Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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 activation of eosinophils by IL-5 plays a crucial role in the pathogenesis of allergic and parasitic disorders. IL-5 has recently been shown to activate Lyn and Jak2 tyrosine kinases, MAP kinases, and STAT1 nuclear factor. We have previously reported that TGF-beta blocks the IL-5-induced activation of eosinophils. In this study, we investigated the effect of TGF-beta on the IL-5-induced signaling molecules in eosinophils. Purified eosinophils from mildly allergic patients were preincubated with TGF-beta and then stimulated with IL-5. The cell lysates were then immunoprecipitated and blotted with antiphosphotyrosine Abs. The activity of the kinases was further studied in the immune-complex kinase assay. We found that TGF-beta inhibited the tyrosine phosphorylation of multiple proteins in eosinophils. The identity of some of the proteins was established by immunoprecipitation. We found that TGF-beta inhibited tyrosine phosphorylation of Lyn, Jak2, and a 44-kDa MAP kinase. In further experiments, it blocked the activation of the above kinases as determined by immune-complex kinase assay. TGF-beta also inhibited phosphorylation of the STAT1 (p91) nuclear protein in eosinophils. We believe that the inhibition of Lyn, Jak2, MAP kinase, and the STAT1 nuclear protein may underlie the inhibitory activity of TGF-beta on eosinophils.
 ...
PMID:Mechanism of inhibition of eosinophil activation by transforming growth factor-beta. Inhibition of Lyn, MAP, Jak2 kinases and STAT1 nuclear factor. 759 7

The c-fos serum response element (SRE) forms a ternary complex with the transcription factors SRF (serum response factor) and TCF (ternary complex factor). By itself, SRF can mediate transcriptional activation induced by serum, lysophosphatidic acid, or intracellular activation of heterotrimeric G proteins. Activated forms of the Rho family GTPases RhoA, Rac1, and CDC42Hs also activate transcription via SRF and act synergistically at the SRE with signals that activate TCF. Functional Rho is required for signaling to SRF by several stimuli, but not by activated CDC42Hs or Rac1. Activation of the SRF-linked signaling pathway does not correlate with activation of the MAP kinases ERK, SAPK/JNK, or MPK2/p38. Functional Rho is required for regulated activity of the c-fos promoter. These results establish SRF as a nuclear target of a novel Rho-mediated signaling pathway.
 ...
PMID:The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF. 2478 41

We have shown that the interaction of interleukin (IL)-5 with the receptor activates Lyn tyrosine kinase within 1 min and Jak2 tyrosine kinase within 1-3 min. IL-5 also stimulates GTP binding to p21ras. The signal is subsequently propagated through the activation of Raf-1, MEK, and MAP kinases as shown by their increased autophosphorylation in vitro and phosphorylation in situ. Jak2 kinase has been shown to phosphorylate STAT nuclear proteins. The activation of STAT nuclear factors was studied by electrophoretic mobility shift assay using a gamma activation site (GAS) probe. We found that IL-5 induces two GAS-binding proteins in eosinophils, one of which is STAT1. We conclude that IL-5 induced signals are propagated through two distinct pathways: (1) Lyn-->Ras-->Raf-1-->MEK-->MAP kinase and (2) Jak2-->STAT1.
 ...
PMID:The interleukin-5/receptor interaction activates Lyn and Jak2 tyrosine kinases and propagates signals via the Ras-Raf-1-MAP kinase and the Jak-STAT pathways in eosinophils. 761 38

Simultaneous inactivation of pyp1 and pyp2 PTPases in fission yeast leads to aberrant cell morphology and growth arrest. Spontaneous recessive mutations that bypass the requirement for pyp1 and pyp2 and reside in two complementation groups were isolated, sty1 and sty2. sty1- and sty2- mutant cells are substantially delayed in the timing of mitotic initiation. We have isolated the sty1 gene, which encodes a MAP kinase that is closely related to a subfamily of MAP kinases regulated by osmotic stress including Saccharomyces cervisiae HOG1 and human CSBP1. We find that sty2 is allelic to the wis1 MAP kinase kinase and that delta sty1 and delta wis1 cells are unable to grow in high osmolarity medium. Osmotic stress induces both tyrosine phosphorylation of Sty1 and a reduction in cell size at division. Pyp2 associates with and tyrosine dephosphorylates Sty1 in vitro. We find that wis1-dependent induction of pyp2 mRNA is responsible for tyrosine dephosphorylation of Sty1 in vivo on prolonged exposure to osmotic stress. We conclude that Pyp1 and Pyp2 are tyrosine-specific MAP kinase phosphatases that inactivate an osmoregulated MAP kinase, Sty1, which acts downstream of the Wis1 MAP kinase kinase to control cell size at division in fission yeast.
 ...
PMID:Pyp1 and Pyp2 PTPases dephosphorylate an osmosensing MAP kinase controlling cell size at division in fission yeast. 765 64

