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)

Incubation of HER14 cells with phorbol myristate acetate (PMA) decreases epidermal growth factor (EGF)-dependent protein tyrosine phosphorylation, except for a 40-kDa MAP kinase II-like protein, whose tyrosine phosphorylation is further enhanced. The inhibitory effect of PMA on EGF-dependent protein tyrosine phosphorylation is reversed if cell are pre-incubated with a combination of Na3VO4 and NaF, two known inhibitors of protein tyrosine phosphatase activity. Protein tyrosine phosphatase activity of cell homogenate was measured on immunopurified EGF receptor, and was found to be enhanced in PMA-treated cells. These data suggest that the inhibitory effect of PMA on EGF-dependent protein tyrosine phosphorylation in HER14 cells may be mediated by protein tyrosine phosphatase activity.
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PMID:Inhibition of epidermal growth factor-dependent protein tyrosine phosphorylation by phorbol myristate acetate is mediated by protein tyrosine phosphatase activity. 750 70

The p53 tumor suppressor protein is tightly regulated in the cell and is phosphorylated at multiple sites by several different protein kinases. We have investigated the phosphorylation of p53 by mitogen-activated protein (MAP) kinase, a protein kinase that plays a central role in mediating many mitogenic and differentiation signals. Recombinant wild-type mouse p53 was phosphorylated in vitro by activated recombinant p42-MAP kinase but not by inactive MAP kinase or by the activating protein, MAP kinase kinase. Phosphorylation of p53 by MAP kinase occurred at two N-terminal sites, threonine residues 73 and 83. Tryptic phosphopeptides of recombinant p53 phosphorylated in vitro by MAP kinase comigrated on two-dimensional maps with p53 from SV3T3 cells labeled in vivo with [32P]orthophosphate, suggesting that MAP kinase targets a site in p53 that is phosphorylated in the cell. Following serum stimulation of quiescent C57MG cells, two p53 kinases, which were resolved by chromatography on Mono Q, were stimulated 15-20-fold within 5 min. Each of these kinase activities co-eluted with myelin basic protein kinase activity and could be inactivated following treatment with protein phosphatase 2A, a serine/threonine phosphatase, or leukocyte antigen receptor, a protein tyrosine phosphatase, suggesting that these activities were members of the MAP kinase family. The two kinase activities from the lysates targeted the same phosphorylation sites on p53 as the purified recombinant MAP kinase. These protein kinase activities were also stimulated following exposure of the cells to ultraviolet radiation, but with slightly delayed kinetics. Phorbol ester treatment of SV3T3 cells led to increased phosphorylation of the peptide containing the residues targeted by MAP kinase. The data suggest that p53 may be phosphorylated by MAP kinase physiologically and that this interaction may be involved in the cell's response to UV exposure, growth factor stimulation, or transformation by oncogenes.
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PMID:Phosphorylation of the tumor suppressor protein p53 by mitogen-activated protein kinases. 751 Jul 6

The enzyme glycogen synthase kinase-3 (GSK-3) has been implicated in the control of several metabolic enzymes and transcription factors in response to extracellular signals. In the past, the enzyme has been considered to be a protein Ser/Thr kinase although it was recently reported to contain Tyr(P) (Hughes, K., Nikolakaki, E., Plyte, S. E., Totty, N. F., and Woodgett, J. R. (1993) EMBO J. 12, 803-808). A cDNA encoding rabbit skeletal muscle GSK-3 beta was cloned and expressed in Escherichia coli as an active protein kinase, with apparent M(r) 46,000, capable of phosphorylating several known GSK-3 substrates. Recombinant GSK-3 beta autophosphorylated on Ser, Thr, and Tyr residues although the enzyme already contained Tyr(P) as judged by its recognition by anti-Tyr(P) antibodies. The net result of the autophosphorylation was a 3-5-fold reduction in enzyme activity. GSK-3 alpha, purified from rabbit muscle, also underwent autophosphorylation but only on Ser and Thr residues. In this case, the autophosphorylation stabilized the enzyme activity compared with the control lacking ATP/Mg2+. Of several phosphatases tested, the lambda-phage phosphatase was the most effective in dephosphorylating at Ser and Thr residues but did not dephosphorylate at Tyr residues. The action of the lambda-phosphatase caused a reactivation of GSK-3 beta to approximately 80% of the starting activity. The protein tyrosine phosphatase PTP1B was able to dephosphorylate at Tyr residues leading to a reduction in enzyme activity. A truncated form of GSK-3 beta, apparent M(r) 40,000, had a significantly higher specific activity, was defective in autophosphorylation, and was not inactivated in the autophosphorylation reaction. We conclude that GSK-3 beta is a dual specificity protein kinase in the same sense as the mitogen-activated protein kinase/ERK family of enzymes. Phosphorylation at different residues differentially controls enzyme activity, Ser/Thr phosphorylation causing inactivation and Tyr phosphorylation resulting in increased activity.
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PMID:Glycogen synthase kinase-3 beta is a dual specificity kinase differentially regulated by tyrosine and serine/threonine phosphorylation. 751 73

