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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)

Growth factors or serum can induce transcription and translation of a dual specificity MAP (mitogen-activated protein) kinase phosphatase, MKP-1 (MAP kinase phosphatase-1). The role of induction of MKP-1 (formerly 3CH134) in the rapid phase of MAP kinase deactivation was studied in rat pheochromocytoma (PC12) cells. MAP kinase was nearly completely deactivated in PC12 cells by 10 min after stimulation with epidermal growth factor (EGF) whereas MAP kinase activity remained elevated at 30% of the maximal response after stimulation with nerve growth factor. Protocols for treating cells with actinomycin D and cycloheximide were established that eliminate detection of MKP-1 mRNA and protein in PC 12 cells. Treatment of PC12 cells with actinomycin D and cycloheximide did not affect the rapid deactivation of MAP kinase. Thus, the rapid phase of MAP kinase deactivation in PC12 cells is not dependent on the induction of the MAP kinase phosphatase MKP-1.
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PMID:Rapid deactivation of MAP kinase in PC12 cells occurs independently of induction of phosphatase MKP-1. 792 31

Mitogen-activated protein kinases (MAP kinases) are common components of signaling pathways induced by diverse growth stimuli. Although the guanidine nucleotide-binding Ras proteins are known to be upstream activators of MAP kinases, the extent to which MAP kinases directly contribute to the mitogenic effect of Ras is as yet undefined. In this study, inhibition of MAP kinases by the MAP kinase phosphatase MKP-1 blocked the induction of DNA synthesis in quiescent rat embryonic fibroblast REF-52 cells by an activated mutant of Ras, V12Ras. These results suggest an essential role for activation of MAP kinases in the transition from the quiescent to the DNA replication phase of the eukaryotic cell cycle.
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PMID:Inhibition of Ras-induced DNA synthesis by expression of the phosphatase MKP-1. 793 66

Like early Xenopus embryos, extracts made from Xenopus eggs lack the cell cycle checkpoint that keeps anaphase from occurring before spindle assembly is complete. At very high densities of sperm nuclei, however, microtubule depolymerization arrests the extracts in mitosis. The arrested extracts have high levels of maturation-promoting factor activity, fail to degrade cyclin B, and contain activated ERK2/mitogen-activated protein (MAP) kinase. The addition of the purified MAP kinase-specific phosphatase MKP-1 demonstrates that MAP kinase activity is required for both the establishment and maintenance of the mitotic arrest induced by spindle depolymerization. Increased calcium concentrations, which release unfertilized frog eggs from their natural arrest in metaphase of meiosis II, have no effect on the mitotic arrest.
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PMID:A MAP kinase-dependent spindle assembly checkpoint in Xenopus egg extracts. 795 13

Vaccinia phosphatase VH-1 and its mammalian counterparts, including protein-tyrosine phosphatases (PTPase) CL100 and VHR, constitute a novel subfamily of protein-tyrosine phosphatases that exhibits dual substrate specificity for phosphotyrosine- and phosphoserine/threonine-containing substrates. The expression of human VH-1-like PTPase CL100 is rapidly inducible by mitogen stimulation and oxidative stress, suggesting that this gene is transcriptionally regulated. In order to study the mechanism underlying this transcriptional regulation, we isolated the first human gene of this subfamily, the CL100 gene, and characterized its promoter. The gene consists of four exons intervened by three short introns 400-500 base pairs in length. Analysis of the protein sequence encoded by each exon revealed that there is a second region of similarity between CL100 protein and cdc25 in addition to the PTPase catalytic domain. Promoter analysis of the CL100 gene indicates that an 800-base pair region flanking the transcriptional initiation site is sufficient to confer a transcriptional response to serum and 12-O-tetradecanoylphorbol-13-acetate stimulation. The CL100 gene is expressed in numerous tissues, including nonmitotic cells in the brain. Within the brain, CL100 mRNA is localized in discrete neuronal populations, suggesting that this PTPase is likely to play a key role in neurotransmission as well as in mitotic signaling. Finally, although extracellular signal-regulated kinase has recently been shown to act as substrate for CL100 in vitro, we find no clear correspondence between the distribution of extracellular signal-regulated kinase and CL100 mRNA in the brain. The potential significance of a second cdc25 homology domain of CL100 is discussed.
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PMID:Isolation and characterization of a human dual specificity protein-tyrosine phosphatase gene. 810 4

