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At least 19 recordsLinked to original sources
PubMed1993

Mitogen-activated protein kinase (MAP kinase), MAP kinase kinase and c-Mos stimulate glucose transport in Xenopus oocytes.

Mitogens and growth factors acutely stimulate glucose transport in all cells to supply energy for their growth and division, but little is known about the signalling mechanism by which these agonists promote sugar uptake. Here we show that the transport of deoxyglucose and 3-O-methylglucose into Xenopus laevis oocytes is stimulated about 2.5-fold when mitogen-activated protein kinase (MAP kinase) is microinjected into these oocytes. We also demonstrate that microinjection of the proto-oncogene product c-Mos (an activator of MAP kinase kinase, which activates MAP kinase in Xenopus oocytes), and purified MAP kinase kinase produce similar increases in deoxyglucose transport. Since the activation of MAP kinase is a general response to almost all mitogens and growth factors, we propose that one of its downstream effects is the stimulation of glucose-transport activity.

3-O-Methylglucose↗
PubMed1994

MAP kinase kinase kinase, MAP kinase kinase and MAP kinase.

Signal transduction pathways that respond to external signals through the MAP kinase family of protein kinases are involved in diverse responses in eukaryotic cells. MAP kinases are one element in a series of kinases that serve to connect the plasma membrane with cytoplasmic and nuclear events. MAP kinases have the unusual feature that their activation requires threonine and tyrosine phosphorylation carried out by a dual specificity protein kinase. Recent advances have shown that in two MAP kinase pathways (the mating response pathway in the fission yeast Schizosaccharomyces pombe, and receptor tyrosine kinase signalling), the small GTP binding protein ras p21 links membrane events to kinase pathway activation.

Animals↗
PubMed1998

Feedback regulation of Raf-1 and mitogen-activated protein kinase (MAP) kinase kinases 1 and 2 by MAP kinase phosphatase-1 (MKP-1).

Inactivation of growth factor-regulated mitogen-activated protein (MAP) kinases (ERK1 and ERK2) has been proposed to occur in part through dephosphorylation by the dual specificity MAP kinase phosphatase-1 (MKP-1), an immediate early gene that is induced by mitogenic signaling. In this study, we examined the effect of MKP-1 on signaling components upstream of ERK1 and ERK2. Coexpression of MKK1 or MKK2 with MKP-1 resulted in 7-10-fold activation of mitogen-activated protein kinase kinase (MKK), which required the presence of regulatory serine phosphorylation sites. Endogenous MKK1 and MKK2 were also activated upon MKP-1 expression. Raf-1, a direct regulator of MKK1 and MKK2, was activated under these conditions, and a synergistic activation of MKK was observed upon coexpression of Raf-1 and MKP-1. This effect did not appear to involve synthesis of autocrine growth factors or the inhibition of basal extracellular signal-regulated kinase (ERK) activity but was inhibited by a dominant negative Ras mutant, indicating that MKP-1 enhances Ras-dependent activation of Raf-1 in a cell autonomous manner. This study demonstrates positive feedback regulation of Raf-1 and MKK by the MKP-1 immediate early gene and a potential mechanism for activating Raf-1/MKK signaling pathways alternative to those involving ERK.

3T3 Cells↗
PubMed1993

Mitogen-activated protein kinase (MAP kinase) activation in Xenopus oocytes: roles of MPF and protein synthesis.

Mitogen-activated protein kinase (MAP kinase) is a serine/threonine kinase whose enzymatic activity is thought to play a crucial role in mitogenic signal transduction and also in the progesterone-induced meiotic maturation of Xenopus oocytes. We have purified MAP kinase from Xenopus oocytes and have shown that the protein is present in metaphase II oocytes under two different forms: an inactive 41-kD protein able to autoactivate and to autophosphorylate in vitro, and an active 42-kD kinase resolved into two tyrosine phosphorylated isoforms on 2D gels. During meiotic maturation, MAP kinase becomes tyrosine phosphorylated and activated following the activation of the M-phase promoting factor (MPF), a complex between the p34cdc2 kinase and cyclin B. In vivo, MAP kinase activity displays a different stability in metaphase I and in metaphase II: protein synthesis is required to maintain MAP kinase activity in metaphase I but not in metaphase II oocytes. Injection of either MPF or cyclin B into prophase oocytes promotes tyrosine phosphorylation of MAP kinase, indicating that its activation is a downstream event of MPF activation. In contrast, injection of okadaic acid, which induces in vivo MPF activation, promotes only a very weak tyrosine phosphorylation of MAP kinase, suggesting that effectors other than MPF are required for the MAP kinase activation. Moreover, in the absence of protein synthesis, cyclin B and MPF are unable to promote in vivo activation of MAP kinase, indicating that this activation requires the synthesis of new protein(s).

