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)

The mechanism by which fertilization initiates S-phase in the zygote is examined by manipulating the activity of MAP kinase in mature starfish eggs. These unfertilized eggs, which are arrested at G1-phase after the completion of meiosis, have high MAP kinase activity but undetectable cdc2 kinase activity. Either fertilization or inhibition of protein synthesis causes a decrease in MAP kinase activity, which is followed by DNA synthesis. Inactivation of MAP kinase with its specific phosphatase, CL100, initiates DNA synthesis in the absence of fertilization, while constitutive activation of MAP kinase with MEK represses the initiation of DNA synthesis following fertilization. Thus, in unfertilized mature starfish eggs, a capacity for DNA replication is already acquired, but entry into S-phase is negatively regulated by MAP kinase activity that is supported by a continuously synthesized protein(s) but not by cdc2 kinase. Upon fertilization, downregulation of MAP kinase activity is necessary and sufficient for triggering the G1/S-phase transition.
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PMID:MAP kinase links the fertilization signal transduction pathway to the G1/S-phase transition in starfish eggs. 925 Jun 77

Mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) is a dual-specificity protein phosphatase encoded by an immediate-early gene responsive to growth factors and stress. The MKP-1 protein selectively inactivates MAP kinases in vitro by dephosphorylation of the regulatory Thr and Tyr residues. Little is known on the mechanisms that regulate MKP-1 gene expression. Here, we demonstrate that Ca2+ is both necessary and sufficient for the induction of MKP-1 gene expression. Treatment of Rat1 fibroblasts with the Ca2+ chelating agent BAPTA completely suppressed serum-induced MKP-1 expression in a dose- and time-dependent manner. The inhibitory effect of BAPTA was observed at the level of the protein and the mRNA. Importantly, Ca2+ chelation blocked the induction of MKP-1 expression in response to all stimuli tested and in different cell types. Increasing the intracellular concentration of Ca2+ with the ionophore A23187 was sufficient to induce MKP-1 mRNA and protein expression in rat fibroblasts. We also provide evidence that activation of MAP kinases is not an absolute requirement for induction of the MKP-1 gene. Exposure of rat fibroblasts to A23187 induced MKP-1 expression without activating the JNK and p38 MAP kinase pathways. Also, inhibition of the ERK pathway with the selective MEK inhibitor PD98059 did not interfere with serum-stimulated MKP-1 mRNA expression. These results will help define the regulatory mechanisms that govern MKP-1 gene transcription in target cells.
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PMID:Essential role of calcium in the regulation of MAP kinase phosphatase-1 expression. 926 12

Exposure of cells to ionizing radiation (IR) or tumor necrosis factor-alpha (TNF-alpha) results in the stimulation of the DNA binding activities of transcription factors, AP-1 and NF-kappaB. HVH1/CL100, a dual specificity protein phosphatase, may attenuate the AP-1 response by dephosphorylating a key upstream element, mitogen-activated protein kinase (MAPK). The members of IkappaB family of proteins regulate the NF-kappaB response. We examined the effects of IR and TNF-alpha on HVH1 and IkappaB alpha gene expression. Our data demonstrate that IR or TNF-alpha treatment of head and neck squamous carcinoma cells (PCI-04A) increased the steady-state levels of HVH1 and IkappaB alpha mRNAs; however, the induction patterns were different. TNF-alpha treatment led to a relatively prolonged stimulation of HVH1 and IkappaB alpha mRNAs lasting at least 7 h, while IR caused a transient stimulation of these mRNAs and the expression returned to basal levels within 6 h post-IR treatment. Treatment of cells with cycloheximide did not prevent the IR orTNF-alpha-inducible expression of HVH1 and IkappaB alpha genes, indicating that these responses were independent of the new protein synthesis. These data imply that protein phosphatase HVH1 and regulatory factor IkappaB alpha may play important roles in cellular response to IR and TNF-alpha. In addition, the kinetics of responsiveness indicates that the mechanisms of IR and TNF-alpha-induced signalling are distinct.
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PMID:Ionizing radiation and TNF-alpha stimulate gene expression of a Thr/Tyr-protein phosphatase HVH1 and inhibitory factor IkappaB alpha in human squamous carcinoma cells. 927 72

