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)

Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine that induces mesenchymal cell proliferation in vivo while inhibiting growth of most cells directly via serine-threonine receptor(s) binding/activation in vitro. In this study, the ability of TGF-beta1 to regulate the receptor expression of classical mitogenic growth factors that bind receptor tyrosine kinases was examined. TGF-beta1 markedly increased the protein expression of the fibroblast growth factor (FGF) receptors FGFR-1 (Flg) and FGFR-2 (Bek) in a time- and dose-dependent manner in human lung fibroblasts. This resulted in a potentiation of the mitogenic response of multiple FGF ligands that bind to these receptors. TGF-beta1 had no effect on epidermal growth factor (EGF) or platelet-derived growth factor (PDGF)-beta receptor expression and the mitogenic responses mediated by specific ligands for these receptors were not increased. These results demonstrate a novel action of TGF-beta1 to selectively upregulate the expression of FGF receptor family members leading to enhanced mitogenesis by FGFs.
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PMID:Upregulated expression of fibroblast growth factor (FGF) receptors by transforming growth factor-beta1 (TGF-beta1) mediates enhanced mitogenic responses to FGFs in cultured human lung fibroblasts. 979 92

Cloning and characterization of MEKK1 in 1993 revealed that in addition to Raf there were other pathways activated by extracellular stimuli that were responsible for ERK activation. Since then, three additional MEKK family members have been cloned adding even further diversity to the regulation of MAPK pathways. The MEKK family members are regulated by a diverse array of extracellular stimuli ranging from growth factors to DNA damaging stimuli and so are important for the cell to sense exposure to various environmental stimuli. One important aspect of MEKK biology is that they can potentially serve in more than one pathway. Regulation of MEKK family members often involves LMWG proteins, phosphorylation and subcellular localization. With regard to at least MEKK1, serine/threonine kinases such as NIK, GLK and HPK1 appear also to be important for regulation. Of the MEKK family members, the biological role of MEKK1 is best characterized and studies have shown that MEKK1 is important in mediating survival vs. apoptosis, possibly via its ability to regulate transcription factors, the expression of death receptors and their ligands. The biological roles of MEKK2, 3 and 4 are under investigation and undoubtedly homologous deletion of these MEKK family members will be invaluable at determining the biological functions of these MEKKs. At present, the MEKK family members are characterized as localized sensors that control cell responses at the level of gene expression, metabolism and the cytoskeleton
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PMID:The TAO of MEKK. 982 Jul 41

Extracellular signal-regulated kinases (ERK, also known as mitogen-activated protein kinases) are serine-threonine kinases transducing signals elicited upon ligand binding to several tyrosine kinase-associated receptors. We have reported that ERK2 phosphorylation and activation follows engagement of the low affinity receptor for the Fc portion of IgG (CD16) on NK cells, and is necessary for CD16-induced TNF-alpha mRNA expression. Here, we analyzed the involvement of ERK in NK cell-mediated cytotoxicity and IFN-gamma expression induced upon stimulation with targets cells, coated or not with Abs. Our data indicate that, as with immune complexes, ERK2 phosphorylation occurs in human primary NK cells upon interaction with target cells sensitive to granule exocytosis-mediated spontaneous cytotoxicity, and that this regulates both target cell- and immune complex-induced cytotoxicity and IFN-gamma mRNA expression. A specific inhibitor of mitogen-activated protein kinase kinase reduced both spontaneous and Ab-dependent cytotoxicity in a dose-dependent manner involving, at least in part, inhibition of granule exocytosis without affecting effector/target cell interaction and rearrangement of the cytoskeleton proteins actin and tubulin. Involvement of ERK in the regulation of Ca2+-dependent cell-mediated cytotoxicity was confirmed, using a genetic approach, in primary NK cells infected with a recombinant vaccinia virus encoding an ERK inactive mutant. These data indicate that the biochemical pathways elicited in NK cells upon engagement of receptors responsible for either spontaneous or Ab-dependent recognition of target cells, although distinct, utilize ERK as one of their downstream molecules to regulate effector functions.
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PMID:Dependence of both spontaneous and antibody-dependent, granule exocytosis-mediated NK cell cytotoxicity on extracellular signal-regulated kinases. 986 93

TC21 is a member of the Ras superfamily of small GTP-binding proteins and, like Ras, has been implicated in the regulation of growth-stimulating pathways. Point mutations introduced into TC21 based on equivalent H-Ras oncogenic mutations are transforming in cultured cells, and oncogenic mutations in TC21 have been isolated from several human tumours. The mechanism of TC21 signalling in transformation is poorly understood. While activation of the serine/threonine kinases Raf-1 and B-Raf has been implicated in signalling pathways leading to transformation by H-Ras, it has been argued that TC21 does not activate Raf-1 or B-Raf. Since the Raf-signalling pathway is important in transformation by other Ras proteins, we assessed whether the Raf pathway is important to transformation by TC21. Raf-1 and B-Raf are constitutively active in TC21-transformed cells and the ERK/MAPK cascade is required for the maintenance of the transformed state. We demonstrate that oncogenic V23 TC21, like Ras, interacts with Raf-1 and B-Raf (but not with A-Raf), resulting in the translocation of the Raf proteins to the plasma membrane and in their activation. Furthermore, using point mutations in the effector loop of TC21, we show that the interaction of TC21 with Raf-1 is crucial for transformation.
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PMID:Activation of the Raf/MAP kinase cascade by the Ras-related protein TC21 is required for the TC21-mediated transformation of NIH 3T3 cells. 1006 93

