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)

Urea (200-400 milliosmolar) activates transcription, translation of, and trans-activation by the immediate-early gene transcription factor Egr-1 in a renal epithelial cell-specific fashion. The effect at the transcriptional level has been attributed to multiple serum response elements and their adjacent Ets motifs located within the Egr-1 promoter. Elk-1, a principal ternary complex factor and Ets domain-containing protein, is a substrate of the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases. In the renal medullary mIMCD3 cell line, urea (200-400 milliosmolar) activated both ERK1 and ERK2 as determined by in-gel kinase assay and immune-complex kinase assay of epitope-tagged] ERK1 and ERK2. Importantly, urea did not affect abundance of either ERK. Urea-inducible Egr-1 transcription was a consequence of ERK activation because the ERK-specific inhibitor, PD98059, abrogated transcription from the murine Egr-1 promoter in a luciferase reported gene assay. In addition, activators of protein kinase A, including forskolin and 8-Br-cAMP, which are known to inhibit ERK-mediated events, also inhibited urea-inducible Egr-1 transcription. Furthermore, urea-inducible activation of the physiological ERK substrate and transcription factor, Elk-1, was demonstrated through transient cotransfection of a chimeric Elk-1/GAL4 expression plasmid and a GAL4-driven luciferase reporter plasmid. Taken together, these data indicate that, in mIMCD3 cells, urea activates ERKs and the ERK substrate, Elk-1, and that ERK inhibition abrogates urea-inducible Egr-1 transcription. These data are consistent with a model of urea-inducible renal medullary gene expression wherein sequential activation of ERKs and Elk-1 results in increased transcription of Egr-1 through serum response element/Ets motifs.
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PMID:Urea-inducible Egr-1 transcription in renal inner medullary collecting duct (mIMCD3) cells is mediated by extracellular signal-regulated kinase activation. 885 40

Hydrolysis of phosphatidylcholine via receptor-mediated stimulation of phospholipase D produces phosphatidate that can be converted to lysophosphatidate and diacylglycerol. Diacylglycerol is an activator of protein kinase C, whereas phosphatidate and lysophosphatidate stimulate tyrosine kinases and activate the Ras-Raf-mitogen-activated protein kinase pathway. These three lipids can stimulate cell division. Conversely, activation of sphingomyelinase by agonists (e.g., tumor necrosis factor-alpha) causes ceramide production that inhibits cell division and produces apoptosis. If ceramides are metabolized to sphingosine and sphingosine 1-phosphate, then these lipids can stimulate phospholipase D and are also mitogenic. By contrast, ceramides inhibit the activation of phospholipase D by decreasing its interaction with the G-proteins, ARF and Rho, which are necessary for its activation. In whole cells, ceramides also stimulate the degradation of phosphatidate, lysophosphatidate, ceramide 1-phosphate, and sphingosine 1-phosphate through a multifunctional phosphohydrolase (the Mg(2+)-independent phosphatidate phosphohydrolase), whereas sphingosine inhibits phosphatidate phosphohydrolase. Tumor necrosis factor-alpha causes insulin resistance, which may be partly explained by ceramide production. Cell-permeable ceramides decrease insulin-stimulated glucose uptake in 3T3-L1 adipocytes after 2-24 h, whereas they stimulate basal glucose uptake. These effects do not depend on decreased tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 or the interaction of insulin receptor substrate-1 with phosphatidylinositol 3-kinase. They appear to rely on the differential effects of ceramides on the translocation of GLUT1-and GLUT4-containing vesicles. It is concluded that there is a significant interaction and "cross-talk" between the sphingolipid and glycerolipid pathways that modifies signal transduction to control vesicle movement, cell division, and cell death.
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PMID:"Cross talk" between the bioactive glycerolipids and sphingolipids in signal transduction. 896 Mar 53

Inner medullary collecting duct (IMCD) cells adapt to a hypertonic environment by synthesizing transporters that allow for accumulation of organic osmolytes. To examine for activation of additional mitogen-activated protein (MAP) kinases, extracts of IMCD-3 cells subjected to a hypertonic medium (600 mosmol/kgH2O) for 15 min were fractionated by Mono Q fast-performance liquid chromatography and assayed with the epidermal growth factor receptor [EGFR-(662-681)] peptide as substrate. Three peaks of activity were identified. Western blotting revealed that these peaks coincided with Jun NH2-terminal kinase (JNK), extracellular signal-regulated protein kinases, ERK1 and ERK2, and p38 MAP kinase. To assess the functional significance of ERK2 activation in IMCD-3 cells, the effect of PD-098059, an inhibitor of the upstream regulatory protein kinase MAP/ERK kinase (MEK) was assessed. PD-098059 inhibited ERK activation by hypertonicity. Yet, the stimulation of inositol uptake, a marker of adaptation, after 16 h was unaltered. Direct measurements of JNK activity [phosphorylation of GST-cJun-(1-79)] revealed a marked (20- to 40-fold) increase in activity as medium osmolality was increased from 300 to 900 mosmol/kgH2O with either NaCl or mannitol. Urea induced a more modest increase in activity. The response is prompt and detected as early as 2 min after exposure, reaching a maximum activation at 10-15 min. Downregulation of cellular protein kinase C (PKC) by chronic exposure to phorbol esters only minimally attenuated the JNK response to hyperosmolality, indicating a lack of involvement of PKC. We conclude that, in IMCD-3 cells, inhibition of ERK activation by hyperosmolality does not prevent osmoregulatory increase in inositol transport. This is not consistent with a role for ERKs in the response. The roles for JNK and p38 have not been ruled out, and these pathways may represent the initiating event in the subsequent transcription of organic osmolyte transporter genes and adaptation to extracellular hypertonicity.
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PMID:Multiple mitogen-activated protein kinases are regulated by hyperosmolality in mouse IMCD cells. 908 72