Anti-c-Src and anti-phosphotyrosine immunoprecipitates from receptor-like protein tyrosine phosphatase alpha (PTP alpha)-transfected and control rat embryo fibroblasts contain a 39-kDa phosphoprotein (p39) whose phosphorylation is enhanced by PTP alpha expression. The p39 that co-immunoprecipitates with c-Src has been identified as c-Jun by immunological and functional criteria; it is recognized by several different anti-c-Jun antibodies and binds to a c-Jun recognition element-containing oligonucleotide. Whereas the association of c-Src and c-Jun is unexpected, it may be of significance in PTP alpha signaling since we have previously demonstrated that c-Src is activated by PTP alpha (Zheng, X. M., Wang, Y., and Pallen, C. J. (1992) Nature 359, 336-339. Examination of c-Jun activity in these fibroblasts demonstrates that c-Jun DNA binding activity and c-Jun-mediated transcription of a chloramphenicol acetyltransferase reporter gene are elevated in PTP alpha-expressing cells. In addition to c-Jun activation, mitogen-activated protein kinase is activated in PTP alpha-expressing cells and translocated to the nuclei of these cells. The nuclear localization of activated mitogen-activated protein kinase and c-Jun suggests that their activation represents downstream events in the receptor-like PTP alpha-initiated signaling pathway(s).
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PMID:Expression of receptor-like protein tyrosine phosphatase alpha in rat embryo fibroblasts activates mitogen-activated protein kinase and c-Jun. 752 77

Phosphorylation of the catalytic subunit of protein phosphatase 2A (PP2A) on threonines with a distinct autophosphorylation-activated protein kinase [Guo and Damuni (1993) Proc. Natl. Acad. Sci. USA 90, 2500-2504] inactivated the phosphatase with 32P-labelled myelin basic protein prepared by incubation with the kinase domain of the epidermal growth factor receptor, the src-family protein kinases p56lck and p60c-src, myelin basic protein kinase-1, or protamine kinase. Phosphoamino acid analysis demonstrated that the kinase domain of the epidermal growth factor receptor, p56lck and p60c-src phosphorylated myelin basic protein on tyrosines, that the protamine kinase phosphorylated myelin basic protein on serines, and that myelin basic protein kinase-1 phosphorylated myelin basic protein on threonines. The results demonstrate that the autophosphorylation-activated protein kinase not only inactivates the protein serine/threonine phosphatase, but also the protein tyrosine phosphatase activity of PP2A. This autophosphorylation-activated protein kinase-mediated inactivation of PP2A may, in response to extracellular stimuli, not only contribute to the enhanced phosphorylation of cellular proteins on serines and threonines but also on tyrosines.
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PMID:Autophosphorylation-activated protein kinase inactivates the protein tyrosine phosphatase activity of protein phosphatase 2A. 752 89

The family of mitogen activated protein (MAP) kinases appear to play a central role in relaying signals generated by receptor protein tyrosine kinases (RPTK) from the cell surface to the nucleus. We previously demonstrated that undifferentiated and mitotically active crypt cells have high levels of tyrosine phosphorylated proteins (DR Burgess, W Jiang, S Mamajiwalla and W Kinsey. 1989. J. Cell Biol., 109: 2139) possibly due to the activation of RPTKs and also have high pp60c-src protein tyrosine kinase activity (CA Cartwright, SN Mamajiwalla, SA Skolnik, W Eckhart and DR Burgess. 1993. Oncogene. 8: 1033) when compared to differentiated, non-mitotic villus cells. Since activation of RPTKs leading to cell proliferation or differentiation involves activation of the Ras-MAP kinase pathway, we chose to determine in this study if the activity of the MAP kinases were also regulated during differentiation of normal adult enterocytes. Our data show that although the 42 kD MAP kinase (p42mapk) was expressed in both crypt and villus cells, it was phosphorylated on tyrosine and active only in the crypt cells. Our data further suggest that p42mapk is inactivated during differentiation, possibly by a protein tyrosine phosphatase. Immunofluorescence studies revealed that p42mapk localized to the nuclei in both undifferentiated and differentiated enterocytes and colocalized with phosphotyrosine containing proteins at the region of the junctional complex. These results suggest that p42mapk and its regulators are tightly controlled during enterocyte differentiation in vivo and implicate p42mapk as a key regulatory molecule in the normal development of the adult intestinal epithelium.
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PMID:Differential regulation of the activity of the 42 kD mitogen activated protein kinase (p42mapk) during enterocyte differentiation in vivo. 754 64

