinase. Stat3betatc was quantitatively phosphorylated by this kinase domain. Gel filtration chromatography revealed a Stat3betatc dimer. Y705 was identified as the major phosphorylated residue of Stat3betatc. This corresponds to the tyrosine residue which is phosphorylated by the Janus kinase in vivo. The phosphorylated Stat3betatc specifically bound to DNA binding sites. The described protocol allows the production of large amounts of activated protein for biochemical and pharmaceutical studies.
...
PMID:Expression of a tyrosine phosphorylated, DNA binding Stat3beta dimer in bacteria. 987 82

A novel homology model of the kinase domain of Janus kinase (JAK) 3 was used for the structure-based design of dimethoxyquinazoline compounds with potent and specific inhibitory activity against JAK3. The active site of JAK3 in this homology model measures roughly 8 A x 11 A x 20 A, with a volume of approximately 530 A3 available for inhibitor binding. Modeling studies indicated that 4-(phenyl)-amino-6,7-dimethoxyquinazoline (parent compound WHI-258) would likely fit into the catalytic site of JAK3 and that derivatives of this compound that contain an OH group at the 4' position of the phenyl ring would more strongly bind to JAK3 because of added interactions with Asp-967, a key residue in the catalytic site of JAK3. These predictions were consistent with docking studies indicating that compounds containing a 4'-OH group, WHI-P131 [4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline], WHI-P154 [4-(3'-bromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline], and WHI-P97 [4-(3',5'-dibromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazolin e], were likely to bind favorably to JAK3, with estimated K(i)s ranging from 0.6 to 2.3 microM. These compounds inhibited JAK3 in immune complex kinase assays in a dose-dependent fashion. In contrast, compounds lacking the 4'-OH group, WHI-P79 [4-(3'-bromophenyl)-amino-6,7-dimethoxyquinazoline], WHI-P111 [4-(3'-bromo-4'-methylphenyl)-amino-6,7-dimethoxyquinazoline], WHI-P112 [4-(2',5'-dibromophenyl)-amino-6,7-dimethoxyquinazoline], WHI-P132 [4-(2'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline], and WHI-P258 [4-(phenyl)-amino-6,7-dimethoxyquinazoline], were predicted to bind less strongly, with estimated K(i)s ranging from 28 to 72 microM. These compounds did not show any significant JAK3 inhibition in kinase assays. Furthermore, the lead dimethoxyquinazoline compound, WHI-P131, which showed potent JAK3-inhibitory activity (IC50 of 78 microM), did not inhibit JAK1 and JAK2, the ZAP/SYK family tyrosine kinase SYK, the TEC family tyrosine kinase BTK, the SRC family tyrosine kinase LYN, or the receptor family tyrosine kinase insulin receptor kinase, even at concentrations as high as 350 microM. WHI-P131 induced apoptosis in JAK3-expressing human leukemia cell lines NALM-6 and LC1;19 but not in melanoma (M24-MET) or squamous carcinoma (SQ20B) cells. Leukemia cells were not killed by dimethoxyquinazoline compounds that were inactive against JAK3. WHI-P131 inhibited the clonogenic growth of JAK3-positive leukemia cell lines DAUDI, RAMOS, LC1;19, NALM-6, MOLT-3, and HL-60 (but not JAK3-negative BT-20 breast cancer, M24-MET melanoma, or SQ20B squamous carcinoma cell lines) in a concentration-dependent fashion. Potent and specific inhibitors of JAK3 such as WHI-P131 may provide the basis for the design of new treatment strategies against acute lymphoblastic leukemia, the most common form of childhood cancer.
...
PMID:Structure-based design of specific inhibitors of Janus kinase 3 as apoptosis-inducing antileukemic agents. 1038 46

IL-9 is a Th2 cytokine active on various cell types such as T and B lymphocytes, mast cells, and eosinophils, and potentially involved in allergy and asthma. To understand better the molecular mechanisms underlying the activity of this cytokine, we used a cDNA subtraction method to identify genes specifically induced by IL-9 in mouse T cells. One of the IL-9-regulated genes isolated by this approach turned out to encode a 180-amino acid long protein, including a potential signal peptide, and showing 22% amino acid identity with IL-10. This protein, designated IL-10-related T cell-derived inducible factor (IL-TIF), is induced by IL-9 in thymic lymphomas, T cells, and mast cells, and by lectins in freshly isolated splenocytes. Experiments concerning the mechanism regulating IL-TIF expression in T cells indicate that IL-9 induction is rapid (within 1 h), does not require protein synthesis, and depends on the activation of the Janus kinase (JAK)-STAT pathway. In vivo, constitutive expression of IL-TIF was detected by RT-PCR in thymus and brain, suggesting that the role of this new factor is not restricted to the immune system. Transfection of HEK293 cells with the IL-TIF cDNA resulted in the production of a glycosylated protein of about 25 kDa that was found to induce STAT activation in mesangial and neuronal cell lines. Further studies will have to address the possibility that some of the IL-9 activities may be mediated by IL-TIF.
...
PMID:Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9. 1065 29

