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)

Irradiation of mammalian cells with short wavelength ultraviolet light (UVC) evokes a cascade of phosphorylation events leading to altered gene expression. Both the classic mitogen-activated protein (MAP) kinases and the distantly related c-Jun N-terminal kinases (JNK) contribute to the response via phosphorylation of transcription factors including AP-1. These kinases are themselves regulated via reversible phosphorylation, and several recently identified specific MAP kinase phosphatases (MKP) have been implicated in down-regulating MAP kinase-dependent gene expression in response to mitogens. Here, we provide evidence that MKP-1 plays a role in regulating transcriptional activation in response to UVC as well as another genotoxic agent, methyl methanesulfonate (MMS). We further demonstrate that JNK is a likely target for MKP-1. JNK is shown to be activated by UVC and MMS treatment, while MAP kinase activation occurs only with UVC. Like JNK activation, MKP-1 mRNA is induced by both treatments, and elevated MKP-1 expression coincides with a decline in JNK activity. Constitutive expression of MKP-1 in vivo inhibits JNK activity and reduces UVC- and MMS-induced activation of AP-1-dependent reporter genes.
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PMID:Role of mitogen-activated protein kinase phosphatase during the cellular response to genotoxic stress. Inhibition of c-Jun N-terminal kinase activity and AP-1-dependent gene activation. 772 28

Stress-activated protein kinases (SAPKs) or c-Jun amino-terminal kinases (JNKs), which belong to a subgroup of the mitogen-activated protein kinase (MAPK) superfamily, are activated in response to a variety of stresses in mammalian cells. An activity to activate a recombinant rat SAPK alpha was detected in extracts obtained from rat fibroblastic 3Y1 cells exposed to hyperosmolar media and was resolved into unadsorbed and adsorbed fractions on Q-Sepharose chromatography. The adsorbed activity was identified as XMEK2/SEK1/MKK4 by using several anti-XMEK2 antibodies. Thus, a 45-kDa protein that was recognized specifically by these anti-XMEK2 antibodies co-eluted with the SAPK alpha activating activity during chromatography on Q-Sepharose and Superose 6, and the activity could be immunoprecipitated by the antibodies from these fractions. The unadsorbed activity, whose level was much greater than that of the adsorbed activity, did not contain XMEK2/SEK1/MKK4 and was also activated in a time-dependent manner by osmotic shock. This activity was further resolved into several peaks during chromatography on heparin-Sepharose and hydroxylapatite. Most of these peaks eluted separately from major peaks of a kinase activity toward p38/MPK2, another subgroup of the MAPK superfamily, whereas the activated XMEK2/SEK1/MKK4 could phosphorylate p38/MPK2 efficiently. These results indicate the existence of multiple activators for SAPK/JNK; one is XMEK2/SEK1/MKK4, and the others are previously undescribed factors.
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PMID:Evidence for multiple activators for stress-activated protein kinase/c-Jun amino-terminal kinases. Existence of novel activators. 776 85

Protein phosphorylation is commonly used to modulate transcription factor activity. However, all existing genetic evidence for stimulation of transcription factor activity by phosphorylation rests on loss-of-function mutations. To demonstrate conclusively that phosphorylation of a transcription factor potentiates its transactivation potential in vivo, we constructed a c-Jun mutant that is phosphorylated by the cAMP-sensitive protein kinase A (PKA) instead of the UV- and Ras-responsive protein kinase JNK. The transcriptional activity of this mutant is enhanced by PKA, but not by JNK activation. These results provide a positive and conclusive proof that phosphorylation of c-Jun on a critical site (Ser73) located in its activation domain is directly responsible for enhancing its transactivation function.
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PMID:Altering the specificity of signal transduction cascades: positive regulation of c-Jun transcriptional activity by protein kinase A. 781 38

The c-Fos and c-Jun proteins bind an AP1 site and activate transcription synergistically. These two proteins have a common activation domain which has two co-operating motifs, HOB1 and HOB2. The HOB1 motif of c-Jun includes S73 which is required for Ha-Ras-induced super-activation and phosphorylation by MAP kinase-like enzymes. Since c-Fos HOB1 has a conserved Thr residue (T232) analogous to c-Jun S73 we have proposed that c-Fos HOB1 will be regulated in the same way as c-Jun HOB1. Here we show that the HOB1-containing activation domain of c-Fos is stimulated by Ha-Ras in vivo and phosphorylated by a MAP kinase family member in vitro and that mutating T232 to Ala abolishes both functions. Collectively these results suggest that phosphorylation of the HOB1 motif increases its activation capacity. To provide direct evidence for this we change the context of c-Fos T232 to a PKA recognition site, and show that HOB1 activity is now stimulated by the catalytic subunit of PKA. This 'PKA specificity' experiment represents a novel and powerful way to analyse phosphorylation events involved in a variety of biological functions.
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PMID:Phosphorylation of the c-Fos and c-Jun HOB1 motif stimulates its activation capacity. 781 2

