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 90-kDa ribosomal S6 kinases, the p90 Rsks, are a family of intracellular serine/threonine protein kinases distinguished by two distinct kinase domains. Rsks are activated downstream of the ERK1 (p44) and ERK2 (p42) mitogen-activated protein (MAP) kinases in diverse biological contexts, including progression through meiotic and mitotic M phases in Xenopus oocytes and cycling Xenopus egg extracts, and are critical for the M phase functions of Xenopus p42 MAPK. Here we report the cloning and biochemical characterization of Xenopus Rsk2. Xenopus Rsk1 and Rsk2 are specifically recognized by commercially available RSK1 and RSK2 antisera on immunoblots, but both Rsk1 and Rsk2 are immunoprecipitated by RSK1, RSK2, and RSK3 sera. Rsk2 is about 20-fold more abundant than the previously described Xenopus Rsk1 protein; their concentrations are approximately 120 and 5 nm, respectively. Rsk2, like Rsk1, forms a heteromeric complex with p42 MAP kinase. This interaction depends on sequences at the extreme C terminus of Rsk2 and can be disrupted by a synthetic peptide derived from the C-terminal 20 amino acids of Rsk2. Finally, we demonstrate that p42 MAP kinase can activate recombinant Rsk2 in vitro to a specific activity comparable to that found in Rsk2 that has been activated maximally in vivo. These findings underscore the importance of the Rsk2 isozyme in the M phase functions of p42 MAP kinase and provide tools for further examining Rsk2 function.
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PMID:Cloning and characterization of Xenopus Rsk2, the predominant p90 Rsk isozyme in oocytes and eggs. 1093 12

Fibroblast growth factor-2 (FGF-2) interacts with a dual receptor system consisting of tyrosine kinase receptors and heparan sulfate proteoglycans (HSPGs). In rat mammary fibroblasts, FGF-2 stimulated DNA synthesis and induced a sustained phosphorylation of p42/44(MAPK) and of its downstream target, p90(RSK). Moreover, FGF-2 also stimulated the transient degradation of IkappaBalpha and IkappaBbeta. PD098059, a specific inhibitor of p42/44(MAPK) phosphorylation, inhibited FGF-2-stimulated DNA synthesis, phosphorylation of p42/44(MAPK) and p90(RSK), and degradation of IkappaBbeta. In contrast, in chlorate-treated and hence sulfated glycosaminoglycan-deficient cells, FGF-2 was unable to stimulate DNA synthesis. However, FGF-2 was able to trigger a transient phosphorylation of both p42/44(MAPK) and p90(RSK), which peaked at 15 min and returned to control levels at 30 min. In these sulfated glycosaminoglycan-deficient cells, no degradation of IkappaBalpha and IkappaBbeta was observed after FGF-2 addition. However, in chlorate-treated cells, the addition of heparin or purified HSPGs simultaneously with FGF-2 restored DNA synthesis, the sustained phosphorylation of p42/44(MAPK) and p90(RSK), and the degradation of IkappaBalpha and IkappaBbeta. These results suggest that the HSPG receptor for FGF-2 not only influences the outcome of FGF-2 signaling, e.g. cell proliferation, but importantly regulates the immediate-early signals generated by this growth factor.
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PMID:Fibroblast growth factor-2 stimulation of p42/44MAPK phosphorylation and IkappaB degradation is regulated by heparan sulfate/heparin in rat mammary fibroblasts. 1094 32

Regulatory light chain of myosin II (MRLC) was identified as a novel substrate of p90 ribosomal S6 kinase (RSK)-2, a Ser/Thr protein kinase which is phosphorylated and activated by mitogen-activated protein kinase (MAPK) in vitro and in vivo. Phosphopeptide map of MRLC phosphorylated by RSK-2 was identical to that by myosin light chain kinase (MLCK). Phosphoserine was recovered by the phosphoamino acid analysis of MRLC phosphorylated by RSK-2. Further, phosphorylation using recombinant glutathione S-transferase (GST) fusion proteins of HeLa MRLC2 revealed that RSK-2 phosphorylated wild-type MRLC2 (GST-wtMRLC2) but not its mutants GST-MRLC2(S19A) or GST-MRLC2(T18AS19A) (alanine substituted for Ser19 or both Ser19 and Thr18). These results revealed that RSK-2 phosphorylates MRLC at Ser19 as did MLCK. Phosphorylation of myosin II by RSK-2 resulted in activation of actin-activated MgATPase activity of myosin II. Interestingly, RSK-2 activity to phosphorylate MRLC was suppressed by phosphorylation with MAPK. RSK-2 might be a mediator that regulates myosin II activity through the MAPK cascade.
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PMID:Activation of actin-activated MgATPase activity of myosin II by phosphorylation with MAPK-activated protein kinase-1b (RSK-2). 1096 42