Animals↗
PubMed2001

Kinetics of meiotic progression, M-phase promoting factor (MPF) and mitogen-activated protein kinase (MAP kinase) activities during in vitro maturation of porcine and bovine oocytes: species specific differences in the length of the meiotic stages.

The kinetics of nuclear maturation, M-phase promoting factor (MPF) and mitogen-activated protein kinase (MAP kinase) activities during in vitro maturation of porcine and bovine oocytes were examined. A further objective was to determine the duration of the meiotic stages during the maturation process. Porcine and bovine cumulus-oocyte complexes (COCs) were incubated in TCM 199 supplemented with 20% (v/v) heat inactivated fetal calf serum (FCS), 0.05microg/ml gentamycin, 0.02mg/ml insulin, 2.5microg/ml FSH and 5microg/ml LH. COCs were removed from the culture media in hourly intervals starting immediately after recovery from the follicle until 24 (bovine) or 48h (porcine) of culture. Oocytes were either fixed to evaluate the maturation status or the activity of MPF, assessed by its histone H1 kinase activity, and MAP kinase were determined by a radioactive assay simultaneously. In oocytes of both species, the MPF activity oscillated during the culture period with two maxima corresponding with the two metaphases: between 27-32 and after 46h (porcine) and between 6-9 and after 22h (bovine). There was a temporary decline in activity after 33-38 (porcine) and after 19h (bovine), which corresponded with anaphase I and telophase I. MAP kinase activity increased during the whole culture period and reached maximum levels after 47 (porcine) and after 22h (bovine). In porcine oocytes, the MAP kinase was activated before GVBD and MPF activation. In bovine oocytes, MPF and MAP kinase were activated at approximately the same time as the GVBD (8-9h of incubation). In average porcine, oocytes remain 23.4h in the germinal vesicle (GV) stage (13h in GV I, 5.7h in GV II, 3.2h in GV III and 1.5h in GV IV), 0.9h in diakinese, 9.6h in the metaphase I, 2.8h in anaphase I and 1.9h in telophase I of the first meiotic division. In bovine oocytes, the temporal distribution of the meiotic stages were 8.5h for the GV stage, 1.2h for diakinese, 8.3h for metaphase I, 1.6h for anaphase I and 1.9h for telophase I. These results indicate that the duration of the meiotic stages differs between the species and that MAP kinase is activated before MPF and GVBD in porcine oocytes.

Animals↗
PubMed1994

Expression of protein phosphatases (PP-1, PP-2A, PP-2B and PTP-1B) and protein kinases (MAP kinase and P34cdc2) in the hippocampus of patients with Alzheimer disease and normal aged individuals.

Microtubule-associated protein tau is abnormally hyperphosphorylated in the brain of patients with Alzheimer disease (AD). Previous studies have shown (i) that in vitro tau can be phosphorylated to an Alzheimer abnormally phosphorylated state-like protein by proline-directed protein kinases MAP kinase and p34cdc2, and (ii) that the AD abnormally phosphorylated tau can be in vitro dephosphorylated by protein phosphatases PP-2B, PP-2A and PP-1 and not by PP-2C. However, to have a direct effect on the regulation of phosphorylation of tau, these enzymes should be present in the affected neurons. In the present study immunocytochemical localization of protein phosphatases PP-1, PP-2A, PP-2B and PTP, and protein kinases MAP kinase and p34cdc2 were studied in the hippocampal formation of AD and as a control in non-demented elderly patients. All the protein phosphatases and protein kinases studied were localized to both granular and pyramidal neurons. In the pyramidal neurons, the enzymes staining was observed in neuronal soma and neurites. PTP-1B, PP-1 and PP-2A were also highly expressed in microglia. The topographical distributions of all the enzymes studied were similar, i.e. the intensity of immunostaining in hippocampus in end-plate (CA3 and CA4) > prosubiculum, subiculum > entorhinal cortex > dentate gyrus > CA2 > CA1. Furthermore, the expression of all the enzymes was also observed in the tangle-bearing neurons. The PP-2B staining of the tangle-bearing neurons was weaker than the unaffected neurons in the same tissue section field in AD cases.

