Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.11.18 (MAP)
 7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MAP kinases (MAPK) are a family of serine/threonine (Ser/Thr) kinases that link cell surface signals to changes in enzyme activity and gene expression. They are the products of the newly described gene family referred to as extracellular signal regulated kinases (ERKs). Moreover, MAPKs phosphorylate tau in vitro at Ser/Thr Proline sites, generating a multiply phosphorylated tau protein that is similar to the hyperphosphorylated tau found in Alzheimer neurofibrillary tangles (NFTs). We studied MAPK immunoreactivity and in situ hybridization patterns of the two major genes that comprise MAPK activity, ERK1 and ERK2, in the human hippocampal formation. Our goal was to determine whether the pattern of ERK expression is consistent with the hypothesis that MAPKs contribute to NFT formation. ERK1 mRNA is present in small amounts and confined primarily to dentate gyrus granule cells. ERK2 mRNA, by contrast, gives a much stronger hybridization signal and is present in dentate gyrus granule cells and pyramidal cells throughout all hippocampal subfields and adjacent temporal neocortex. Quantitative measures of ERK2 mRNA reveal that NFT-bearing neurons contain approximately 15% less ERK2 mRNA than nearest neighbors that do not contain NFT. NFT-bearing neurons contain approximately 25% less polyA mRNA, suggesting a relative preservation of ERK2 mRNA even in metabolically compromised cells. MAPK immunoreactivity (which represents both ERK1 and ERK2) is seen in neuronal soma, dendrites, axons, and in reactive astrocytes. In Alzheimer's disease, neurons that contain NFTs are also MAPK immunoreactive, but neurons that contain the highest amounts of MAPK immunoreactivity are not necessarily vulnerable for NFT. MAPK immunoreactivity is present in the same neurons as NFT and in the same subcellular compartments as tau, supporting a role for MAPKs in tau phosphorylation in Alzheimer's disease. However, the presence of ERK immunoreactivity is not sufficient to predispose neurons to NFT formation.
 ...
PMID:Extracellular signal regulated kinases. Localization of protein and mRNA in the human hippocampal formation in Alzheimer's disease. 812 42

Ligation of Ag receptors in T and B lymphocytes initiates signal transduction cascades which alter the expression of genes that regulate cellular proliferation and differentiation. The transmission of signals from the membrane to the nucleus is mediated principally through the action of protein tyrosine and serine/threonine kinases. We have identified and characterized a novel serine/threonine kinase that phosphorylated the proto-oncogene product, c-Fos, and is termed Fos kinase. Fos kinase was rapidly activated after ligation of the CD3 and CD2 receptors in Jurkat and normal human T lymphocytes and in response to IL-6 and anti-IgM in the human B cell lines AF10 and Ramos, respectively. The phorbol ester, PMA, was also a potent inducer of Fos kinase activity in all of the above populations, suggesting that PKC plays a role in the regulation of this enzyme. Fos kinase phosphorylates c-Fos at a site near the C-terminus, as well as a peptide derived from this region (residues 359-370, RKGSSSNEPSSD), and Fos peptide competitively inhibited c-Fos phosphorylation. Fos kinase was shown to be distinct from other identified serine/threonine kinases, including protein kinase A, protein kinase C, casein kinase II, MAP kinases, p70S6K and p90RSK. Fos kinase was purified by anion exchange chromatography and exhibited an apparent M(r) = 65,000 and isoelectric point = 6.1. Fos kinase may play a role in transcriptional regulation through its capacity to phosphorylate c-Fos at a site required for expression of the transcriptional transrepressive activity of this molecule. Moreover, its rapid activation suggests it may have a wider role within signal transduction cascades in lymphocytes.
 ...
PMID:Activation of a novel serine/threonine kinase that phosphorylates c-Fos upon stimulation of T and B lymphocytes via antigen and cytokine receptors. 815 58

