Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Basic fibroblast growth factor (bFGF) plays an important role in development of the central nervous system and is neurotropic for a variety of neurons. In this study, we investigated whether bFGF is neurotropic for GT1 GnRH neuronal cell lines and if these cells express functional FGF receptors (FGFRs). The GT1 cell lines generated by genetically targeted tumorigenesis display highly differentiated properties of GnRH neurons. Addition of 2 and 10 ng/ml bFGF increased neurite outgrowth of GT1-7 cells and resulted in a significant increase of GT1 cell survival in serum-free medium. However, bFGF had no effect on [3H]thymidine incorporation at 24 or 48 h. RNase protection assays using riboprobes specific for murine FGFRs 1-3 showed that GT1 cells express FGFRs 1 and 3 but not 2. Occupancy of FGFRs with 10 ng/ml bFGF stimulated the sustained tyrosine phosphorylation of both the 42- and 44-kilodalton mitogen-activated protein kinases (MAPKs) for up to 6 h as shown by Western blot analysis. In addition, phosphorylation of the MAPKs was associated with enzyme activation as shown by an in-gel MAPK assay. GT1-1 and GT1-7 cells also express messenger RNA for bFGF, although the level of bioactive bFGF synthesized by GT1 cells appears suboptimal because GT1 cells can further respond to exogenously added bFGF. Thus, we have demonstrated that bFGF is a neurotropic factor in GT1 GnRh neuronal cell lines, raising the possibility that bFGF may play a role in the neurobiology of GnRH neurons.
Endocrinology 1995 Sep
PMID:Basic fibroblast growth factor is a neurotropic factor in GT1 gonadotropin-releasing hormone neuronal cell lines. 764 90

In soluble peptidoglycan (PGN) from staphylococcal cell walls as well as soluble PGN (sPGN) secreted by staphylococci in the presence of beta-lactam antibiotics induced TNF-alpha mRNA and secretion of bioactive TNF-alpha in the murine RAW264.7 macrophage cell line, PGN and sPGN also induced rapid and dose-dependent tyrosine phosphorylation of several cellular proteins, including lyn and mitogen-activated protein kinases (extracellular signal-regulated kinases; but not hck, fgr, or vav) and increased the activities of mitogen-activated protein and rsk kinases. These PGN- and sPGN-induced effects were qualitatively similar to the effects induced by ReLPS, but higher concentrations of PGN and sPGN than ReLPS were required. In contrast to the ReLPS-induced effects, the PGN- and sPGN-induced effects were not inhibited by polymyxin B. All PGN-, sPGN-, and ReLPS-induced effects were serum independent, since they were observed both in RAW264.7 cells grown and stimulated in the presence of serum and in the cells adapted to growth and stimulated in a serum- and albumin-free medium. These results indicate that lyn, extracellular signal-regulated kinase, and rsk signal transduction molecules may be involved in macrophage activation by PGN and further support the idea that PGN and LPS may activate the cells through similar mechanisms.
J Immunol 1995 Sep 01
PMID:Peptidoglycan induces transcription and secretion of TNF-alpha and activation of lyn, extracellular signal-regulated kinase, and rsk signal transduction proteins in mouse macrophages. 765 Mar 92