Yeast genes were isolated that are required for restoring the osmotic gradient across the cell membrane in response to increased external osmolarity. Two of these genes, HOG1 and PBS2, encode members of the mitogen-activated protein kinase (MAP kinase) and MAP kinase kinase gene families, respectively. MAP kinases are activated by extracellular ligands such as growth factors and function as intermediate kinases in protein phosphorylation cascades. A rapid, PBS2-dependent tyrosine phosphorylation of HOG1 protein occurred in response to increases in extracellular osmolarity. These data define a signal transduction pathway that is activated by changes in the osmolarity of the extracellular environment.
 ...
PMID:An osmosensing signal transduction pathway in yeast. 768 Dec 20

Phorbol ester tumor promoters (TPA) activate the endogenous erk/MAP kinases and Rsk S6 kinases but not the p70S6 kinase in COS cells. DNA sequences encoding the rat Rsk-1 S6 kinase (homologous to Xenopus rsk alpha), modified by insertion of a peptide epitope at the polypeptide aminoterminus, were expressed transiently in COS cells. TPA stimulates the 40S and peptide kinase activity of the recombinant epitope-tagged Rsk-1, as well as the extent of Rsk-1 autophosphorylation in vitro (32P-Ser >> 32P-Thr). Indications that the conformation of the recombinant Rsk-1 polypeptide is substantially changed after activation by TPA in situ include a retarded mobility of the Rsk-1 polypeptide on SDS-PAGE and the appearance of new 32P-peptides during autophosphorylation in vitro. All these features of the TPA-activated Rsk-1 S6 kinase are abolished by dephosphorylation of the kinase in vitro with Ser/Thr phosphatase-2A. TPA increases 32P incorporation into recombinant Rsk-1 by 2-3-fold (32P-Ser >> 32P-Thr). Peptide mapping exhibits a single major 32P-peptide in Rsk-1 isolated from unstimulated cells and 10-12 additional 32P peptides after TPA treatment in situ. Phosphorylation of basal or phosphatase-2A-treated recombinant Rsk-1 in vitro with erk2/MAP kinase increases Rsk-1 40S kinase, peptide kinase, and autophosphorylating activity, retards migration of Rsk-1 polypeptides on SDS-PAGE, and generates new sites of Rsk-1 autophosphorylation in vitro. By contrast, TPA-activated Rsk-1 is not altered in these properties by autophosphorylation in vitro. By contrast, TPA-activated Rsk-1 is not altered in these properties by phosphorylation in vitro with erk2/MAP kinase. Activation of Rsk-1 in situ with TPA diminishes by over 90% the extent of Rsk-1 phosphorylation achieved in vitro by erk2/MAP kinase, as compared to the parallel phosphorylation of a phosphatase-2A-treated Rsk-1; basal Rsk-1 is intermediate. Peptide maps of phosphatase-2A-treated Rsk-1 after phosphorylation in vitro with erk2/MAP kinase exhibit 32P-peptides that comigrate with nearly all of the 32P-peptides present in TPA-activated-32P Rsk-1 labeled in situ, plus several 32P-peptides characteristic of Rsk-1 autophosphorylation in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Regulation of an epitope-tagged recombinant Rsk-1 S6 kinase by phorbol ester and erk/MAP kinase. 768 67