Insulin signaling involves the transient activation/inactivation of various proteins by a cycle of phosphorylation/dephosphorylation. This dynamic process is regulated by the action of protein kinases and protein phosphatases. One family of protein kinases that is important in insulin signaling is the mitogen-activated protein (MAP) kinases, whose action is reversed by specific MAP kinase phosphatases (MKPs). Insulin stimulation of Hirc B cells overexpressing the human insulin receptor resulted in increased MKP-1 mRNA levels. MKP-1 mRNA increased in a dose-dependent manner to a maximum of 3- to 4-fold over basal levels within 30 min, followed by a gradual return to basal. The mRNA induction did not require the continuous presence of insulin. The induction of MKP-1 protein synthesis followed MKP-1 mRNA induction; MKP-1 protein was maximally expressed after 120 min of insulin stimulation. MKP-1 mRNA induction by insulin required insulin receptor tyrosine kinase activity, since overexpression of an altered insulin receptor with impaired intrinsic tyrosine kinase activity prevented mRNA induction. Forskolin, (Bu)2-cAMP, 8-bromo-cAMP, and 8-(4-chlorophenylthio)-cAMP increased the MKP-1 mRNA content moderately above basal. These agents also augmented the insulin-stimulated expression of MKP-1 mRNA. However, in some cases the increase in MKP-1 mRNA expression was less than additive. Nevertheless, these results indicate that multiple signaling motifs might regulate MKP-1 expression and suggest another mechanism for the attenuation of insulin-stimulated MAP kinase activity by cAMP. Overexpression of MKP-1 in Hirc B cells inhibited both insulin-stimulated MAP kinase activity and MAP kinase-dependent gene transcription. The results of these studies led us to conclude that insulin regulates MKP-1 and strongly suggest that MKP-1 acts as a negative regulator of insulin signaling.
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PMID:Insulin-induced mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) attenuates insulin-stimulated MAP kinase activity: a mechanism for the feedback inhibition of insulin signaling. 928 68

We recently reported that insulin stimulation results in the serine phosphorylation of STAT3 (signal transducer and activator of transcription-3). In the present study, we identified serine 727 as the site of insulin-stimulated STAT3 serine phosphorylation. This phosphorylation event occurs independent of tyrosine phosphorylation. Furthermore, interleukin-6-induced tyrosine phosphorylation can occur independent of serine phosphorylation, demonstrating that these two phosphorylation pathways are mechanistically unrelated. Selective activation of the JNK and p38 family of mitogen-activated protein (MAP) kinases by anisomycin treatment did not result in the phosphorylation of STAT3. In contrast, activation of the ERK MAP kinase pathway with both insulin and osmotic shock resulted in the serine phosphorylation of STAT3. In addition, expression of a dominant-interfering Ras mutant (N17Ras) or treatment with the specific MEK inhibitor (PD98059) prevented the insulin stimulation of STAT3 serine phosphorylation. Blockade of ERK activation by expression of the MAP kinase phosphatase (MKP-1) had no effect on insulin-stimulated STAT3 serine phosphorylation. Together, these data demonstrate that the insulin-stimulated serine phosphorylation of STAT3 occurs by a MEK-dependent pathway that is independent of ERK activation.
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PMID:Signal transducer and activator of transcription-3 serine phosphorylation by insulin is mediated by a Ras/Raf/MEK-dependent pathway. 932 21

Interaction of type I collagen (COL(I)) with alpha2beta1 integrin causes differentiation and transforming growth factor (TGF)-beta receptor down-regulation in osteoblastic cells (Takeuchi, Y., Nakayama, K., and Matsumoto, T. (1996) J. Biol. Chem. 271, 3938-3644). The TGF-beta receptor down-regulation enables cells to escape from the inhibition of differentiation by TGF-beta. To clarify how the cell-matrix interaction regulates these phenotypic changes, signaling pathways were examined in murine MC3T3-E1 cells. Attachment of cells to COL(I) stimulated tyrosine phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK), a mitogen-activated protein kinase (MAPK), and enhanced MAPK activity. Inhibition of tyrosine kinase by herbimycin A, destruction of focal adhesion by cytochalasin D, or overexpression of antisense FAK mRNA prevented the activation of ERK/MAPK and the increase in alkaline phosphatase (ALP) activity. Transient expression of a MAPK-specific phosphatase, CL100, also suppressed the elevation of ALP activity. In addition, introduction of a constitutively active MAPK kinase enhanced ALP activity in the absence of collagen production. TGF-beta receptor down-regulation was abrogated by treatments that inactivate FAK, whereas the expression of CL100 had no effect. These results demonstrate that COL(I)-alpha2beta1 integrin interaction facilitates differentiation and down-regulates TGF-beta receptors via the activation of FAK and its diverse downstream signals. These signaling pathways may play an important role in the sequential differentiation of osteoblasts during bone formation.
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PMID:Differentiation and transforming growth factor-beta receptor down-regulation by collagen-alpha2beta1 integrin interaction is mediated by focal adhesion kinase and its downstream signals in murine osteoblastic cells. 936 Oct 11