Urea activates a characteristic subset of signaling pathways in a tissue-specific fashion, including transcription of immediate early genes through activation of the mitogen-activated protein kinase (MAPK), ERK (extracellular signal-regulated kinase), and activation of its transcription factor substrate, Elk-1. The ability of urea to activate the ERK effector and pivotal regulatory kinase, ribosomal S6 kinase (RSK), was investigated in mIMCD3 renal inner medullary collecting duct cells. Urea upregulated RSK activity in a time-dependent fashion in serum-deprived mIMCD3 cells; the effect was maximal at 5 min. Activation by hypertonic NaCl, in contrast, was negligible at 5 min and peaked at 15 min. Both stimuli induced the nuclear translocation of cytosolic RSK, as determined via immunofluorescence. Importantly, activation of RSK by both solutes was MAPK/ERK kinase (MEK) dependent, as determined by the ability of the specific MEK inhibitor, PD-98059, to abrogate the response. Taken together, these data indicate that urea activates the ERK effector, RSK, in cells of the renal medulla in an ERK-dependent fashion, further emphasizing the functional significance of urea signaling through ERK activation in renal medullary cells.
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PMID:Urea activates ribosomal S6 kinase (RSK) in a MEK-dependent fashion in renal mIMCD3 cells. 945 25

Two cytosolic tyrosine kinases, focal adhesion kinase (FAK) and the newly described FAK homolog, related adhesion focal tyrosine kinase (RAFTK, also called PYK2 and CAKbeta), have been implicated in signaling to multiple mitogen-activated protein kinase (MAPK) pathways. Therefore, the ability of NaCl and urea to activate these kinases was investigated by in vitro kinase assay and anti-phosphotyrosine immunoblotting. RAFTK was promptly but only transiently activated by urea (within 1 min; 45%), whereas NaCl activated this kinase at 1, 5, 15, and 30 min of treatment (35-60%). In contrast, FAK exhibited only subtle regulation by the two solutes; however, the time course of induction was distinct for each solute. NaCl activated FAK at 1, 5, and 15 min (25-40%), whereas urea-inducible FAK activation (30%) was not evident until fully 15 min of treatment. At 5 min of treatment with increasing concentrations of solute, both urea and NaCl activated RAFTK in a dose-dependent and comparable fashion, culminating in an approximately twofold activation at 800 mosmol/kgH2O solute. Consistent with these data, solute treatment also enhanced tyrosine phosphorylation of RAFTK.
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PMID:Urea and NaCl differentially regulate FAK and RAFTK/PYK2 in mIMCD3 renal medullary cells. 972 19

1. Cells of the mammalian renal medulla are routinely subjected to an enormously elevated and labile ambient osmolality as a consequence of the renal concentrating mechanism. The present review focuses on the most recent advances in hyperosmotic solute-mediated signal transduction and regulation of gene transcription in cells of the kidney medulla. 2. On the basis of osmolality alone, NaCl and urea are the principal renal medullary solutes. 3. Urea, which is membrane permeant, activates transcription of immediate-early genes via an extracellular signal-regulated kinase (ERK)/Elk-1-dependent pathway. Urea also activates multiple effectors characteristic of a receptor tyrosine kinase-like signalling cascade. 4. In contrast, the functionally impermeant solute NaCl activates transcription of tonicity responsive genes (principally genes encoding proteins essential for osmolyte uptake or synthesis) via a unique consensus element contained within their 5' flanking sequences. 5. An activity exhibiting tonicity inducible sequence-specific interaction with this DNA element has been identified. 6. Hypertonicity, like thermal stress, activates transcription of genes encoding heat shock proteins. The relationship between signalling events leading to tonicity mediated and heat shock-mediated gene transcription remains to be established.
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PMID:Signalling and gene regulation by urea and NaCl in the renal medulla. 1002 73