Mos is a germ cell-specific serine/threonine protein kinase that activates mitogen-activated protein kinase (MAPK) through MAPK kinase (MKK). In Xenopus oocytes, Mos synthesis is required for progesterone-induced activation of MAPK and maturation promoting factor. Injection of Mos or active MAPK causes mitotic arrest in early embryos, suggesting that Mos also acts via MKK and MAPK to induce the arrest of unfertilized eggs in metaphase of meiosis II. We have investigated whether Mos activity is regulated by phosphorylation. Previous studies have identified Ser-3 as the principal autophosphorylation site. We show that Mos interacts with the catalytic domain of MKK in a Saccharomyces cerevisiae two-hybrid test. Acidic substitutions of the sites phosphorylated by Mos in MKK reduce the interaction, implying that the complex may dissociate after phosphorylation of MKK by Mos. Furthermore, the Mos-MKK interaction requires Mos kinase activity, suggesting that Mos autophosphorylation may be involved in the interaction. Substitution of Ser-3 of Mos with Ala reduces the interaction with MKK and also reduces both the activation of MKK by Mos in vitro and cleavage arrest induced by Mos fusion protein in Xenopus embryos. By contrast, substitution of Ser-3 by Glu, an acidic amino acid that mimics phosphoserine, fosters the Mos interaction with MKK and permits activation of MKK in vitro and Mos-induced cleavage arrest. Moreover, the Glu-3 substitution increases the interaction of a kinase-inactive Mos mutant with MKK. Taken together, these results suggest that an important step in Mos activation involves the phosphorylation at Ser-3, which promotes Mos interaction with and activation of MKK.
Mol Cell Biol 1995 Sep
PMID:Ser-3 is important for regulating Mos interaction with and stimulation of mitogen-activated protein kinase kinase. 765 90

Inhibitors of protein synthesis, such as anisomycin and cycloheximide, lead to superinduction of immediate-early genes. We demonstrate that these two drugs activate intracellular signaling pathways involving both the mitogen-activated protein kinase (MAPK) and stress-activated protein kinase (SAPK) cascades. The activation of either pathway correlates with phosphorylation of the c-fos regulatory transcription factor Elk-1. In HeLa cells, anisomycin stabilizes c-fos mRNA when protein synthesis is inhibited to only 50%. Under these conditions, anisomycin, in contrast to cycloheximide, rapidly induces kinase activation and efficient Elk-1 phosphorylation. However, full inhibition of translation by either drug leads to prolonged activation of SAPK activity, while MAPK induction is transient. This correlates with prolonged Elk-1 phosphorylation and c-fos transcription. Elk-1 induction and c-fos activation are also observed in KB cells, in which anisomycin strongly induces SAPKs but not MAPKs. Purified p54 SAPK alpha efficiently phosphorylates the Elk-1 C-terminal domain in vitro and comigrates with anisomycin-activated kinases in in-gel kinase assays. Thus, Elk-1 provides a potential convergence point for the MAPK and SAPK signaling pathways. The activation of signal cascades and control of transcription factor function therefore represent prominent processes in immediate-early gene superinduction.
Mol Cell Biol 1995 Sep
PMID:Protein synthesis inhibitors reveal differential regulation of mitogen-activated protein kinase and stress-activated protein kinase pathways that converge on Elk-1. 765 11

A mutant rat cell clone that suppresses the transformation defects of RAS effector loop substitutions is heterozygous for mutations in c-raf1 and MEK1. The mutant cells can be transformed by many otherwise defective RAS effector mutants, including RAS genes with the effector regions of distantly related GTPases, even though the encoded RAS proteins do not interact with either the mutant or wild-type RAF in Saccharomyces cerevisiae. While the significance of the c-raf1 mutation is unclear, the MEK1 mutation increases MEK1 activity and leads to activation of mitogen-activated protein kinase. The mutant MEK1 is coupled to the epidermal growth factor pathway but exhibits decreased physical interaction with RAF. When overexpressed, the MEK1 mutation is transforming and causes hyperphosphorylation of RAF. Signalling from RAS to MEK1 may be mediated by something other than RAF alone, but signalling through MEK1 is probably sufficient for RAS transformation.
Mol Cell Biol 1995 Sep
PMID:RAS signalling is abnormal in a c-raf1 MEK1 double mutant. 765 28