The major RNA polymerase from mustard chloroplasts is a multi-subunit enzyme consisting of core components and associated factors. Among the latter is a heterotrimeric factor named PTK (plastid transcription kinase) because of its serine/threonine-type protein kinase activity. PTK activity itself depends on its phosphorylation state. In addition, we show that it responds to glutathione but not to other redox-reactive reagents that were tested, and both glutathione and phosphorylation act antagonistically. Using a homologous in vitro system, we find that PTK selectively phosphorylates subunit(s) of plastid RNA polymerase and is involved in determining the level of faithful transcription from the chloroplast psbA promoter. Together, these results establish a role for phosphorylation and redox state in the regulation of plastid gene expression.
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PMID:PTK, the chloroplast RNA polymerase-associated protein kinase from mustard (Sinapis alba), mediates redox control of plastid in vitro transcription. 1034 6

Down-regulation of receptor tyrosine kinase activity plays an essential role in coordinating and controlling cellular growth/differentiation. Ca2+/calmodulin-dependent kinase II (CaM kinase II)-mediated phosphorylation of threonine 1172 in the cytoplasmic tail of HER2/c-erbB2 can modulate tyrosine kinase activity and consensus phosphorylation sites are also found at serines 1046/1047 in the structurally related epidermal growth factor receptor (EGFR). We show that serines 1046/1047 are sites for CaM kinase II phosphorylation, although there is a preference for serine 1047, which resides within the consensus -R-X-X-S-. In addition, we have identified major phosphorylation sites at serine 1142 and serine 1057, which lie within a novel -S-X-D- consensus. Mutation of serines 1046/1047 in full-length EGFR enhanced both fibroblast transformation and tyrosine autokinase activity that was significantly potentiated by additional mutation of serines 1057 and 1142. A single CaM kinase II site was also identified at serine 744 within sub-kinase domain III, and autokinase activity was significantly affected by mutation of this serine to an aspartic acid making this site appear constitutively phosphorylated. We have addressed the mechanism by which CaM kinase II phosphorylation of the EGFR might regulate receptor autokinase activity and show that this modification can hinder association of the cytoplasmic tail with the kinase domain to prevent an enzyme-substrate interaction. We postulate that the location and greater number of CaM kinase II phosphorylation sites in the EGFR compared with HER-2/c-erbB2, leading to differential regulation of autokinase activity, contributes to differences in the strength of downstream signaling events and may explain the higher relative transforming potential of HER-2/cerbB2.
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PMID:Ca2+/calmodulin-dependent kinase II phosphorylates the epidermal growth factor receptor on multiple sites in the cytoplasmic tail and serine 744 within the kinase domain to regulate signal generation. 1034 70

Zymosan-activated serum (ZAS), a source of C5a, stimulates the rat alveolar macrophages (AM) to release superoxide anion. Here we show that treatment of rat AM with ZAS induced a time-dependent increase in the tyrosine phosphorylation of several proteins (116, 105-110, 82-78, 66-72, 62, 45, 42, and 38 kDa). This increase was sensitive to genistein, a tyrosine kinase inhibitor. ZAS stimulated the tyrosine phosphorylation and activation of three members of a family of serine/threonine kinases known as the mitogen-activated protein kinases (MAPK), i.e., ERK1 and ERK2, as assessed by immunoblotting, immunoprecipitation, and phosphotransferase activity, and p38 MAPK, as determined by immunoblotting with phospho-specific antibodies. In addition, ZAS induced the tyrosine phosphorylation of the SHC proteins and their association with GRB2, suggesting a role for this complex in the activation of the ERK pathway. Addition of extracellular catalase during ZAS stimulation significantly reduced the tyrosine phosphorylation response and the activation of ERK1 and ERK2 and their activator MEK1/2 while it did not affect that of p38 MAPK and MKK3/MKK6. Superoxide dismutase marginally increased the response to ZAS, supporting a role for hydrogen peroxide. In contrast to the results with AM, stimulation of human neutrophils with ZAS in the presence of catalase minimally altered the activation of ERK1 and ERK2. These data show that, in ZAS-stimulated rat AM, activation of the respiratory burst and production of hydrogen peroxide via superoxide dismutation are largely responsible for the activation of the ERK pathway through an upstream target.
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PMID:Activation of several MAP kinases upon stimulation of rat alveolar macrophages: role of the NADPH oxidase. 1035 88