In KB cells, interleukin-1 (IL-1), epidermal growth factor and phorbol ester transiently activated both MAP kinase and a serine kinase which phosphorylated the heat shock protein hsp27. Extracts made from IL-1-stimulated KB cells phosphorylated recombinant hsp27, in vitro, on serine residues 78 and 82 which are contained within Arg-X-X-Ser motifs similar to those phosphorylated by the ribosomal protein S6 kinases. Upon size exclusion chromatography, however, hsp27 kinase eluted as a single peak of activity at 50-60 kDa, clearly separated from ribosomal protein S6 kinases. Treatment of partially purified hsp27 kinase with protein phosphatase-2a reduced its activity by 80%. De-phosphorylated hsp27 kinase could be approximately 50% reactivated by a factor present in IL-1-treated cell extracts in the presence of ATP. This factor co-eluted with MAP kinase after partial purification by DEAE-cellulose, phenyl Sepharose, and size exclusion chromatography. Purified sea star p44mpk and recombinant ERK2 MAP kinases were also capable of re-activating hsp27 kinase to a similar extent. These data suggest that hsp27 kinase is downstream from, and probably a direct target of MAP kinase.
 ...
PMID:The interleukin-1-stimulated protein kinase that phosphorylates heat shock protein hsp27 is activated by MAP kinase. 830 52

Production of reactive oxygen metabolites by the NADPH oxidase is an essential mechanism underlying the microbicidal role of phagocytes. Receptor-mediated activation of the oxidase was originally thought to be mediated by calcium and/or by protein kinase C (PKC). However, recent evidence suggests that additional signalling pathways exist. In this article the possible role of tyrosine phosphorylation is discussed. In addition, results obtained using an in vitro kinase renaturation assay are described. The latter assay revealed the existence of at least four serine/threonine kinases that are activated in cells stimulated with chemoattractants. One of these, of molecular weight 41,000 was identified as a member of the ERK or MAP-kinase family. The existence of multiple, possibly redundant or synergistic signaling pathways is considered.
 ...
PMID:Involvement of multiple kinases in neutrophil activation. 831 67

Mitogen-activated protein kinases (MAP kinases) or meiosis-activated myelin basic protein kinase (p44mpk) are known to be activated by a mechanism involving dual phosphorylation at both tyrosine and serine/threonine in response to many extracellular stimuli. There has been considerable speculation as to whether MAP kinases are autophosphorylated and activated by an upstream protein kinase (MAP kinase kinase) or an activator of autophosphorylation or both. Here we report that the ets-related proteins elk-1 and delta elk-1 to be potential physiological substrates and activators of MAP kinases. Our results demonstrate for the first time that MAP kinase activators can also be non-kinase proteins that enhance the autophosphorylation and activation of MAP kinase. These findings could establish a general mechanism wherein specific MAP kinase activator protein(s) may function by interacting with MAP kinases ensuring a conformational change and stimulating their autophosphorylation and activation property. Our results also suggest that the amino-terminal truncated elk-1 proteins are better activators of MAP kinase than full length proteins indicating the presence of a potential negative regulatory region which may control the kinase activator function of elk-1 proteins. Our results suggest differential regulation of elk-1 and delta elk-1 proteins in fibroblasts stimulated by epidermal growth factor implicating a key role for these proteins in the signal transduction pathway. These results establish the presence of an alternative pathway for activation of MAP kinases. Thus we propose that elk-1 proteins may represent key intermediates which would transmit signals arriving at the surface of the cell from activated receptors to downstream MAP kinases in the cytoplasm to reach the transcriptional factors in the nucleus.
 ...
PMID:Elk-1 proteins are phosphoproteins and activators of mitogen-activated protein kinase. 833 45