Adult↗
PubMed1992

Renaturation and partial peptide sequencing of mitogen-activated protein kinase (MAP kinase) activator from rabbit skeletal muscle.

Mitogen-activated protein kinase (MAP kinase) activator was purified 2000-fold from skeletal muscle, and proteins which co-purified with the activator were analysed after SDS/PAGE by renaturation and partial sequencing. Activity for tyrosine and threonine phosphorylation of MAP kinase was present in two bands of approx. 48 and 46 kDa, which have sequence similarity to small GTP-binding protein p25 GDP dissociation inhibitor and protein kinases (PBS2, SPK1+, STE7, BYR1) respectively.

Amino Acid Sequence↗
PubMed1993

Okadaic acid activates p42 mitogen-activated protein kinase (MAP kinase; ERK-2) in B-lymphocytes but inhibits rather than augments cellular proliferation: contrast with phorbol 12-myristate 13-acetate.

Ligation of the membrane immunoglobulin M receptor as well as stimulation with the protein kinase C agonist phorbol 12-myristate 13-acetate leads to a B-lymphocyte proliferation and differentiation. Both stimuli activate p42 mitogen-activated protein (MAP) kinase in human B-lymphocytes [Casillas, Hanekom, Williams, Katz and Nel (1991) J. Biol. Chem. 266, 19088-19094]. MAP kinase activation is dependent on tyrosine as well as threonine phosphorylation of the kinase and its activity is inhibited by tyrosine as well as threonine/serine phosphatases. Okadaic acid, a specific inhibitor of type 1 and 2A serine/threonine phosphatases, induced MAP kinase activity in a potent and dose-dependent fashion, but failed to induce [3H]thymidine incorporation into normal human tonsil B-cells. Moreover, in combination with membrane immunoglobulin M ligation, okadaic acid decreased rather than increased [3H]thymidine incorporation. The kinetics of MAP kinase activation by okadaic acid differed from phorbol 12-myristate 13-acetate and anti-membrane immunoglobulin M stimulation. Okadaic acid induced tyrosine phosphorylation of 42 kDa and 44 kDa proteins which co-electrophoresed and co-chromatographed with ERK-2 and ERK-1 respectively. Ramos cells also contained a constitutively active 46 kDa MAP kinase which appeared as a separate peak in chromatography and could be immunoprecipitated by an antiserum against a rat ERK-1 fusion protein.

B-Lymphocytes↗
PubMed1991

Identification of the regulatory phosphorylation sites in pp42/mitogen-activated protein kinase (MAP kinase).

Mitogen-activated protein kinase (MAP kinase) is a 42 kd serine/threonine protein kinase whose enzymatic activity requires phosphorylation of both tyrosyl and threonyl residues. As a step in elucidating the mechanism(s) for activation of this enzyme, we have determined the sites of regulatory phosphorylation. Following proteolytic digestion of 32P-labeled pp42/MAP kinase with trypsin, only a single phosphopeptide was detected by two-dimensional peptide mapping, and this peptide contained both phosphotyrosine and phosphothreonine. The amino acid sequence of the peptide, including the phosphorylation sites, was determined using a combination of Fourier transform mass spectrometry and collision-activated dissociation tandem mass spectrometry with electrospray ionization. The sequence for the pp42/MAP kinase tryptic phosphopeptide is similar (but not identical) to a sequence present in the ERK1- and KSS1-encoded kinases. The two phosphorylation sites are separated by only a single residue. The regulation of activity by dual phosphorylations at closely spaced threonyl and tyrosyl residues has a functional correlate in p34cdc2, and may be characteristic of a family of protein kinases regulating cell cycle transitions.