The effects of pituitary and extrapituitary prolactin include cellular proliferation and differentiation. PC12 cells was used as a model to delineate respective signaling of prolactin. Prolactin acted as a mitogen for undifferentiated PC12 cells, as measured by significant increases in bromodeoxyuridine incorporation and in cell numbers, with an efficacy equal to epidermal growth factor. Both the long and short form of the prolactin receptor was expressed, yet only the long isoform was tyrosine-phosphorylated upon agonist binding. Functional prolactin receptor signaling was further demonstrated in the activation of JAK2 and phosphorylation activation of the transcription factors Stat1, -3, and -5a. Surprisingly, prolactin stimulated a sustained activation of Raf-B, without activation of the MAP kinases ERK1 or -2. Instead, in solid phase kinase assays using a glutathione S-transferase-c-Jun fusion protein (amino acids 1-79) as the substrate, a significant activation of the mitogen-activated protein Janus kinase (c-Jun N-terminal kinase; JNK) was observed. The prolactin-induced activation of JNK was prolonged and accompanied by a significant increase in c-Jun mRNA abundance and c-Jun protein synthesis. Moreover, analysis of bromodeoxyuridine incorporation at the single cell level revealed that epidermal growth factor-dependent incorporation was inhibited by PD98059 and independent of SB203580, whereas prolactin-induced incorporation was ERK and mitogen-activated protein kinase p38 independent but was abolished with JNK inhibition by 30 microm SB203580. Our studies suggest that prolactin may have a role in the growth of PC12 cells, where it stimulates concurrent mitogenic and differentiation-promoting signaling pathways.
...
PMID:Prolactin-induced cell proliferation in PC12 cells depends on JNK but not ERK activation. 1080 11

In normal development, embryonic astrocytes progress through their cell lineage by acquiring differentiation, by apoptosis, and by proliferation. In this study, we show that embryonic astrocytes may maintain and make gains in differentiation as they simultaneously progress through one cell cycle when induced by prolactin (PRL). Prolactin induced the majority of astrocytes to incorporate bromodeoxyuridine (BrdU) with a four-fold increase over controls after 18 h of exposure. Investigating possible mitogenic signaling pathways we show for the first time that prolactin is coupled to a sustained phospholipase D (PLD) activation, with an efficacy similar to the phorbol ester and astrocytic mitogen 12-tetradecanoylphorbol-13-acetate (TPA). Both cyclosporine and suramin abolished this activation. Staurosporine and calphostin C also inhibited the PRL effect by 50%, consistent with involvement of protein kinase C-(PKC)-alpha, the major PKC isoform in astrocytes. Genistein and PP1 blocked the activation indicating additional regulation by cytosolic tyrosine kinases. This profile of PLD activation was suggestive of a PLD I isoform and a mitogenic response. Upon completion of the cell cycle, analysis of glia fibrillary acidic protein (GFAP) and vimentin abundance, and glutamine synthetase (GS) activity showed that astrocytes had gained in expression of differentiation markers. Moreover, the intensity of GFAP immunofluorescence was greater per cell, as was the length of the cell processes. In exploring the signaling for prolactin-induced differentiation we found that prolactin activated the tyrosine kinase Janus kinase (JAK) 2 and significantly stimulated tyrosine, phosphorylation of the prolactin receptor. Stat 1 and 3 were also activated presumably downstream to JAK2 activation. A rapid translocation of the cytosolic Stats over the nucleus was seen in nearly every astrocyte corresponding well with the gains in GFAP per cell. The Stats translocation did not depend on MEK-ERK inhibition by PD98059, inhibition of p38 by 1 microm SB203580, or Src kinase family inhibition by PP1. Our results demonstrate the ability of PRL to concurrently induce activation of PLD, a mitogenic signaling pathway in astrocytes, and prolonged stimulation of Stat1, compatible with the increased GFAP upregulation and cell differentiation. Considered together this data may provide an explanation on the fast gain in both numbers and differentiation in the astrocytic population during development (HD 09402, CRF).
...
PMID:Prolactin concurrently activates src-PLD and JAK/Stat signaling pathways to induce proliferation while promoting differentiation in embryonic astrocytes. 1097 48