Protein kinase C (PKC) phosphorylates the juxtamembrane domain of many growth factor receptors, but the physiologic effect of this modification on ligand signalling and desensitisation is unclear. Here we show that PKC-dependent transmodulation of EGFR and ErbB2 signalling is schedule-specific: prolonged pre-treatment of A431 cells with the PKC agonist phorbol dibutyrate potently inhibits subsequent ligand-induced EGFR signalling as expected, but EGF pre-treatment reverses the inhibitory effect of phorbol. The agonist activity of PKC on receptor signalling is even more apparent when cells are treated with phorbol in the presence of a tyrosine phosphatase inhibitor. Because these findings suggested a synergistic interaction between tyrosine- and PKC-dependent phosphorylation events, we sought to define the interactions of tyrosine-phosphorylated and PKC-modified ErbB2 subsets within EGF-inducible hetero-oligomers. Growth factor-dependent PKC transphosphorylation takes place exclusively within endocytosed tyrosine-phosphorylated receptor oligomers. Moreover, phorbol differentially affects two ErbB2 C-terminal autophosphorylation sites: whereas phosphorylation of Tyr1222 is reduced, phosphorylation of Tyr1139 is increased. These results suggest that PKC-dependent phosphorylation of the juxtamembrane domain may contribute positively to both internalisation and signalling of ligand-activated receptors, simultaneously accelerating termination of growth factor action. We propose that transient PKC-dependent signal amplification results from enhanced stability of liganded receptor oligomers due to phosphorylation-dependent juxtamembrane domain interactions, analogous to the protein-protein binding now known to be induced by serine-threonine phosphorylation of CREB and SMAD.
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PMID:Intensification of growth factor receptor signalling by phorbol treatment of ligand-primed cells implies a dimer-stabilizing effect of protein kinase C-dependent juxtamembrane domain phosphorylation. 1037 2

In many peripheral tissues, calcitonin gene-related peptide (CGRP) is released from peptidergic sensory nerve fibres and acts like a growth factor during tissue development and regeneration. However, the ability of CGRP to influence gingival tissue has not been studied. To address this question, we have now examined the effects of CGRP on the proliferation of human gingival fibroblasts (Gin-1) in vitro. Gin-1 cells have approximately 3100 specific CGRP-binding sites with a Kd of 38.6 pM on their surface. Treatment with CGRP (0.1-100 nM) significantly stimulated cell proliferation in a dose-dependent manner, with maximal effects at 1-10 nM CGRP after 2 d. As one early cellular response to CGRP, p44-MAPK protein (also known as the extracellular signal response kinase [ERK]) was tyrosine- and threonine-phosphorylated within 2 min, and this phosphorylation was sustained for at least 1 h. The dose-response curve of MAPK activation was very similar to that observed for CGRP's stimulation of cell proliferation. In addition, CGRP's activation of MAPK stimulated its ability to phosphorylate the Elk-1 transcription factor. When cells were pretreated with PD98059, a selective inhibitor of MAPK kinase (also known as MEK), CGRP not only failed to induce phosphorylation of MAPK but also failed to stimulate Gin-1 cell proliferation. Our present data indicate that CGRP rapidly activates the MAPK signalling pathway, an effect which consequently stimulates the proliferation of gingival fibroblasts. Our data demonstrate specific cellular responses to CGRP by gingival fibroblasts and support the possibility that CGRP acts as a targeted local factor in the regulation of development, generation and/or regeneration of gingival tissues.
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PMID:Calcitonin gene-related peptide acts as a mitogen for human Gin-1 gingival fibroblasts by activating the MAP kinase signalling pathway. 1038 4

Several mutations were identified in the kinase domain of the RET proto-oncogene in patients with multiple endocrine neoplasia (MEN) 2B, familial medullary thyroid carcinoma (FMTC) or sporadic medullary thyroid carcinoma. We introduced seven mutations (glutamic acid 768-->aspartic acid (E768D), valine 804-->leucine (V804L), alanine 883-->phenylalanine (A883F), serine 891-->alanine (S891A), methionine 918-->threonine (M918T), alanine 919-->proline (A919P) and E768D/A919P) into the short and long isoforms of RET cDNA and transfected the mutant cDNAs into NIH3T3 cells. The transforming activity of the long isoform of Ret with each mutation was much higher that that of its short isoform. Based on the levels of the transforming activity, these mutant RET genes were classified into two groups; a group with high transforming activity (A883F, M918T and E768D/A919P) and a group with low transforming activity (E768D, V804L, S891A and A919P) (designated high group and low group). Interestingly, the level of transforming activity correlated with clinical phenotypes; high group Ret with the A883F or M918T mutation and low group Ret with the E768D, V804L or S891A mutation were associated with the development of MEN 2B and FMTC, respectively. In addition, we found that substitution of phenylalanine for tyrosine 905 present in the kinase domain abolished both transforming and autophosphorylation activities of low group Ret whereas it did not affect the activities of high group Ret.
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PMID:Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma. 1044 57


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