The induction of T-cell growth by the T-cell antigen receptor (TcR) is dependent on a co-ordinated process of phosphorylation and dephosphorylation of intracellular proteins. An intermediary in this signalling pathway is the serine kinase, p42 mitogen-activated protein kinase (p42MAPK), also known as microtubule-associated protein-2 kinase (MAP-2K). MAP-kinase is activated upon the acquisition of tyrosine as well as threonine phosphate groups and removal of either by specific tyrosine or serine/threonine phosphatases abrogates kinase activity. Okadaic acid (OA), a tumour promoter and potent inhibitor of type 1 and 2A serine/threonine protein phosphatases (PP1 and PP2A), induced MAP-kinase activity in Jurkat T cells in a dose-dependent fashion with optimal effect at 1 microM. Compared to rapid activation (peak < 10 min) of MAP-kinase by another tumour promoter, the phorbol ester, PMA, the effect of OA was delayed (> 30 min) and more sustained. In spite of activating a growth-promoting kinase, OA differed from PMA by its lack of mitogenic activity and failure to induce CD25 [interleukin-2R alpha (IL-2R alpha)] expression in normal human T cells. This implies that PP1 and PP2A also act downstream of MAP-kinase to facilitate later cell cycle events. PMA induced a 42,000 MW tyrosine phosphoprotein which co-electrophoresed and co-chromatographed with ERK-2, a p42 MAP-kinase. Although OA induced an identical Mono-Q peak, there was less avid tyrosine phosphorylation of p42. OA also differed from PMA to the extent by which it induced mobility shift of the tyrosine protein kinase, p56lck, which has been implicated in p42MAPK activation in T cells. Taken together, these results indicate that OA and PMA exert both overlapping as well as divergent effects on lymphocyte growth pathways.
 ...
PMID:Contrasting effects of two tumour promoters, phorbol myristate acetate and okadaic acid, on T-cell responses and activation of p42 MAP-kinase/ERK-2. 838 30

Mitogen-activated protein kinases (p42mapk and p44mapk) are serine/threonine kinases that are activated rapidly in cells stimulated with various extracellular signals. This activation is mediated via MAP kinase kinase (p45mapkk), a dual specificity kinase which phosphorylates two key regulatory threonine and tyrosine residues of MAP kinases. We reported previously that the persistent phase of MAP kinase activation is essential for mitogenically stimulated cells to pass the "restriction point" of the cell cycle. Here, using specific polyclonal antibodies and transfection of epitope-tagged recombinant MAP kinases we demonstrate that these signaling protein kinases undergo distinct spatio-temporal localization in growth factor-stimulated cells. In G0-arrested hamster fibroblasts the activator p45mapkk and MAP kinases (p42mapk, p44mapk) are mainly cytoplasmic. Subsequent to mitogenic stimulation by serum or alpha-thrombin both MAP kinase isoforms translocate into the nucleus. This translocation is rapid (seen in 15 min), persistent (at least during the entire G1 period up to 6 h), reversible (by removal of the mitogenic stimulus) and apparently 'coupled' to the mitogenic potential; it does not occur in response to nonmitogenic agents such as alpha-thrombin-receptor synthetic peptides and phorbol esters that fail to activate MAP kinases persistently. When p42mapk and p44mapk are expressed stably at high levels, they are found in the nucleus of resting cells; this nuclear localization is also apparent with kinase-deficient mutants (p44mapk T192A or Y194F). In marked contrast the p45mapkk activator remains cytoplasmic even during prolonged growth factor stimulation and even after high expression levels achieved by transfection. We propose that the rapid and persistent nuclear transfer of p42mapk and p44mapk during the entire G0-G1 period is crucial for the function of these kinases in mediating the growth response.
 ...
PMID:Growth factors induce nuclear translocation of MAP kinases (p42mapk and p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts. 839 45