Mammalian mitogen-activated protein (MAP) kinases include extracellular signal-regulated protein kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38 subgroups. These MAP kinase isoforms are activated by dual phosphorylation on threonine and tyrosine. Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. These MKK isoforms did not activate the ERK subgroup of MAP kinases, but MKK4 did activate JNK. These data demonstrate that the activators of p38 (MKK3 and MKK4), JNK (MKK4), and ERK (MEK1 and MEK2) define independent MAP kinase signal transduction pathways.
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PMID:Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. 783 44

c-Mil is the avian homologue of the mammalian serine/threonine kinase c-Raf-1. c-Mil/Raf is a mediator of signal transduction leading to gene expression via the c-Jun DNA-binding site, AP-1. Here we show that c-Mil immunopurified from MC29-virus-transformed quail fibroblasts phosphorylates c-Jun in vitro near its N terminus (Ser-63 and -73). Furthermore, the viral oncogene product Gag-Mil of the avian wild-type retrovirus MH2 phosphorylates c-Jun in vitro. A contribution by other known kinases phosphorylating c-Jun, such as the mitogen-activated protein kinases (MAPKs) and the c-Jun N-terminal kinases, was excluded by control reactions. c-Raf-1 and c-Jun directly interact in vitro as shown by various immobilized glutathione S-transferase-Raf fusion proteins which specify the cysteine-rich region of c-Mil/Raf as the major N-terminal binding site. An additional minor binding site is located in the C-terminal region. The biological relevance of these results is demonstrated by coimmunoprecipitation of c-Jun and c-Mil from 32P-labeled MC29- and MH2-transformed fibroblasts as well as normal quail embryo fibroblasts, whereby c-Jun was identified by tryptic phosphopeptide analysis. The complexed c-Jun exhibits a decreased electrophoretic mobility corresponding to a more highly phosphorylated state. Cell fractionation analyses indicate that the c-Mil/c-Jun complex is located in the cytoplasm. The data demonstrate that c-Jun can be a direct target of the protein kinase c-Mil/Raf, suggesting an alternative pathway, which leads to c-Jun phosphorylation independent of the MAPKs and MAPK-related proteins.
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PMID:Direct interaction and N-terminal phosphorylation of c-Jun by c-Mil/Raf. 787 94

The p53 tumor suppressor protein is thought to play a major role in the defense of the cell against agents that damage DNA. In this report, we describe the identification and characterization of a protein kinase that phosphorylates mouse p53 at a single site, serine 34, a major site of phosphorylation in the cell. The protein kinase is activated strikingly following treatment of cells with ultraviolet radiation, has a native molecular weight of approximately 45,000, and can be resolved from mitogen-activated protein (MAP) kinase by chromatography on Superose 6 and DEAE-cellulose. The p53 kinase activity co-purifies with UV-activated c-Jun kinase activity on heparin-Sepharose and on a c-Jun (but not a v-Jun-) affinity column. Treatment of the partially purified kinase with CL100, a protein phosphatase that specifically dephosphorylates MAP kinase homologues, inhibits its activity. Taken together, the data suggest that this p53 kinase is likely to be activated by phosphorylation and may be a member of the stress-activated protein kinase subfamily of MAP kinases. UV irradiation of SV3T3 cells leads to increased phosphorylation of p53 at serine 34, indicating that phosphorylation of p53 by this kinase is likely to be physiological. Phosphorylation of p53 by this protein kinase may be a key event in a signal transduction mechanism that coordinately controls key nuclear proteins in response to oxidative stress or DNA damaging agents.
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PMID:p53 is phosphorylated in vitro and in vivo by an ultraviolet radiation-induced protein kinase characteristic of the c-Jun kinase, JNK1. 789 Jun 69