Amino Acid Sequence↗
PubMed1997

Pituitary adenylate cyclase-activating polypeptide (PACAP-38) protects cerebellar granule neurons from apoptosis by activating the mitogen-activated protein kinase (MAP kinase) pathway.

Pituitary adenylate cyclase-activating polypeptides (PACAP-27 and PACAP-38) are neuropeptides of the vasoactive intestinal polypeptide (VIP)/secretin/glucagon family. PACAP receptors are expressed in different brain regions, including cerebellum. We used primary culture of rat cerebellar granule neurons to study the effect of PACAP-38 on apoptosis induced by potassium deprivation. We demonstrated that PACAP-38 increased survival of cerebellar neurons in a dose-dependent manner by decreasing the extent of apoptosis estimated by DNA fragmentation. PACAP-38 induced activation of the extracellular signal-regulated kinase (ERK)-type of mitogen-activated protein (MAP) kinase through a cAMP-dependent pathway. PD98059, an inhibitor of MEK (MAP kinase kinase), completely abolished the antiapoptotic effect of PACAP-38, suggesting that MAP kinase pathway activation is necessary for PACAP-38 action.

Animals↗
PubMed1992

ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK.

p21c-ras plays a critical role in mediating tyrosine kinase-stimulated cell growth and differentiation. However, the pathways through which p21c-ras propagates these signals remain unknown. We report that in PC12 cells, expression of a dominant inhibitory mutant of ras, c-Ha-ras(Asn-17), antagonizes growth factor- and phorbol ester-induced activation of the erk-encoded family of MAP kinases, the 85-92 kd RSKs, and the kinase(s) responsible for hyperphosphorylation of the proto-oncogene product Raf-1. In addition, we find that expression of the activated ras oncogene is sufficient to stimulate these events. These data indicate that ras mediates nerve growth factor receptor and protein kinase C modulation of MAP kinases, RSKs, and Raf-1.

Animals↗
PubMed1994

Extracellular signal-regulated kinase (MAP kinase) immunoreactivity in the rhesus monkey brain.

Extracellular signal regulated kinases (ERKs) are a recently cloned family of genes that encode the MAP kinase protein kinases. They are highly expressed in brain and are believed to play an integral role in neural cellular responses to receptor activation. A role for ERKs has been postulated in Alzheimer's disease, where they have been implicated in phosphorylation of tau in neurofibrillary tangles. We explored the neuroanatomic distribution of ERK immunoreactivity in the rhesus monkey brain. The hippocampal formation, especially the mossy fiber zone and the molecular layer of the dentate gyrus are the most heavily immunostained areas. Cerebral cortex is, in general, more intensely stained in the supragranular layers. The caudate, putamen, and substantia nigra contain more immunoreactivity than the claustrum, globus pallidus, or thalamus with the exception of midline thalamic structures. These results suggest a marked regional and laminar distribution of ERKs in the primate brain.

Animals↗
PubMed1996

Platelet-activating factor and somatostatin activate mitogen-activated protein kinase (MAP kinase) and arachidonate release.

Platelet-activating factor (PAF) receptor and somatostatin receptor (SSTR4) were cloned, and their primary structures were identified. They are both highly expressed in the rat hippocampus. When expressed in Chinese hamster ovary cells, these receptors activated mitogen-activated protein (MAP) kinase cascade and phospholipase A2. Arachidonic acid or its derivatives, thus produced by the activation of these receptors may play some roles in synaptic transmission and synaptic plasticity.

Animals↗
PubMed1995

Production of tumor necrosis factor induced by synthetic low-toxicity lipid A analog, DT-5461a, is mediated by LPS receptor sites and tyrosine kinase-MAP kinase signaling pathway in murine macrophages.

The synthetic low-toxicity lipid A analog DT-5461a induces endogenous TNF production in mice. The activity of TNF so induced is probably the main contributor to the antitumor effect of this compound. In the present study, we investigated the mechanism by which DT-5461a induces TNF production in murine macrophage RAW 264 cells. DT-5461a mimicked the ability of LPS to induce TNF production in a dose-dependent manner. DT-5461a at higher concentrations inhibited specific binding of [3H]LPS to the cells and reduced LPS-induced TNF production to the level induced by DT-5461a alone. In addition, DT-5461a, as well as LPS, induced tyrosine phosphorylation of MAP kinases, the early signal transduction pathway of this production. Herbimycin A, an inhibitor of tyrosine kinase, inhibited the LPS- and DT-5461a-induced tyrosine phosphorylation, expression of TNF mRNA, and subsequent TNF secretion. These results suggest that DT-5461a and LPS induce TNF production in murine macrophages through the common receptor sites and the similar early signaling pathway.

