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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We demonstrate that members of the erk-encoded family of mitogen-activated protein (MAP) kinases (pp44/42mapk/erk) and members of the rsk-encoded protein kinases (RSKs or pp90rsk) are present in the cytoplasm and nucleus of HeLa cells. Addition of growth factors to serum-deprived cells results in increased tyrosine and threonine phosphorylation and in the activation of cytosolic and nuclear MAP kinases. Activated MAP kinases then phosphorylate (serine/threonine) and activate RSKs. Concurrently, a fraction of the activated MAP kinases and RSKs enter the nucleus. In addition, a distinct growth-regulated RSK-kinase activity (an enzyme[s] that phosphorylates recombinant RSK in vitro and that may be another member of the erk-encoded family of MAP kinases) was found associated with a postnuclear membrane fraction. Regulation of nuclear MAP kinase and RSK activities by growth factors and phorbol ester is coordinate with immediate-early gene expression. Indeed, in vitro, MAP kinase and/or RSK phosphorylates histone H3 and the recombinant c-Fos and c-Jun polypeptides, transcription factors phosphorylated in a variety of cells in response to growth stimuli. These in vitro studies raise the possibility that the MAP kinase/RSK signal transduction pathway represents a protein-Tyr/Ser/Thr phosphorylation cascade with the spatial distribution and temporal regulation that can account for the rapid transmission of growth-regulating information from the membrane, through the cytoplasm, and to the nucleus.
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PMID:Nuclear localization and regulation of erk- and rsk-encoded protein kinases. 154 23

Treatment of Swiss mouse 3T3 fibroblasts with certain cyclic nucleotide phosphodiesterase inhibitors (theophylline, SQ 20,006, and MY-5445) prevents the activation of the M(r) 70,000 S6 kinase (p70S6k) induced by a variety of external stimuli. Concentrations giving half-maximal inhibition were 800, 50, and 25 microM, respectively. Western blot analysis and immunocomplex kinase assays showed that these compounds inhibit the phosphorylation and activation of p70S6k without affecting the erk-encoded mitogen-activated protein (MAP) kinases or the rsk-encoded S6 kinase (p90rsk). A distinct collection of cAMP and cGMP agonists and analogues did not suppress p70S6k activation, indicating that 1) high intracellular cyclic nucleotide concentrations do not antagonize the p70S6k pathway and 2) phosphodiesterase inhibitors block p70S6k activation by a mechanism that is independent of cAMP or cGMP production. The effect of theophylline and SQ 20,006, but not MY-5445, on p70S6k signaling may be due in part to the inhibition of a phosphatidylinositol 3-kinase that acts upstream of p70S6k. Finally, in contrast to many other cell types, cAMP and cGMP were also found to have no inhibitory effect on the MAP kinase/p90rsk signaling pathway in Swiss 3T3 fibroblasts.
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PMID:Activation of p70 S6 kinase and erk-encoded mitogen-activated protein kinases is resistant to high cyclic nucleotide levels in Swiss 3T3 fibroblasts. 759 86

The metabolic and mitogenic actions of insulin have been proposed to be mediated by cellular serine/threonine kinases such as the ribosomal protein S6 kinases pp70-S6 (pp70-S6 kinase) and pp90rsk and the erk-encoded mitogen-activated protein kinases (pp42mapk and pp44mapk). Rapamycin completely blocked activation of pp70-S6 kinase by insulin in 3T3-L1 adipocytes, but did not inhibit insulin-stimulated glucose transport, translocation of GLUT4 to the cell surface, or activation of pp90rsk or pp44mapk by insulin. Concordant with the inhibition of kinase activity, rapamycin prevented the insulin-induced decrease in mobility of pp70-S6 kinase visualized by SDS-polyacrylamide gel electrophoresis, reflecting a reduction in the hormone-stimulated phosphorylation of the enzyme. The structurally related macrolide, FK506, had no effect on pp70-S6 kinase or hexose uptake. These data demonstrate that rapamycin blocks insulin activation of pp70-S6 kinase in 3T3-L1 adipocytes and that pp70-S6 kinase is not required in the signaling pathway leading to insulin-stimulated glucose transport.
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PMID:Dissociation of pp70 ribosomal protein S6 kinase from insulin-stimulated glucose transport in 3T3-L1 adipocytes. 767 6