Expression of the human CL100 gene is induced in skin fibroblasts in response to oxidative/heat stress and growth factors. The CL100 gene encodes a dual specificity (Tyr/Thr) protein phosphatase that specifically inactivates mitogen-activated protein (MAP) kinase in vitro. In addition, CL100 is able to suppress the activation of MAP kinase by oncogenic ras in extracts of Xenopus oocytes. Thus, the CL100 phosphatase may play an important role in the negative regulation of cellular proliferation and is a likely candidate for a tumour-suppressor gene. Here, we show that DNA sequences homologous to CL100 are present in genomic DNA isolated from mouse, chicken, Xenopus and Drosophila, indicating that the CL100 gene is highly conserved. Using an assay based on the polymerase chain reaction, in conjunction with genomic DNA obtained from human-rodent somatic-cell hybrids, we have determined that the CL100 gene is situated on chromosome 5. Fluorescence in situ hybridisation using a CL100 genomic probe confirms that the CL100 mRNA is transcribed from a single genetic locus and maps the gene to 5q34.
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PMID:The CL100 gene, which encodes a dual specificity (Tyr/Thr) MAP kinase phosphatase, is highly conserved and maps to human chromosome 5q34. 816 26

Mitogenic stimulation of cells induces rapid and transient activation of MAP kinases. Here we report that a growth factor-inducible gene, 3CH134, encodes a dual specificity phosphatase that dephosphorylates and inactivates p42MAPK both in vitro and in vivo. In vitro, 3CH134 protein dephosphorylates both T183 and Y185 in p42MAPK. In serum-stimulated normal fibroblasts, the kinetics of inactivation of p42MAPK coincides with the appearance of newly synthesized 3CH134 protein, and the protein synthesis inhibitor cycloheximide leads to persistent activation of MAP kinase. Expression of 3CH134 in COS cells leads to selective dephosphorylation of p42MAPK from the spectrum of phosphotyrosyl proteins. 3CH134 blocks phosphorylation and activation of p42MAPK mediated by serum, oncogenic Ras, or activated Raf, whereas the catalytically inactive mutant of the phosphatase, Cys-258-->Ser, augments MAP kinase phosphorylation under similar conditions. The mutant 3CH134 protein also forms a physical complex with the phosphorylated form of p42MAPK. These findings suggest that 3CH134 is a physiological MAP kinase phosphatase; we propose the name MKP-1 for this phosphatase.
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PMID:MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo. 822 88

The activation of extracellular signal-regulated kinase (ERK) or mitogen-activated protein kinase (MAPK) by a dual specific kinase, MEK (MAPK or ERK kinase), is a critical event in the mitogenic signal transduction pathway. However, little is known about the mechanism of ERK inactivation, which occurs after stimulation. In this report, we demonstrated that a dual specific protein phosphatase, HVH1 (human VH1 phosphatase homolog) whose expression is induced by mitogenic growth factors, specifically inactivates ERK. When several phosphoproteins were tested for recombinant HVH1, only MEK-activated ERK1 was dephosphorylated. HVH1 selectively dephosphorylated threonine and tyrosine residues but not serine residues of the activated ERK1. Inactivation of ERK1 by HVH1 could be reversed by MEK, suggesting that HVH1 dephosphorylates the same residues that are recognized and phosphorylated by MEK. Our results suggest that mitogenic growth factors transiently activate ERK (peak at 5 min followed by a rapid decline) by temporally activating MEK (the on signal) and inducing the expression of HVH phosphatase (the off signal).
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PMID:Dephosphorylation and inactivation of the mitogen-activated protein kinase by a mitogen-induced Thr/Tyr protein phosphatase. 834 96