The mitogen-activated protein kinases (MAP kinases) p42mapk and p44mapk are serine/threonine kinases rapidly activated in cells stimulated with various extracellular signals by dual phosphorylation of tyrosine and threonine residues. They are thought to play a pivotal role in integrating and transmitting transmembrane signals required for growth and differentiation. Here we demonstrate that activation of these ubiquitously expressed MAP kinases is essential for growth. To specifically suppress MAP kinase activation in fibroblasts, we transiently expressed either the entire p44mapk antisense RNA or p44mapk kinase-deficient mutants (T192A or Y194F). As expected, and through independent mechanisms, both approaches strongly inhibited MAP kinase activation. The antisense reduced the expression of endogenous p42mapk and p44mapk by 90%, whereas overexpression of the T192A mutant inhibited growth factor activation of both endogenous MAP kinases by up to 70%. As a consequence, we found that the antisense as well as the T192A mutant of p44mapk inhibited growth factor-stimulated gene transcription (collagenase promoter assay with chloramphenicol acetyltransferase reporter) and cell growth. These effects were proportional to the extent of MAP kinase inhibition and reversed by coexpression of the wild-type p44mapk. Therefore we conclude that growth factor activation of p42mapk and p44mapk is an absolute requirement for triggering the proliferative response.
 ...
PMID:Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. 839 1

We have partially purified and characterized two protein kinases that were strongly activated by interleukin-1 (IL-1) or tumor necrosis factor (TNF) in MRC-5 fibroblasts. The kinases were separated by anion exchange chromatography of cytosolic fractions. They phosphorylated in vitro the small heat shock protein (hsp27) or beta-casein and were stimulated 3- and 4.5-fold, respectively, in cells that had been exposed to IL-1 or TNF for 10 min. They were distinct from the mitogen-activated protein kinases, whose activation by IL-1 or TNF has been reported recently. The hsp27 kinase phosphorylated its substrate on serine residues. Its molecular mass was estimated to be 45-kDa by gel filtration. It is probably involved in the increase in hsp27 phosphorylation seen in intact cells. The beta-casein kinase behaved as a 65-kDa protein. It phosphorylated its substrate on serine and threonine residues and had little activity on alpha-casein. The hsp27 and beta-casein kinases were not activated after stimulation of the cells with phorbol myristate acetate (PMA). In contrast, the MAP kinases were activated to a similar extent (2-3-fold) by the cytokines and by PMA. The hsp27- and beta-casein kinases probably correspond to novel enzymes whose mechanisms of activation may be independent of protein kinase C or MAP kinases.
 ...
PMID:Interleukin 1 and tumor necrosis factor stimulate two novel protein kinases that phosphorylate the heat shock protein hsp27 and beta-casein. 844 Jul 7

Protein-tyrosine kinases (PTKs) of the JAK family have been characterized on the basis of their ability to mediate the rapid induction of transcription of interferon-responsive genes through the stimulation of a class of latent cytoplasmic transcription factors known as signal transducers and activators of transcription (STATs). STAT activation, which has been described as being Ras-independent, requires tyrosine phosphorylation, but STAT transactivating activity is enhanced by phosphorylation on serine as well, probably by extracellular signal-regulated kinase/mitogen-activated protein kinase(s) (ERK/MAPK). STATs can be activated upon binding of ligands to receptor PTKs, to G-protein-linked receptors, and to cytokine receptors. Whether JAKs are required for the activation of signaling pathways other than that leading to STAT activation is not known. The binding of growth hormone (GH) to its receptor (GHR) activates JAK2 and STATs as well as ERK/MAP kinases. We have used a transient transfection system in 293 cells to evaluate the requirement for JAK2 in the activation of ERK2/MAPK by GH. We found that JAK2 is required for GH-simulated activation of ERK2/MAPK. Employing the transient expression of dominant negative forms of H-Ras and Raf-1, we determined that the GHR/JAK2-mediated activation of ERK2/MAPK is dependent on both Ras and Raf. Thus, JAK protein-tyrosine kinases may represent a common component in the activation of the ERK2/MAPK and STAT signaling pathways, which appear to bifurcate upstream of Ras activation but converge with ERK/MAPK phosphorylation of STATs.
 ...
PMID:JAK2, Ras, and Raf are required for activation of extracellular signal-regulated kinase/mitogen-activated protein kinase by growth hormone. 853 33


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