We compared the role of the Raf-1/mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MEK)/extracellular signal-regulated protein kinase (ERK)/p90(RSK) cascade in gp130-mediated cardiac hypertrophy with the contribution of the Janus kinase (JAK)/signal transduction and activation of transcription (STAT) and phosphatidylinositide 3-kinase (PI3-K) pathways. Primary cultured neonatal rat cardiomyocytes were stimulated with leukemia inhibitory factor (LIF). LIF sequentially activated Raf-1, MEK1/2, ERK1/2, and p90(RSK). We used PD-98059 (a specific MEK inhibitor), AG-490 (a JAK2 inhibitor), and wortmannin (a PI3-K inhibitor) to confirm that this cascade was independent of the JAK/STAT and PI3-K/p70 S6 kinase (S6K) pathways. PD-98059, AG-490, and wortmannin suppressed the LIF-induced increase in [(3)H]phenylalanine uptake by 54.7, 21.5, and 25.6%, respectively, and inhibited the increase in cell area by 61.2, 42.8, and 39.2%, respectively. Reorganization of myofilaments was predominantly suppressed by AG-490. LIF-induced expression of c-fos, brain natriuretic peptide, and skeletal alpha-actin mRNA was markedly suppressed by PD-98059 and moderately suppressed by wortmannin and AG-490. Atrial natriuretic peptide was significantly suppressed by AG-490. These findings indicate that this pathway is critically involved in protein synthesis, induction of c-fos, brain natriuretic peptide, and skeletal alpha-actin expression and is partially involved in myofilament reorganization and atrial natriuretic peptide induction in gp130-mediated cardiac hypertrophy.
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PMID:Significance of ERK cascade compared with JAK/STAT and PI3-K pathway in gp130-mediated cardiac hypertrophy. 1100 50

We have identified and characterized the human Mnk2 gene (HGMW-approved gene symbol MKNK2) through a yeast two-hybrid screen in which the Mnk2 protein interacted with the ligand-binding domain of estrogen receptor beta (ERbeta). Human Mnk2 is homologous to murine Mnk2 ( approximately 94% identical) and human Mnk1 (71% identical), both of which encode MAP kinase interacting kinases that are phosphorylated and activated by ERK1 and 2. This report presents a thorough genomic sequence analysis revealing that the human Mnk2 gene has two C-terminal splice variants, designated here as Mnk2a and Mnk2b. These two isoforms are identical over the first 385 amino acids of the coding sequence and differ only in the final exon which encodes an additional 80 residues for Mnk2a and 29 residues for Mnk2b. A more detailed biological analysis in yeast showed that the Mnk2 interaction was selective for ERbeta as opposed to ERalpha and that the interaction was specific to Mnk2b as opposed to Mnk2a or Mnk1. This pattern was reproduced in a mammalian two-hybrid system using a completely different set of fusion partners; and in both yeast and mammalian systems, the addition of estradiol decreased the interaction. While it remains unknown whether ERbeta is a substrate of Mnk2, the interaction of these two proteins is reminiscent of ERalpha and ribosomal S6 kinase (p90-RSK), another MAP kinase-regulated kinase homologous to Mnk2 that is known to phosphorylate ERalpha.
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PMID:Identification of the human Mnk2 gene (MKNK2) through protein interaction with estrogen receptor beta. 1101 76

Insulin and a number of metabolic factors stimulate glycogen synthesis and the enzyme glycogen synthase. Using human muscle cells we find that glycogen synthesis is stimulated by treatment of the cells with lithium ions, which inhibit glycogen synthase kinase 3. Insulin further stimulates glycogen synthesis in the presence of lithium ions, an effect abolished by wortmannin and rapamycin. We report also that amino acids stimulate glycogen synthesis and glycogen synthase, these effects also being blocked by rapamycin and wortmannin. Amino acids stimulate p70(s6k) and transiently inhibit glycogen synthase kinase 3 without effects on the activity of protein kinase B or the mitogen-activated protein kinase pathway. Thus, the work reported here demonstrates that amino acid availability can regulate glycogen synthesis. Furthermore, it demonstrates that glycogen synthase kinase 3 can be inactivated within cells independent of activation of protein kinase B and p90(rsk).
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PMID:Regulation of glycogen synthesis by amino acids in cultured human muscle cells. 1101 37

The Raf family of serine/threonine protein kinases is intimately involved in the transmission of cell regulatory signals controlling proliferation and differentiation. The best characterized Raf substrates are MEK1 and MEK2. The activation of MEK1/2 by Raf is required to mediate many of the cellular responses to Raf activation, suggesting that MEK1/2 are the dominant Raf effector proteins. However, accumulating evidence suggests that there are additional Raf substrates and that subsets of Raf-induced regulatory events are mediated independently of Raf activation of MEK1/2. To examine the possibility that there is bifurcation at the level of Raf in activation of MEK1/2-dependent and MEK1/2-independent cell regulatory events, we engineered a kinase-active Raf1 variant (RafBXB(T481A)) with an amino acid substitution that disrupts MEK1 binding. We find that disruption of MEK1/2 association uncouples Raf from activation of ERK1/2, induction of serum-response element-dependent gene expression, and induction of growth and morphological transformation. However, activation of NF-kappaB-dependent gene expression and induction of neurite differentiation were unimpaired. In addition, Raf-dependent activation of p90 ribosomal S6 kinase was only slightly impaired. These results support the hypothesis that Raf kinases utilize multiple downstream effectors to regulate distinct cellular activities.
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PMID:Uncoupling Raf1 from MEK1/2 impairs only a subset of cellular responses to Raf activation. 1101 21