Reactive gliosis is the most prominent response to diverse forms of central nervous system (CNS) injury. The signaling events that mediate this characteristic response to neural injury are under intense investigation. Several studies have demonstrated the activation of phosphoproteins within the mitogen-activated protein kinase (MAPK) and Janus kinase (JAK) pathways following neural insult. These signaling pathways may be involved or responsible for the glial response following injury, by virtue of their ability to phosphorylate and dynamically regulate the activity of various transcription factors. This study sought to delineate, in vivo, the relative contribution of MAPK- and JAK-signaling components to reactive gliosis as measured by induction of glial-fibrillary acidic protein (GFAP), following chemical-induced neural damage. At time points (6, 24, and 48 h) following methamphetamine (METH, 10 mg/kg x 4, s.c.) administration, female C57BL/6J mice were sacrificed by focused microwave irradiation, a technique that preserves steady-state phosphorylation. Striatal (target) and nontarget (hippocampus) homogenates were assayed for METH-induced changes in markers of dopamine (DA) neuron integrity as well as differences in the levels of activated phosphoproteins. GFAP upregulation occurred as early as 6 h, reaching a threefold induction 48 h following METH exposure. Neurotoxicant-induced reductions in striatal levels of DA and tyrosine hydroxylase (TH) paralleled the temporal profile of GFAP induction. Blots of striatal homogenates, probed with phosphorylation-state specific antibodies, demonstrated significant changes in activated forms of extracellular-regulated kinase 1/2 (ERK 1/2), c-jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), MAPK/ERK kinase (MEK1/2), 70-kDa ribosomal S6 kinase (p70 S6), cAMP responsive element binding protein (CREB), and signal transducer and activator of transcription 3 (STAT3). MAPK-related phosphoproteins exhibited an activation profile that peaked at 6 h, remained significantly increased at 24, and fell to baseline levels 48 h following neurotoxicant treatment. The ribosomal S6 kinase was enhanced over 60% for all time points examined. Immunoreactivity profiles for the transcription factors CREB and STAT3 indicated maximal increases in phosphorylation occurring at 24 h, and measuring greater than 2- or 17-fold, respectively. Specific signaling events were found to occur with a time course suggestive of their involvement in the gliotic response. The toxicant-induced activation of these growth-associated signaling cascades suggests that these pathways could be obligatory for the triggering and/or persistence of reactive gliosis and may therefore serve as potential targets for modulation of glial response to neural damage.
...
PMID:Protein phosphorylation cascades associated with methamphetamine-induced glial activation. 1108 25

Herein, we investigated the activity of mitogen-activated protein kinase (MAPK), a key component of downstream signaling events, which is activated subsequent to platelet-derived growth factor (PDGF)-BB stimulation. Specifically, p42(MAPK) activity peaked 60 min after addition of PDGF-BB, declined thereafter, and was determined not to be a direct or necessary component of glycosaminoglycan (GAG) synthesis. PDGF-BB also activated MAPK kinase 2 (MAPKK2) but had no effect on MAPKK1 and Raf-1 activity. Chemical inhibition of Janus kinase, phosphatidylinositol 3-kinase, Src kinase, or tyrosine phosphorylation inhibition of the PDGF beta-receptor (PDGFR-beta) did not abrogate PDGF-BB-induced p42(MAPK) activation or its threonine or tyrosine phosphorylation. A dominant negative cytoplasmic receptor for hyaluronan-mediated motility variant 4 (RHAMMv4), a regulator of MAPKK-MAPK interaction and activation, did not inhibit PDGF-BB-induced p42(MAPK) activation nor did a construct expressing PDGFR-beta with cytoplasmic tyrosines mutated to phenylalanine. However, overexpression of a dominant negative PDGFR-beta lacking the cytoplasmic signaling domain abrogated p42(MAPK) activity. These results suggest that PDGF-BB-mediated activation of p42(MAPK) requires the PDGFR-beta but is independent of its tyrosine phosphorylation.
...
PMID:PDGF-BB-mediated activation of p42(MAPK) is independent of PDGF beta-receptor tyrosine phosphorylation. 1155 82


1 2 3 4 5 6 7 8 9 Next >>

---