Urea- and NaCl-inducible extracellular signal-regulated kinase (ERK) phosphorylation exhibited dissimilar kinetics. Among cell lines examined, the effect of urea was unique to mIMCD3 inner medullary collecting duct cells and MDCK cells. Urea-inducible ERK activation was approximately 10-fold less sensitive to the MEK inhibitor, PD-98059, than was that of NaCl. This difference did not appear to be accounted for by differential activation of MEK isoforms. Interestingly, the inhibitor of p38 activation, SB-203580, abrogated the effect of both urea and NaCl upon both ERK and MEK activation; however, the former was much less sensitive to the inhibitor. Consistent with this observation, NaCl was much more effective than urea at inducing p38 phosphorylation. The effect of hypertonic stress (e.g., sorbitol 100 mM) could be blocked by appropriate medium dilution such that isotonicity was maintained. In marked contrast, the effect of hyperosmotic urea could not be blocked in this fashion, implying the absence of dependence upon cell volume. Together, these data suggest that cells of the renal inner medulla are potentially uniquely responsive to urea and that urea and hypertonic stressors induce ERK activation through distinct mechanisms.
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PMID:ERK activation by urea in the renal inner medullary mIMCD3 cell line. 1044 71

The kidney medulla is exposed to very high interstitial osmolarity leading to the activation of mitogen-activated protein kinases (MAPK). However, the respective roles of increased intracellular osmolality and of cell shrinkage in MAPK activation are not known. Similarly, the participation of MAPK in the regulatory volume increase (RVI) following cell shrinkage remains to be investigated. In the rat medullary thick ascending limb of Henle (MTAL), extracellular hypertonicity produced by addition of NaCl or sucrose increased the phosphorylation level of extracellular signal-regulated kinase (ERK) and p38 kinase and to a lesser extent c-Jun NH(2)-terminal kinase with sucrose only. Both hypertonic solutions decreased the MTAL cellular volume in a dose- and time-dependent manner. In contrast, hypertonic urea had no effect. The extent of MAPK activation was correlated with the extent of MTAL cellular volume decrease. Increasing intracellular osmolality without modifying cellular volume did not activate MAPK, whereas cell shrinkage without variation in osmolality activated both ERK and p38. In the presence of 600 mosmol/liter NaCl, the maximal cell shrinkage was observed after 10 min at 37 degrees C and the MTAL cellular volume was reduced to 70% of its initial value. Then, RVI occurred and the cellular volume progressively recovered to reach about 90% of its initial value after 30 min. SB203580, a specific inhibitor of p38, almost completely inhibited the cellular volume recovery, whereas inhibition of ERK did not alter RVI. In conclusion, in rat MTAL: 1) cell shrinkage, but not intracellular hyperosmolality, triggers the activation of both ERK and p38 kinase in response to extracellular hypertonicity; and 2) RVI is dependent on p38 kinase activation.
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PMID:Cell shrinkage triggers the activation of mitogen-activated protein kinases by hypertonicity in the rat kidney medullary thick ascending limb of the Henle's loop. Requirement of p38 kinase for the regulatory volume increase response. 1056 79

Hypertonicity has pleiotropic effects on cell function, including activation of transporters and regulation of gene expression. It is important to investigate the action of hypertonicity on cystic fibrosis gene expression because cystic fibrosis transmembrane conductance regulator (CFTR), the cAMP-regulated Cl(-) channel, regulates ion transport across the secretory epithelia, which are often in a hypertonic environment. We found that adding >150 mosmol/l NaCl, urea, or mannitol to the culture medium reduced the amount of CFTR mRNA in colon-derived HT-29 cells in a time-dependent manner. Studies with inhibitors of various kinases [H-89 (protein kinase A inhibitor), bisindolylmaleimide (protein kinase C inhibitor), staurosporine (serine/threonine kinase inhibitor) and herbimycin A (tyrosine kinase inhibitor), SB-203580 and PD-098059 (mitogen-activated protein kinase inhibitors)] showed that CFTR gene expression and its decrease by added NaCl required p38 kinase cascade activity. The CFTR gene activity is regulated at the transcriptional level, since adding NaCl diminished the luciferase activity of HeLa cells transiently transfected with the CFTR promoter. This regulation requires protein synthesis. The complexity of the reactions involved in blocking CFTR gene transcription by NaCl strongly suggests that the decrease in CFTR mRNA is part of a general cell response to hyperosmolar stress.
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PMID:Modulation of CFTR gene expression in HT-29 cells by extracellular hyperosmolarity. 1064 11

The effect of hyperosmolarity on the induction of the mitogen-activated protein kinases (MAPK) was studied in bovine aortic endothelial cell (EC). Different types of agents were used to differentiate the effects of osmolarity from other variables. Hypertonic treatment with physiologically relevant levels of NaCl (350 mOsm/kg H(2)O) significantly increased the level of expression of p38 within 2 min, and ERK-1/2 and JNK after 10 min. The inductions peaked between 30 and 60 min and returned to baseline levels within 2 h. A similar pattern of induction occurred with ionic contrast agent. p38 induction by glucose and mannitol showed a similar pattern, although the level of ERK-1/2 phosphorylation was not as robust, and JNK was not induced by glucose. Urea did not affect the level of induction of the MAPK isoforms. It is concluded that MAPK plays an important role in hyperosmolality-induced signal transduction. Different osmotic agents induce MAPK expression differently. No MAPK induction with urea implies that cell shrinkage may be an important component of hyperosmolality-induced MAPK phosphorylation.
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PMID:Mitogen-activated protein phosphorylation in endothelial cells exposed to hyperosmolar conditions. 1065 76


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