RSKB, a p90 ribosomal S6 protein kinase with two catalytic domains, is activated by p38- and extracellular signal-regulated kinase mitogen-activated protein kinase pathways. The sequences between the two catalytic domains and of the C-terminal extension contain elements that control RSKB activity. The C-terminal extension of RSKB presents a putative bipartite (713)KRX(14)KRRKQKLRS(737) nuclear location signal. The distinct cytoplasmic and nuclear locations of various C-terminal truncation mutants supported the hypothesis that the nuclear location signal was essential to direct RSKB to the nuclear compartment. The (725)APLAKRRKQKLRS(737) sequence also was essential for the intermolecular association of RSKB with p38. The activation of RSKB through p38 could be dissociated from p38 docking, because RSKB truncated at Ser(681) strongly responded to p38 pathway activity. Interestingly, Delta(725-772)-RSKB was nearly nonresponsive to p38. Sequence alignment with the autoinhibitory C-terminal extension of Ca+2/calmodulin-dependent protein kinase I predicted a conserved regulatory (708)AFN(710) motif. Alanine mutation of the key Phe709 residue resulted in strongly elevated basal level RSKB activity. A regulatory role also was assigned to Thr687, which is located in a mitogen-activated protein kinase phosphorylation consensus site. These findings support that the RSKB C-terminal extension contains elements that control activation threshold, subcellular location, and p38 docking.
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PMID:C-terminal elements control location, activation threshold, and p38 docking of ribosomal S6 kinase B (RSKB). 1103 4

Exercise/contraction is a powerful stimulator of mitogen-activated protein (MAP) kinase cascades in skeletal muscle. Little is known regarding the physiological activation of enzymes downstream of MAP kinase. We investigated whether acute exercise results in activation of mitogen- and stress-activated kinases (MSK) 1 and 2, p90 ribosomal S6 kinase (p90rsk), and MAP kinase-activated protein kinase 2 (MAPKAPK2). Muscle biopsies were obtained from healthy volunteers before, during, and after 60 min one-leg cycle ergometry, from exercising and resting legs. MSK1 and MSK2 activities were increased 400-500% and 200-300%, respectively, in exercised muscle (P < 0.05 vs. rest). A dramatic increase in activity of p90rsk (MAPKAPK1) (>2,500%), and to a lesser extent MAPKAP2 (300%), was noted with exercise (P < 0.05 vs. rest). MSK1, MSK2, p90rsk, and MAPKAP2 activities were sustained throughout exercise. Exercise-induced activation of these enzymes was limited to working muscle, indicating that local rather than systemic factors activate these signaling cascades. Thus physical exercise leads to activation of multiple enzymes downstream of MAP kinase.
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PMID:Effects of exercise on mitogen- and stress-activated kinase signal transduction in human skeletal muscle. 1104 54

The p90 ribosomal S6 kinase (RSK), a cytosolic substrate for the extracellular signal-regulated kinase (ERK), is involved in transcriptional regulation, and one isoform (RSK2) has been implicated in the activation of glycogen synthase by insulin. To determine RSK2 function in vivo, mice lacking a functional rsk2 gene were generated and studied in response to insulin and exercise, two potent stimulators of the ERK cascade in skeletal muscle. RSK2 knockout (KO) mice weigh 10% less and are 14% shorter than wild-type (WT) mice. They also have impaired learning and coordination. Hindlimb skeletal muscles were obtained from mice 10, 15, or 30 min after insulin injection or immediately after strenuous treadmill exercise for 60 min. While insulin and exercise significantly increased ERK phosphorylation in skeletal muscle from both WT and KO mice, the increases were twofold greater in the KO animals. This occurred despite 27% lower ERK2 protein expression in skeletal muscle of KO mice. KO mice had 18% less muscle glycogen in the fasted basal state, and insulin increased glycogen synthase activity more in KO than WT mice. The enhanced insulin-stimulated increases in ERK and glycogen synthase activities in KO mice were not associated with higher insulin receptor or with IRS1 tyrosine phosphorylation or with IRS1 binding to phosphatidylinositol 3-kinase. However, insulin-stimulated serine phosphorylation of Akt was significantly higher in the KO animals. c-fos mRNA was increased similarly in muscle from WT and KO mice in response to insulin (2. 5-fold) and exercise (15-fold). In conclusion, RSK2 likely plays a major role in feedback inhibition of the ERK pathway in skeletal muscle. Furthermore, RSK2 is not required for activation of muscle glycogen synthase by insulin but may indirectly modulate muscle glycogen synthase activity and/or glycogen content by other mechanisms, possibly through regulation of Akt. RSK2 knockout mice may be a good animal model for the study of Coffin-Lowry syndrome.
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PMID:Altered extracellular signal-regulated kinase signaling and glycogen metabolism in skeletal muscle from p90 ribosomal S6 kinase 2 knockout mice. 1111 83


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