mRNA levels of mitogen-activated protein kinase phosphatases, MKP-1 and MKP-2, were determined during chemical hepatocarcinogenesis and during regeneration of rat liver. In chemical hepatocarcinogenesis, the mRNA levels of MKP-1 were increased in primary hepatomas but decreased in rat ascites hepatomas as compared with normal liver. MKP-2 was undetectable in normal liver but strongly expressed in hepatomas. The MKP-2 mRNA level was increased with expression of malignant phenotypes in hepatomas. In regenerating liver, the mRNA level of MKP-1 increased immediately but transiently after partial hepatectomy, and peaked again on day 10, the time when hepatocytes cease proliferation. The elevated expression of MKP-1 on day 10 suggests some roles of MKP-1 as a negative regulator in hepatocyte proliferation.
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PMID:The characteristic gene expressions of MAPK phosphatases 1 and 2 in hepatocarcinogenesis, rat ascites hepatoma cells, and regenerating rat liver. 936 40

Growth factor stimulated receptor tyrosine kinases activate a protein kinase cascade via the serine/threonine protein kinase Raf-1. Direct upstream activators of Raf-1 are Ras and Src. This study shows that MEK1, the direct downstream effector of Raf-1, can also stimulate Raf-1 kinase activity by a positive feedback loop. Activated MEK1 mediates hyperphosphorylation of the amino terminal regulatory as well as of the carboxy terminal catalytic domain of Raf-1. The hyperphosphorylation of Raf-1 correlates with a change in the tryptic phosphopeptide pattern only at the carboxy terminus of Raf-1 and an increase in Raf-1 kinase activity. MEK1-mediated Raf-1 activation is inhibited by co-expression of the MAPK specific phosphatase MKP-1 indicating that the MEK1 effect is exerted through a MAPK dependent pathway. Stimulation of Raf-1 activity by MEK1 is independent of Ras, Src and tyrosine phosphorylation of Raf-1. MEK1 can however synergize with Ras and leads to further increase of the Raf-1 kinase activity. Thus, MEK1 can mediate activation of Raf-1 by a novel positive feedback mechanism which allows fast signal amplification and could prolong activation of Raf-1.
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PMID:MEK1 mediates a positive feedback on Raf-1 activity independently of Ras and Src. 938 Apr 2

Beraprost sodium, an analogue of prostacyclin, increases intracellular cyclic adenosine monophosphate (cAMP) in cultured glomerular mesangial cells. We examined the effect of beraprost on mesangial cell proliferation. Beraprost was able to inhibit fetal bovine serum-stimulated proliferation of mesangial cells in concentrations enough to increase cellular cAMP. By northern blot analysis, beraprost induced the expression of MKP-1, a mitogen-activated protein kinase phosphatase, in a dose- and time-dependent manner, similarly to dibutyryl cAMP and adrenomedullin. These results indicate that beraprost inhibits the proliferation of mesangial cells and one of the mechanisms might be cAMP-dependent induction of MKP-1.
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PMID:Beraprost sodium, an analogue of prostacyclin, induces the expression of mitogen-activated protein kinase phosphatase and inhibits the proliferation of cultured mesangial cells. 938 45

In this study we show that protein tyrosine kinases and also protein tyrosine phosphatases are involved in the uptake of Listeria monocytogenes by J774 macrophages to a different extent than in the uptake of inert latex beads. In addition, protein tyrosine kinases are necessary for the intracellular growth and survival of L. monocytogenes. The expression of the MAP kinase phosphatase MKP-1, a protein tyrosine phosphatase, is induced upon infection, and phagocytosis of L. monocytogenes by J774 cells overexpressing the MKP-1 protein is reduced compared to control cells. The decreased phagocytosis of L. monocytogenes as a result of the MKP-1 overexpression in J774 macrophages suggests that the activation of the MAP kinase(s) ERK-1 and/or ERK-2 is an essential requirement for the uptake of L. monocytogenes by J774 macrophages.
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PMID:Involvement of MAP-kinases and -phosphatases in uptake and intracellular replication of Listeria monocytogenes in J774 macrophage cells. 941 48


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