We have successfully established normal neonatal and adult human melanocyte cultures in a growth medium containing the physiologic mitogens basic fibroblast growth factor (bFGF; 0.6 ng/ml), endothelin-1 (endo-1; 10 nM), and alpha-melanocyte stimulating hormone (alpha-MSH; 10 nM). The latter two factors replaced the commonly used mitogens 12-O-tetradecanoylphorbol 13-acetate (TPA) and bovine pituitary extract (BPE), respectively. Basic FGF alone maintained the viability but did not induce the proliferation of melanocytes. The addition of endo-1 to the bFGF-containing medium resulted in reduction of tyrosinase activity without enhancement of proliferation. However, the addition of alpha-MSH to the bFGF-containing medium potentiated melanocyte proliferation and tyrosinase activity. The concomitant addition of endo-1, alpha-MSH, and bFGF significantly increased the entry of melanocytes into S phase and potentiated their proliferation. Melanocytes maintained under these conditions had the same tyrosinase activity as those maintained in a medium containing alpha-MSH and bFGF. The signal transduction pathway induced by either endo-1 or bFGF, but not alpha-MSH, includes the activation of the mitogen-activated (MAP) kinase pathway. The addition of both endo-1 and bFGF had more than an additive effect on the MAP kinase extracellular signal-regulated kinase 2 (ERK2). This effect was further increased by the addition of alpha-MSH to these two growth factors. In summary, we have devised a growth medium for human melanocytes based on the use of physiologic mitogens that substituted for routinely used artificial and undefined growth factors. The resulting cultures should be desirable for clinical uses and permissive for the expression of in vivo relevant responses to regulatory factors.
 ...
PMID:Long-term proliferation of human melanocytes is supported by the physiologic mitogens alpha-melanotropin, endothelin-1, and basic fibroblast growth factor. 769 46

Stress and mitogens stimulate overlapping sets of MAP kinases in mammalian cells; MAP kinase pathways appear more distinct in yeast, but differences between the two systems may be less than is presently evident.
 ...
PMID:MAP kinase pathways. Straight and narrow or tortuous and intersecting? 770 76

The activation of MAPKAP kinase 2 was investigated under heat-shock conditions in mouse Ehrlich ascites tumor cells and after treatment of human MO7 cells with tumor necrosis factor-alpha (TNF-alpha). MAPKAP kinase 2 activity was determined using the small heat-shock proteins (sHsps) Hsp25 and Hsp27 as substrates. In both cell types, about a threefold increase in MAPKAP kinase 2 activity could be detected in a time interval of about 10-15 min after stimulation either by heat shock or TNF-alpha. Phosphorylation of MAPKAP kinase 2, but not the level of MAPKAP kinase 2 mRNA, was increased after heat shock in EAT cells. It is further shown that activation of MAPKAP kinase 2 in MO7 cells is accompanied by increased MAP kinase activity. These data strongly suggest that increased phosphorylation of the sHsps after heat shock or TNF-alpha treatment results from phosphorylation by MAPKAP kinase 2, which itself is activated by phosphorylation through MAP kinases. Hence, we demonstrate that MAPKAP kinase 2 is responsible not only for phosphorylation of sHsps in vitro but also in vivo. The findings link sHsp phosphorylation to the MAP kinase cascade, explaining the early phosphorylation of sHsp that is stimulated by a variety of inducers such as mitogens, phorbol esters, thrombin, calcium ionophores, and heat shock.
 ...
PMID:MAPKAP kinase 2 is activated by heat shock and TNF-alpha: in vivo phosphorylation of small heat shock protein results from stimulation of the MAP kinase cascade. 775 69

MAP kinase (mitogen activated protein kinase) represents a ubiquitously expressed family of kinases whose long term activation via phosphorylation is essential for the mitogenic response in fibroblasts. Two family members, p42 and p44 MAP kinase are cytosolic proteins in quiescent cells, but become nuclear following mitogenic stimulation. Inactivation of MAP kinases occurs via a specific phosphatase, MKP-1. Hence, we examined the localisation of this phosphatase, to determine the cellular site of MAP kinase inactivation. Transient transfection of CCL39 fibroblasts with epitope-tagged MKP-1 showed the protein to be entirely nuclear in both quiescent and mitogen stimulated cells, whereas a catalytically inactive mutant in which the essential cysteine was mutated to serine (MKP-1CS) was predominately cytoplasmic and again serum stimulation failed to alter the protein's localisation. Expression of either wild type or inactive MKP-1 did not alter the cytosolic localisation of p44 MAP kinase in quiescent cells nor the ability of MAP kinase to translocate to the nucleus following mitogen stimulation. Expression of wild type MKP-1 inhibited serum stimulated early (c-fos promoter) and late (dhfr promoter) transcriptional events as well as entry into S-phase. This inhibition was reversed by the co-expression of an active MAP kinase. We conclude that in the continual expression of MKP-1, the cellular localisation of MAP kinase is unaffected and that inactivation of MAP kinase by MKP-1 is a nuclear process leading to the inhibition of cell division.
 ...
PMID:Constitutive MAP kinase phosphatase (MKP-1) expression blocks G1 specific gene transcription and S-phase entry in fibroblasts. 776 Oct 91


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>