The expression of the human CL100 gene and its mouse homologue 3CH134 is increased up to 40-fold in fibroblasts exposed to oxidative/heat stress and growth factors. CL100 is a member of an expanding family of protein tyrosine phosphatases with amino acid sequence similarity to a Tyr/Ser-protein phosphatase encoded by the late H1 gene of vaccinia virus. Here we show that the CL100 phosphatase, expressed and purified in bacteria, rapidly and potently inactivates recombinant MAP kinase in vitro by the concomitant dephosphorylation of both its phosphothreonine and phosphotyrosine residues. Furthermore, CL100 suppresses the [val12] ras-induced activation of MAP kinase in a cell-free system from Xenopus oocytes. Both activities are abolished by mutagenesis of the highly conserved cysteine (Cys-258) within the phosphatase active site. In contrast to the vaccinia H1 phosphatase, CL100 shows no measurable catalytic activity towards a number of other substrate proteins modified on serine, threonine or tyrosine residues. Our results demonstrate that CL100 is a dual specificity phosphatase and indicate that MAP kinase is one of its physiological targets. CL100 may be the first example of a new class of protein phosphatases responsible for modulating the activation of MAP kinase following exposure of quiescent cells to growth factors and further implicates MAP kinase activation/deactivation in the cellular response to stress.
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PMID:The human CL100 gene encodes a Tyr/Thr-protein phosphatase which potently and specifically inactivates MAP kinase and suppresses its activation by oncogenic ras in Xenopus oocyte extracts. 839 41

The recent discovery of the vaccinia virus protein phosphatase VH1, and its mammalian counterparts has highlighted a novel subfamily of protein tyrosine phosphatases that exhibit dual specificity toward phosphotyrosine- and phosphoserine/threonine-residues. We have identified further members of this subfamily. The characterisation of one clone in particular, which we have named threonine-tyrosine phosphatase 1 (TYP 1), encodes a protein homologous to CL100, but differs dramatically in its regulation. TYP 1 is not expressed in human fibroblasts unlike other CL100-like genes. Furthermore, northern analysis has demonstrated that following mitogenic stimulation of squamous cells, induction of TYP 1 mRNA reaches its maximal levels after four hours, in contrast to the immediate early CL100-like genes. Both TYP 1 and CL100 mRNAs are induced upon TGF-beta treatment of squamous cell lines sensitive to the growth factors antiproliferative effects. When TYP 1 is transfected into COS-1 cells, the gene product inhibits both ERK2 and p54 MAP kinase subfamilies. In addition, we show that purified TYP 1 protein efficiently inactivates recombinant ERK2 in vitro by the concomitant dephosphorylation of both its phosphothreonine and -tyrosine residues. TYP 1 encodes a nuclear protein, which when expressed in COS cells is stabilised by EGF treatment.
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PMID:Isolation and characterisation of a uniquely regulated threonine, tyrosine phosphatase (TYP 1) which inactivates ERK2 and p54jnk. 854 12

Fibroblast growth factors (FGFs) play a role in biological processes such as cell growth and development, angiogenesis, and wound healing. Several genes have been shown to be induced by FGFs, but the underlying mechanisms have not been elucidated. We investigated the effect of FGF-2 (basic FGF) on the urokinase-type plasminogen activator (uPA) gene in NIH 3T3 fibroblasts. We found that the uPA gene is transcriptionally induced by FGF-2 as well as by 12-O-tetradecanoylphorbol-13 -acetate involving a PEA3/AP1 element located 2.4 kb upstream of the transcription initiation site; neither induction requires ongoing protein synthesis. Unlike 12-O-tetradecanoylphorbol-13-acetate induction, FGF-2 induction was not impaired by protein kinase C down-regulation. Analyses of various signaling molecules by Western blotting, extracellular signal-regulated kinase (ERK) activity assays, and transient transfection assays (cotransfection of a uPA-reporter gene construct with expression vectors for wild-type or dominant negative type of these molecules or for ERK-specific protein phosphatase MKP-1) showed that a Ras/Raf-1/MEK/ERK-2/JunD pathway is induced by FGF-2 and 12-O-tetradecanoylphorbol-13-acetate, leading to the activation of the uPA gene.
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PMID:Elucidation of a signaling pathway induced by FGF-2 leading to uPA gene expression in NIH 3T3 fibroblasts. 854 15


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