Interleukin-13 (IL-13) and interleukin-4 (IL-4) are related in structure and function and are thought to share a common receptor component. We have investigated the signal transduction pathways activated by these two growth factors, as well as insulin, in cell-lines and primary cells of lymphohemopoietic origin. All three factors induced the tyrosine phosphorylation of a protein of 170 kDa (p170), which coimmunoprecipitated with the p85 subunit of P13'-kinase, via high affinity interactions mediated by the SH2 domains of p85. Antibodies raised against the entire insulin-receptor substrate-1 (IRS-1) protein immunoprecipitated p170 much less efficiently than they did IRS-1 from 3T3 cells. However, antibodies directed against the conserved pleckstrin homology domain of IRS-1 immunoprecipitated both p170 and IRS-1 with similar efficiency, suggesting they share structural similarities in this region. In lymphohemopoietic cells, IL-13, IL-4, and insulin failed to induce increased tyrosine phosphorylation of Shc, or its association with grb2, modification of Sos1, or activation of erk-1 and erk-2 mitogen-activated protein kinases, suggesting that p170 mediates downstream pathways distinct from those mediated by IRS-1. Both IL-13 and IL-4 induced low levels of tyrosine phosphorylation of Tyk-2 and Jak-1. IL-4 also activated the Jak-3-kinase, but, despite other similarities, IL-13 did not. Insulin failed to activate any of the known members of the Janus family of kinases. In that Jak-3 is reported to associate with the IL-2 gamma c chain, these data suggest that the IL-13 receptor does not utilize this subunit. However, both IL-13 and IL-4 induced tyrosine phosphorylation of the IL-4-140 kDa receptor chain, suggesting that this is a component of both receptors in these cells and accounts for the similarities in signaling pathways shared by IL-13 and IL-4.
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PMID:Interleukin-13 signal transduction in lymphohemopoietic cells. Similarities and differences in signal transduction with interleukin-4 and insulin. 774 81

The activation of erk/mitogen-activated protein kinases and p21ras is strongly associated with progression through the cell cycle. Cell growth induced by the cytokine interleukin-4 (IL-4) effectively dissociates the activation of p44erk-1 and p42erk-2 mitogen-activated protein kinases and p21ras from cell proliferation. In two cell lines of T lymphocyte and myeloid origin that were dependent upon IL-4 for continuous growth, IL-4 failed to detectably activate or induce tyrosine phosphorylation of p44erk-1 and p42erk-2. The activation of p21ras was also not detectably affected by IL-4 treatment of these cells. Treatment of the same cells with other growth factors (colony-stimulating factor-1 and Steel factor) or phorbol esters induced the tyrosine phosphorylation and activation of p44erk-1 and p42erk-2 and stimulated p21ras activity. The presence of IL-4 neither diminished nor enhanced the activation of p44erk-1 and p42erk-2 by colony-stimulating factor-1, Steel factor, or 12-O-tetradecanoylphorbol-13-acetate. Furthermore, IL-4 also failed to activate p44erk-1, p42erk-2, and p21ras in normal T lymphocytes and mast cells derived from spleen and bone marrow, respectively. Significantly, these findings demonstrate that IL-4-induced cell growth may be dissociated from the activation of p44erk-1, p42erk-2, and p21ras, suggesting that their activation may not be an absolute requirement for growth factor-stimulated mitogenesis.
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PMID:Interleukin-4-dependent proliferation dissociates p44erk-1, p42erk-2, and p21ras activation from cell growth. 811 29