Members of the Rho family of small guanosine triphosphatases (GTPases) regulate the organization of the actin cytoskeleton; Rho controls the assembly of actin stress fibers and focal adhesion complexes, Rac regulates actin filament accumulation at the plasma membrane to produce lamellipodia and membrane ruffles, and Cdc42 stimulates the formation of filopodia. When microinjected into quiescent fibroblasts, Rho, Rac, and Cdc42 stimulated cell cycle progression through G1 and subsequent DNA synthesis. Furthermore, microinjection of dominant negative forms of Rac and Cdc42 or of the Rho inhibitor C3 transferase blocked serum-induced DNA synthesis. Unlike Ras, none of the Rho GTPases activated the mitogen-activated protein kinase (MAPK) cascade that contains the protein kinases c-Raf1, MEK (MAPK or ERK kinase), and ERK (extracellular signal-regulated kinase). Instead, Rac and Cdc42, but not Rho, stimulated a distinct MAP kinase, the c-Jun kinase JNK/SAPK (Jun NH2-terminal kinase or stress-activated protein kinase). Rho, Rac, and Cdc42 control signal transduction pathways that are essential for cell growth.
Science 1995 Sep 01
PMID:An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1. 765 75

The relationship between intracellular calcium concentration ([Ca2+]i), the release of arachidonic acid and the synthesis of leukotriene B4 (LTB4) was investigated using Ca(2+)-depleted human polymorphonuclear leucocytes (PMNs) in which [Ca2+]i can be manipulated by varying the concentration of exogenous Ca2+ added with agonists. In this model, Ca2+, platelet-activating factor (PAF) and N-formyl-Met-Leu-Phe (FMLP), added alone, were unable to induce arachidonic acid release or LTB4 synthesis, as assessed by measurements of the products by MS and HPLC, respectively. However, the simultaneous addition of Ca2+ and either PAF or FMLP to these Ca(2+)-depleted PMNs resulted in an influx of Ca2+ proportional to the extracellular concentration of Ca2+ and caused a substantial release of arachidonic acid and synthesis of LTB4. The [Ca2+]i values for threshold and maximal arachidonic acid release were found to be 150 nM and 350 nM respectively, suggesting the involvement of cytosolic phospholipase A2 (cPLA2). Under stimulatory conditions resulting in similar [Ca2+]i, Ca(2+)-depleted PMNs released significant amounts of arachidonic acid but normal (Ca(2+)-repleted) PMNs did not, indicating that Ca2+ depletion of PMNs altered the normal regulation of arachidonic acid release and facilitated the release of the fatty acid upon stimulation with agonists. cPLA2 and mitogen-activated protein kinase (MAP kinase) phosphorylation, as assessed by changes of electrophoretic mobility, occurred in both Ca(2+)-depleted and Ca(2+)-depleted PMNs upon addition of agonist. These data demonstrate that in Ca(2+)-depleted PMNs stimulated with agonists, arachidonic acid release and LTB4 synthesis correlated with extracellular Ca2+ influx.
Biochem J 1995 Sep 01
PMID:Leukotriene synthesis in calcium-depleted human neutrophils: arachidonic acid release correlates with calcium influx. 765 11

The role of the C-terminal domain of CTP: phosphocholine cytidylyltransferase (CT) was explored by the creation of a series of deletion mutations in rat liver cDNA, which were expressed in COS cells as a major protein component. Deletion of up to 55 amino acids from the C-terminus had no effect on the activity of the enzyme, its stimulation by lipid vesicles or on its intracellular distribution between soluble and membrane-bound forms. However, deletion of the C-terminal 139 amino acids resulted in a 90% decrease in activity, loss of response to lipid vesicles and a significant decrease in the fraction of membrane-bound enzyme. Identification of the domain that is phosphorylated in vivo was determined by analysis of 32P-labelled CT mutants and by chymotrypsin proteolysis of purified CT that was 32P-labelled in vivo. Phosphorylation was restricted to the C-terminal 52 amino acids (domain P) and occurred on multiple sites. CT phosphorylation in vitro was catalysed by casein kinase II, cell division control 2 kinase (cdc2 kinase), protein kinases C alpha and beta II, and glycogen synthase kinase-3 (GSK-3), but not by mitogen-activated kinase (MAP kinase). Casein kinase II phosphorylation was directed exclusively to Ser-362. The sites phosphorylated by cdc2 kinase and GSK-3 were restricted to several serines within three proline-rich motifs of domain P. Sites phosphorylated in vitro by protein kinase C, on the other hand, were distributed over the N-terminal catalytic as well as the C-terminal regulatory domain. The stoichiometry of phosphorylation catalysed by any of these kinases was less than 0.2 mol P/mol CT, and no effects on enzyme activity were detected. This study supports a tripartite structure for CT with an N-terminal catalytic domain and a C-terminal regulatory domain comprised of a membrane-binding domain (domain M) and a phosphorylation domain (domain P). It also identifies three kinases as potential regulators in vivo of CT, casein kinase II, cyclin-dependent kinase and GSK-3.
Biochem J 1995 Sep 01
PMID:Functions of the C-terminal domain of CTP: phosphocholine cytidylyltransferase. Effects of C-terminal deletions on enzyme activity, intracellular localization and phosphorylation potential. 765 14