Animals↗
PubMed1993

Phosphorylation of Xenopus mitogen-activated protein (MAP) kinase kinase by MAP kinase kinase kinase and MAP kinase.

Xenopus 45-kDa mitogen-activated protein (MAP) kinase kinase (MAPKK) is a serine/threonine/tyrosine kinase, which activates MAP kinase (MAPK) by phosphorylating its threonine and tyrosine residues. MAPKK is active only when its threonine and/or serine residues are phosphorylated. We have identified from Xenopus eggs two protein kinases responsible for phosphorylation of MAPKK. The two kinases are separated by Sephacryl S-300 gel filtration chromatography. The higher molecular weight kinase phosphorylates MAPKK previously dephosphorylated and inactivated by phosphatase 2A treatment on mainly serine and slightly threonine residues, and reactivates the MAPKK, and is thus assumed to work as MAPKK kinase (MAPKKK) in vivo. The lower molecular weight kinase, identified as MAPK, phosphorylates the dephosphorylated MAPKK on mainly threonine and faintly serine residues, but does not reactivate the MAPKK activity. As Xenopus MAPKK contains a single phosphorylation consensus sequence (PXT388P) for MAPK in the C-terminal region, this T388 residue may be a major phosphorylation site catalyzed by MAPK. Thus, Xenopus MAPKK is phosphorylated in mature oocytes by not only an upstream kinase, MAPKKK, but also a downstream kinase, MAPK.

Amino Acid Sequence↗
PubMed2006

Regulation of MAP kinases by MAP kinase phosphatases.

MAP kinase phosphatases (MKPs) catalyze dephosphorylation of activated MAP kinase (MAPK) molecules and deactivate them. Therefore, MKPs play an important role in determining the magnitude and duration of MAPK activities. MKPs constitute a structurally distinct family of dual-specificity phosphatases. The MKP family members share the sequence homology and the preference for MAPK molecules, but they are different in substrate specificity among MAPK molecules, tissue distribution, subcellular localization and inducibility by extracellular stimuli. Our understanding of their protein structure, substrate recognition mechanisms, and regulatory mechanisms of the enzymatic activity has greatly increased over the past few years. Furthermore, although there are a number of MKPs, that have similar substrate specificities, non-redundant roles of MKPs have begun to be identified. Here we focus on recent findings regarding regulation and function of the MKP family members as physiological regulators of MAPK signaling.

Animals↗
PubMed1994

Transfected platelet-activating factor receptor activates mitogen-activated protein (MAP) kinase and MAP kinase kinase in Chinese hamster ovary cells.

The platelet-activating factor (PAF) was seen to potently activate mitogen-activated protein (MAP) kinase and MAP kinase kinase through the cloned guinea pig PAF receptor stably expressed in Chinese hamster ovary (CHO) cells. Both 42- and 44-kDa MAP kinases were activated and tyrosine-phosphorylated in response to PAF. The PAF receptor also triggered the production of inositol phosphates and the release of arachidonic acid and inhibited cyclic AMP accumulation. Differential inhibitory effects of pertussis toxin (PTX) on these signals suggested that the PAF receptor couples to both PTX-sensitive and -insensitive G proteins in CHO cells. MAP kinase and MAP kinase activations were partially regulated by PTX-sensitive G proteins. The PAF receptor did not trigger any detectable increase in the GTP form of Ras under the conditions in which the human insulin receptor expressed in the same parent CHO cells potently increased the level. Since these agonists induced comparable MAP kinase activations through cognate receptors, Ras seems to play different roles in MAP kinase activation by the two different classes of receptors. The activation of MAP kinase by the cloned PAF receptor may explain part of the mechanisms underlying PAF-induced differentiation and proliferation in non-inflammatory cells.

Animals↗