The expression of human muscarinic acetylcholine receptors (mAChRs) in NIH 3T3 cells has been used as a model for studying proliferative signaling through G protein-coupled receptors. In this biological system, the m1 class of mAChRs can effectively transduce mitogenic signals (Stephens, E.V., Kalinec, G., Brann, M.R., and Gutkind, J.S. (1993) Oncogene 8, 19-26) and induce malignant transformation if persistently activated (Gutkind, J.S., Novotny, E.A., Brann, M.R., and Robbins, K.C. (1991) Proc. Natl. Acad. Sci. U.S.A. 88, 4703-4708). Moreover, available evidence suggests that the m1-signaling pathway converges at the level of p21ras with that emerging from tyrosine kinase receptors (Crespo, P., Xu, N., Simonds, W.F., and Gutkind, J.S. (1994) Nature 369, 418-420). To explore nuclear events involved in growth regulation by G protein-coupled receptors in this setting, we compared the effect of platelet-derived growth factor (PDGF) and the cholinergic agonist, carbachol, on the expression of mRNA for members of the jun and fos family of nuclear proto-oncogenes. We found that activation of m1 receptors by carbachol induces the expression of a distinct set of nuclear transcription factors. In particular, carbachol caused a much greater induction of c-jun mRNA and AP-1 activity. These responses did not correlate with protein kinase C stimulation nor with the activation of mitogen-activated protein (MAP) kinases. Recently, it has been shown that a novel family of kinases structurally related to MAP kinases, stress-activated protein kinases, or Jun kinases (JNKs), phosphorylate in vivo the amino-terminal transactivating domain of the c-Jun protein, thereby increasing its transcriptional activity. In view of our results, this observation prompted us to ask whether m1 and PDGF can differentially activate JNKs. Here, we show that m1 mAChRs can induce a remarkable increase in JNK activity, which was temporally distinct from that of MAP kinase and was entirely protein kinase C independent. In contrast, PDGF failed to activate JNK in these cells, although it stimulated MAP kinase to an extent even greater than that for carbachol. These findings demonstrate that G protein-coupled receptors can signal through pathways leading to the activation of JNK, thus diverging at this level with those signaling routes utilized by tyrosine kinase receptors.
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PMID:Transforming G protein-coupled receptors potently activate JNK (SAPK). Evidence for a divergence from the tyrosine kinase signaling pathway. 789 Jun 82

The present studies have characterized the regulation of interleukin-6 (IL-6) gene expression during pokeweed mitogen (PWM)-driven human B-cell differentiation. PWM induced an early and transient increase in the expression of immediate-early response genes of the jun/fos leucine zipper family (c-jun, jun B, c-fos, and fos-B). The induction of c-jun mRNA by PWM was concentration dependent. Nuclear run-on assays showed that PWM treatment is associated with an increased rate of c-jun gene transcription. The induction of c-jun mRNA precedes the induction of IL-6 gene expression and IL-6 secretion by the B cells. c-Jun antisense, but not sense, oligodeoxynucleotide (ODN) significantly decreases PWM-related B-cell (1) proliferation; (2) IL-6 mRNA induction; (3) IL-6 secretion; and (4) nuclear extract binding to AP-1 in electrophoretic mobility shift assay. In contrast, c-Fos anti-sense ODN did not effect either IL-6 mRNA induction or IL-6 secretion triggered in B cells by PWM. The results further show activation of c-Raf-1 kinase in PWM-treated B cells. Raf-1 acts upstream to mitogen-activated protein (MAP) kinase; therefore, studies were performed to assay for MAP kinase activation in these cells. The results show an increase in phosphorylation of myelin basic protein (MBP) and c-Jun "Y" peptide in PWM-treated B cells. Taken together, these findings suggest that PWM is able to initiate an intracytoplasmic signaling cascade in normal human splenic B cells, which, at least in part, involves serine/threonine protein kinases. These results show transient induction of immediate-early response genes in B cells and support a potential role for the c-jun gene product in regulation of IL-6 transcription and secretion.
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PMID:Identification of upstream signals regulating interleukin-6 gene expression during in vitro treatment of human B cells with pokeweed mitogen. 791 42

Tumor necrosis factor alpha (TNF alpha) has multiple biological functions including the prolonged activation of the collagenase and c-jun genes, which are regulated via their AP-1 binding sites. We show that incubating human fibroblasts with TNF alpha induces prolonged activation of JNK, the c-Jun kinase, which phosphorylates the transactivation domain of c-Jun. Furthermore, an immune complex kinase assay specifically demonstrates that TNF alpha stimulates the activity of JNK1, the recently described predominant form of JNK. TNF alpha also produces a small and transient increase in extracellular signal-regulated kinase (ERK) activity and no measured increase in Raf-1 kinase activity. On the other hand, epidermal growth factor causes a prolonged activation of Raf-1 kinase and ERK activity and a smaller, more transient activation of JNK, whereas the phorbol ester phorbol 12-myristate 13-acetate causes a small stimulation of Raf-1 kinase and a pronounced stimulation of ERK activity. The activation of JNK by TNF alpha does not correlate with Raf-1 or ERK activity. The kinetics of Raf-1, ERK, and JNK induction by epidermal growth factor, phorbol 12-myristate 13-acetate, or TNF alpha indicate distinct mechanisms of activation in human fibroblasts.
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PMID:Tumor necrosis factor alpha stimulates AP-1 activity through prolonged activation of the c-Jun kinase. 792 60


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