Insulin exerts diverse effects on mitogenesis, metabolism, gene expression, and protein synthesis depending on the target cell type. A variety of extracellular serine/threonine kinases, including the ribosomal protein S6 kinases pp70-ribosomal S6 kinase (pp70-S6K) and pp90-ribosomal S6 kinase (pp90rsk) and the erk-encoded mitogen-activated protein (MAP) kinases pp44mapk/ERK-1 and pp42mapk/ERK-2, have been postulated as mediators of insulin action. In this study, we have investigated the role of the MAP kinase/pp90rsk signaling pathway in insulin-stimulated glucose transport in 3T3-L1 adipocytes. Differentiation of 3T3-L1 fibroblasts into adipocyte-like cells was accompanied by a marked increase in the capacity of insulin to activate pp90rsk and pp44mapk. Whereas the maximal insulin-stimulated pp90rsk and pp44mapk activities were only approximately 30% of the serum-stimulated activities in preadipocytes, the insulin-stimulated kinase activities in adipocytes were equal to or greater than the serum-stimulated activities. The increase in hormone receptor number accompanying differentiation accounted for the greater sensitivity, as overexpression of human insulin receptors in NIH-3T3 cells also conferred insulin-stimulatable kinase activity. In 3T3-L1 adipocytes, the stimulation of pp90rsk and pp44mapk activities was sufficiently rapid and hormone sensitive to convey a signal for increased hexose uptake. However, epidermal growth factor and fetal bovine serum were equipotent with insulin in stimulating pp90rsk and pp44mapk activities in adipocytes, but were without effect on hexose uptake. These data indicate that activation of these enzymes is not sufficient for the acute stimulation of glucose transport.
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PMID:Characterization of the mitogen-activated protein kinase/90-kilodalton ribosomal protein S6 kinase signaling pathway in 3T3-L1 adipocytes and its role in insulin-stimulated glucose transport. 829 68

The growth-promoting effects of endothelin-1 (ET-1) were examined in adult heart cells. The activity of mitogen-activated protein kinases (MAPKs) was measured in cytosolic extracts of isolated adult feline cardiac myocytes incubated with and without ET-1. Kinase activity was assessed by phosphorylation of the exogenous substrate, myelin basic protein. ET-1 stimulated the activity of MAPK up to 4-fold, with peak activation occurring between five and ten minutes after addition of ET-1. Polyclonal antisera raised against a 14-amino acid sequence of the erk-2 gene product, a MAPK isoform, identified two major bands in cytosolic extracts of the cardiac myocytes. Partial purification of kinase activities using Mono Q anion-exchange chromatography demonstrated two major peaks of myelin basic protein kinase activity. Subsequent immunoblots of the eluted fractions demonstrated that the immunoreactive bands observed in the cytosolic extracts eluted in those fractions possessing kinase activity. Overnight pretreatment of the cardiac myocytes with 100 ng/ml pertussis toxin inhibited the ET-1 stimulated increase in MAPK activity by 50 - 70%, but did not alter stimulation by 100 nM phorbol 12-myristate 13-acetate (PMA). These data suggest that stimulation of MAPK by ET-1 may be mediated by more than one pathway. MAPK has been shown to be activated in the intracellular transmission of growth factor signals. Indicative of a growth effect in this adult heart cell model, myocytes exposed to increasing concentrations of ET-1 demonstrated a dose dependent increase in [3H]-phenylalanine incorporation into cellular protein. This response was blocked by staurosporine and partially inhibited by pretreatment with pertussis toxin, again suggesting the possible involvement of multiple early signals. These data from isolated adult cardiac myocytes further support the hypothesis that ET-1 has a role in the regulation of cardiac growth.
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PMID:Effects of endothelin on mitogen-activated protein kinase activity and protein synthesis in isolated adult feline cardiac myocytes. 863 15