A novel protein tyrosine phosphatase [homologue of vaccinia virus H1 phosphatase gene clone 5 (hVH-5)] was cloned; it shared sequence similarity with a subset of protein tyrosine phosphatases that regulate mitogen-activated protein kinase. The catalytic region of hVH-5 was expressed as a fusion protein and was shown to hydrolyze p-nitrophenylphosphate and inactivate mitogen-activated protein kinase, thus proving that hVH-5 possessed phosphatase activity. A unique proline-rich region distinguished hVH-5 from other closely related protein tyrosine phosphatases. Another feature that distinguished hVH-5 from related phosphatases was that hVH-5 was expressed predominantly in the adult brain, heart, and skeletal muscle. In addition, in situ hybridization histochemistry of mouse embryo revealed high levels of expression and a wide distribution in the central and peripheral nervous system. Some specific areas of abundant hVH-5 expression included the olfactory bulb, retina, layers of the cerebral cortex, and cranial and spinal ganglia. hVH-5 was induced in PC12 cells upon nerve growth factor and insulin treatment in a manner characteristic of an immediate-early gene, suggesting a possible role in the signal transduction cascade.
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PMID:hVH-5: a protein tyrosine phosphatase abundant in brain that inactivates mitogen-activated protein kinase. 756 81

The pro-inflammatory cytokine, interleukin-1 beta, induces the mRNA for prostaglandin endoperoxide synthase II gene in renal mesangial cells. This inductive effect is selective for prostaglandin endoperoxide synthase II and not prostaglandin endoperoxide synthase I. In the present experiments IL-1 beta increased COX II mRNA, and this was inhibited by genistein and herbimycin A, both inhibitors of protein tyrosine kinases. The dose dependent effect of genistein on inhibition of mRNA for COX II correlated with the inhibition of the release of PGE2 into the media. Induction of COX II by interleukin-1 beta was mimicked by incubating the cells in the presence of a protein tyrosine phosphatase inhibitor, vanadate. These experiments also illustrate selective induction of COX II mRNA without induction of COX I mRNA. Western analysis utilizing antiphosphotyrosine antibodies demonstrated in whole lysates of mesangial cells treated with interleukin-1 beta that the transient phosphorylation of several proteins occurred. Interleukin-1 beta induced the transient phosphorylation of a protein of about 39/40 kD. Similarly, vanadate also produced a rapid and transient phosphorylation of a protein of about 39/40 kD in addition to other proteins. Immunoprecipitation of mesangial cell lysates with agarose conjugated antiphosphotyrosine antibody and Western analysis of precipitated proteins with anti-ERK2 antibody demonstrate that the 39/40 kD protein phosphorylated on tyrosine is ERK2 and suggests participation of one of the MAP kinase family of extracellular receptor kinases in IL-1 beta stimulated induction of the COX II gene.
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PMID:IL-1 beta regulates rat mesangial cyclooxygenase II gene expression by tyrosine phosphorylation. 763 65

A unique and highly conserved structural feature of approximately 90-kDa ribosomal S6 kinase (p90rsk or RSK) is the presence of two non-identical kinase domains. To explore the mechanism of RSK activation, a cloned human RSK cDNA (RSK3) was used to generate and characterize several site-directed RSK mutants; K91A (N-Lys, NH2-terminal ATP-binding mutant), K444A (C-Lys, COOH-terminal ATP-binding mutant), N/C-Lys (double ATP-binding mutant) T570A (C-Thr, mutant of the putative MAPK phosphorylation site in subdomain VIII of the C-domain), S218A (N-Ser, mutant of the corresponding NH2-terminal residue). Epitope-tagged RSKs were expressed in transfected COS cells followed by immunoprecipitation with or without prior in vivo epidermal growth factor stimulation. Kinase activity (S6 peptide) of N/C-Lys and N-Lys was ablated (and partially impaired with N-Ser). In contrast, both C-Lys and C-Thr retained high levels of kinase activity and were capable of responding to stimulation. C-Lys also retained partial kinase activity toward other substrates (c-Fos, S40 ribosomes, protein phosphatase 1 G-subunit, histones, and Leu-Arg-Arg-Ala-Ser-Leu-Gly (Kemptide)) whereas N-Lys did not. The isolated NH2-and COOH-terminal domains were also expressed; the C-domain was inactive, whereas the N-domain retained partial activity. Relative to wild-type, both N-Lys and C-Lys (as well as N-Ser and C-Thr) underwent partial in vitro autophosphorylation that was further stimulated by EGF protein tyrosine phosphatase. We conclude that 1) the NH2-terminal RSK kinase domain mediates substrate phosphorylation; 2) both domains contribute to autophosphorylation; 3) the putative MAPK phosphorylation site is not required for growth factor-stimulated autophosphorylation or kinase activation.
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PMID:Divergent functional roles for p90rsk kinase domains. 764 38

The precise role of the protein tyrosine phosphatase Syp in insulin signaling is not well understood. We previously reported that expression of catalytically inactive Syp phosphatase blocked stimulation of mitogen-activated protein (MAP) kinase by insulin. In this study, we investigated the effect of dominant negative Syp on the intermediates in MAP kinase pathway. The expression of dominant negative Syp blocked the activation of MEK and raf-1 kinase in response to insulin and had no detectable effect on insulin-induced activation of p21ras. These data suggest that the target of the Syp phosphatase may reside in proteins immediately downstream of p21ras.
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PMID:Expression of a catalytically inert Syp blocks activation of MAP kinase pathway downstream of p21ras. 767 89


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