Simultaneous inactivation of pyp1 and pyp2 PTPases in fission yeast leads to aberrant cell morphology and growth arrest. Spontaneous recessive mutations that bypass the requirement for pyp1 and pyp2 and reside in two complementation groups were isolated, sty1 and sty2. sty1- and sty2- mutant cells are substantially delayed in the timing of mitotic initiation. We have isolated the sty1 gene, which encodes a MAP kinase that is closely related to a subfamily of MAP kinases regulated by osmotic stress including Saccharomyces cervisiae HOG1 and human CSBP1. We find that sty2 is allelic to the wis1 MAP kinase kinase and that delta sty1 and delta wis1 cells are unable to grow in high osmolarity medium. Osmotic stress induces both tyrosine phosphorylation of Sty1 and a reduction in cell size at division. Pyp2 associates with and tyrosine dephosphorylates Sty1 in vitro. We find that wis1-dependent induction of pyp2 mRNA is responsible for tyrosine dephosphorylation of Sty1 in vivo on prolonged exposure to osmotic stress. We conclude that Pyp1 and Pyp2 are tyrosine-specific MAP kinase phosphatases that inactivate an osmoregulated MAP kinase, Sty1, which acts downstream of the Wis1 MAP kinase kinase to control cell size at division in fission yeast.
Genes Dev 1995 Sep 01
PMID:Pyp1 and Pyp2 PTPases dephosphorylate an osmosensing MAP kinase controlling cell size at division in fission yeast. 765 64

Neurotrophin-3 binds to the receptor tyrosine kinase, TrkC. Several naturally occurring splice variants of TrkC exist including those with 14- and 39-amino acid inserts within the tyrosine kinase homology region. When expressed in fibroblasts, full-length TrkC, but not the kinase insert variants, mediated neurotrophin-3-stimulated cell proliferation. We investigated the molecular basis of this signaling defect. The kinase inserts blocked the ability of TrkC to mediate neurotrophin-3 stimulated c-myc and c-fos transcription and activation of the AP-1 transcriptional complex. In cells expressing full-length TrkC, neurotrophin-3 promoted a sustained activation of mitogen-activated protein kinase; TrkC containing kinase inserts only mediated transient activation of mitogen-activated protein kinase. The kinase inserts specifically blocked neurotrophin-3-stimulated autophosphorylation of the phospholipase C gamma binding site on TrkC (tyrosine 789) resulting in a severe reduction in phospholipase C gamma association with TrkC and its tyrosine phosphorylation. Neurotrophin-3-stimulated phosphorylation of the Shc binding site (tyrosine 485) on TrkC, and tyrosine phosphorylation of Shc itself, was unaffected by the kinase inserts; however, the kinase inserts blocked high affinity Shc association with TrkC. It is proposed that the lack of high affinity binding of Shc and/or phospholipase C gamma to the TrkC kinase insert variants may be responsible for the inability of these variants to bring about a full biological response in fibroblasts.
J Biol Chem 1995 Sep 01
PMID:Naturally occurring tyrosine kinase inserts block high affinity binding of phospholipase C gamma and Shc to TrkC and neurotrophin-3 signaling. 765 12


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