When HD3 colon carcinoma cells differentiate to fluid-transporting, enterocytic-like cells, they down-regulate their protein kinase C (PKC) beta levels 5-10-fold and lose two responses to basic fibroblast growth factor (FGF): proliferation and the ability to activate p57 mitogen-activated protein (MAP) kinase. HD3 cells were transfected with expression plasmids for the splice variants PKC-beta 1 and PKC-beta 2 and the empty vector for a control. Each of two PKC-beta 1 and each of two PKC-beta 2 transfectant clones exhibited elevated levels of Ca(2+)-and phosphatidylserine-dependent PKC activity. Both PKC-beta 1 transfectant clones had elevated levels of PKC-beta 1 protein compared with the PKC-beta 2 transfectants or controls, whereas both PKC-beta 2 transfectant clones had elevated levels of PKC-beta 2 protein compared with PKC-beta 1 transfectants. Control transfectants had no detectable PKC-beta 2 protein. Similar levels of PKC-alpha were found in all lines. Each PKC-beta transfectant was less differentiated than the parental line and had regained proliferative response to basic FGF. Increased growth rates in athymic mice were seen for PKC-beta 2 and PKC-beta 1 transfectant cells. Immunocytochemistry of the sectioned tumors showed enhanced protein levels of PKC-beta 2 and PKC-beta 1, correlating increased levels of these isonzymes with increased growth. Increased myelin-basic protein (MBP) kinase activities of M(r) 44,000, 57,000, 63,000, 110,000, and 130,000 by in-gel kinase assay characterized each PKC-beta transfectant. Both Western blotting and immunoprecipitation studies from 35S-prelabeled cells with a pan-erk antibody showed no increase in protein abundance of MAP kinases of M(r) 44,000, 57,000, and 63,000, suggesting that elevated PKC-beta levels led to activation of the smaller three MAP and MBP kinases. Activation of p57 MAP kinase in each PKC-beta transfectant was demonstrated by immunoprecipitation with an antiphosphotyrosine monoclonal antibody and then by assay of the immunoprecipitates by in-gel kinase assay on MBP. p57 MAP kinase was distinguished from the M(r) 54,000 stress-activated protein kinases, which migrated more rapidly on SDS gels and could be detected by in-gel kinase assay on MBP only after cellular stress. Thus, expression of elevated levels of PKC-beta 1 and PKC-beta 2 in differentiated HD3 colon carcinoma cells blocked their differentiation, enabled them to proliferate in response to basic FGF like undifferentiated cells, increased their growth rate in athymic mice, and activated several MBP kinases, among them, p57 MAP kinase.
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PMID:Protein kinase C beta 1 and protein kinase C beta 2 activate p57 mitogen-activated protein kinase and block differentiation in colon carcinoma cells. 873 68

Activation of mitogen-activated protein kinases (MAPKs) is a critical event in mitogenic signal transduction. MAPKs are activated by tyrosine phosphorylation and translocate to different cellular compartments affecting protein function and gene expression. MAPK expression and activity was examined in uterine smooth muscle from rats pretreated with estradiol-17 beta alone or with estradiol-17 beta and progesterone. MAPK expression was detected by immunoblotting using erk1/2 antibodies. MAPK activity was detected by measurement of the phosphorylation of a MAPK-specific peptide sequence of myelin basic protein. Steroid treatment caused a modest (20%) decline in erk 1 and 2 expression in membrane and cytosolic fractions. Both estrogen and progesterone increased MAPK tyrosine phosphorylation and membrane-associated MAPK activity. Steroid treatment increased cytosolic MAPK tyrosine phosphorylation, but not enzymatic activity. These data suggest that gonadal steroid hormones, which stimulate uterine hypertrophy, may exert their hypertrophic effects by increasing MAPK activity.
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PMID:Effects of 17 beta-estradiol and progesterone on mitogen-activated protein kinase expression and activity in rat uterine smooth muscle. 873 15

This is the first report on estrogen-dependent growth of human-derived colon carcinoma cells. Under selected conditions, growth of subconfluent Caco-2 cells is triggered by estradiol. Cell growth is estradiol concentration dependent, with maximal effect occurring at about 0.4 nM. Growth is prevented by two different antiestrogens: the partial agonist, OH-Tamoxifen, and the pore antagonist, ICI 182,780. The growth effect is specific for estradiol since other hormonal steroids tested do not affect cell growth. The amount of estradiol receptor in subconfluent Caco-2 cells, detected by blot with monoclonal antibodies directed against the receptor as well as estradiol binding assays, is similar to that of the classical estradiol-responsive, human mammary cancer-derived MCF-7 cells. Estradiol treatment of subconfluent Caco-2 cells rapidly and reversibly stimulates four important intermediates in a signal transduction pathway that is known to trigger cell proliferation: two members of the large family of c-src-related tyrosine kinases, c-src and c-yes, and two serine/threonine kinases, the mitogen-activated protein (MAP) kinases, erk-1 and erk-2. Tyrosine kinases activated by estradiol are up-stream MAP kinases and Caco-2 cell proliferation. In fact, genistein, a specific tyrosine kinase inhibitor, abolishes the estradiol stimulatory effect on both erk-2 activity and cell proliferation. Our findings show that in subconfluent Caco-2 cells, the estradiol-receptor complex activates the c-src, c-yes/MAP kinase pathway and activates growth. This could have important implications for the understanding of human intestinal carcinogenesis.
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PMID:Estradiol activation of human colon carcinoma-derived Caco-2 cell growth. 881 50


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