Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The beta-isoform of glycogen synthase kinase-3 (GSK3 beta) isolated from rabbit skeletal muscle was inactivated 90-95% following incubation with MgATP and either MAP kinase-activated protein kinase-1 (MAPKAP kinase-1, also termed RSK-2) or p70 S6 kinase (p70S6K), and re-activated with protein phosphatase 2A. MAPKAP kinase-1 and p70S6K phosphorylated the same tryptic peptide on GSK3 beta, and the site of phosphorylation was identified as the serine located nine residues from the N-terminus of the protein. The inhibitory effect of Ser-9 phosphorylation on GSK3 beta activity was observed with three substrates, (inhibitor-2, c-jun and a synthetic peptide), and also with glycogen synthase provided that 0.15 M KCl was added to the assays. The results suggest that Ser-9 phosphorylation underlies the reported inhibition of GSK3 beta by insulin and that GSK3 may represent a point of convergence of two major growth-factor-stimulated protein kinase cascades.
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PMID:Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. 825 Aug 35

The specificity determinants for insulin-stimulated protein kinase-I (ISPK-1) have been investigated with synthetic peptides based on naturally-occurring protein phosphoacceptor sequences. Peptides (Arg-Arg-Xaa-Ser-Xaa) that fulfill the consensus sequence for cyclic-AMP-dependent protein kinase (PK-A) are also phosphorylated readily by ISPK-1. The phosphorylation efficiency is improved by increasing the number of N-terminal arginine residues and by moving the arginyl cluster one residue further away from the serine, the nonapeptide (Arg)4-Ala-Ala-Ser-Val-Ala being the best substrate among all the short peptides tested (Km = 15 microM). Conversely, the substitution of either Thr for Ser or Lys for Arg is detrimental. Likewise, two flanking Pro residues and an Arg immediately N-terminal to the Ser act as negative specificity determinants. While the specificity of ISPK-1 shows several similarities to that of PK-A, including an absolute requirement for basic residues on the N-terminal side of the target Ser, it differs in several other respects including (1), the detrimental effect of a Lys for Arg substitution which is still compatible with some phosphorylation by ISPK-1, but not PK-A; (2), the presence of C-terminal acidic residues which are tolerated very well by ISPK-1, but are detrimental to PK-A; (3), the effect of substituting Phe for Val in the peptide Arg-Arg-Ala-Ser-Val-Ala, which improves the efficiency of phosphorylation by PK-A (lowering the Km 4-fold), but has no effect on phosphorylation by ISPK-1. These differences in peptide substrate specificity may account in part for the different rates of phosphorylation of physiological substrates for ISPK-1 and PK-A, such as the G subunit of protein phosphatase-1.
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PMID:An analysis of the substrate specificity of insulin-stimulated protein kinase-1, a mammalian homologue of S6 kinase-II. 834 77

The cAMP-responsive element-binding protein (CREB) transcription factor is required for normal T cell activation following stimulation through the T cell antigen receptor (TCR). CREB is present in resting T cells in an unphosphorylated and inactive state. TCR engagement results in the rapid phosphorylation of CREB on Ser133 and its concomitant activation. In the studies described in this report, we have investigated the signaling pathway(s) that are responsible for CREB activation in normal T cells. Using pharmacological agonists, we show that protein kinase C (PKC)-, calcium/calmodulin-, and protein kinase A-dependent pathways are each capable of independently eliciting CREB phosphorylation in T cells and thymocytes. Pharmacological inhibitor studies demonstrated that the PKC-mediated signaling pathway is required for TCR-mediated activation of CREB. In contrast, inhibitors of protein kinase A and calmodulin kinases had no effect on CREB phosphorylation following TCR cross-linking. T cells lacking the p56(lck) tyrosine kinase failed to phosphorylate CREB in response to TCR engagement. Overexpression of dominant-negative mutant Ras and Raf-1 proteins in Jurkat T cells abolished TCR-mediated CREB phosphorylation, whereas overexpression of the RSK2 serine/threonine kinase significantly potentiated TCR-mediated CREB phosphorylation. Taken together, these experiments are consistent with a model in which TCR engagement leads to the rapid phosphorylation and activation of CREB via a signaling pathway involving the activation of p56(lck), PKC, Ras, Raf-1, MEK, and RSK2. Given the importance of CREB phosphorylation in normal T cell activation, this pathway may be an attractive target for the development of novel immunosuppressive agents.
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PMID:A protein kinase C-, Ras-, and RSK2-dependent signal transduction pathway activates the cAMP-responsive element-binding protein transcription factor following T cell receptor engagement. 971 19

Coffin-Lowry syndrome (CLS) is a syndromal form of X linked mental retardation, in which some associated facial, hand, and skeletal abnormalities are diagnostic features. Accurate diagnosis, critical for genetic counselling, is often difficult, especially in early childhood. We have recently shown that Coffin-Lowry syndrome is caused by mutations in the gene encoding RSK2, a growth factor regulated protein kinase. RSK2 mutations are very heterogeneous and most of them lead to premature termination of translation or to loss of phosphotransferase activity or both. In the present study, we have evaluated immunoblot and RSK2 kinase assays as a rapid and simple diagnostic test for CLS, using cultured lymphoblastoid or fibroblast cell lines. Western blot analysis failed to detect RSK2 in six patients, suggesting the presence of truncated proteins in these patients. This conclusion was confirmed in four patients, in whom the causative mutations, all leading to premature termination of translation, were identified. Of four patients showing a normal amount of RSK2 protein on western blot and tested for RSK2 phosphotransferase activity, one had a dramatically impaired activity. Analysis of the RSK2 cDNA sequence in this patient showed a mutation of a putative phosphorylation site that would be critical for RSK2 activity. Preliminary results show that, at least, the western blot protocol can be successfully applied to lymphocyte protein extracts prepared directly from blood samples. These assays promise to become important diagnostic tools for CLS, particularly with regard to very young patients with no family history of the condition.
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PMID:Rapid immunoblot and kinase assay tests for a syndromal form of X linked mental retardation: Coffin-Lowry syndrome. 983 33

Arginine vasopressin (AVP) and lysophosphatidic acid (LPA) have been shown to stimulate protein kinase C (PKC) and mitogen-activated protein (MAP) kinases and the proliferation of vascular smooth muscle cells. However, the actions of these two agents in cardiomyocytes are less well understood. To investigate the signal transduction pathways of AVP and LPA, freshly isolated adult rat cardiomyocytes were examined. Both AVP and LPA induced concentration- and time-dependent stimulation of the phosphotransferase activities of p90 ribosomal S6 kinases (RSK) and their upstream activators, extracellularly regulated kinases (ERK) 1 and 2. The activation of ERK1 and ERK2 by LPA was PKC- and phosphatidylinositol 3-kinase (PI 3-kinase)-dependent. However, AVP-induced activation of RSK2, a downstream substrate of ERK1 and ERK2, was PKC-dependent and PI 3-kinase-independent. AVP and LPA were also observed to increase the phosphotransferase activity of p70 ribosomal protein S6 kinase (p70 S6K) in a time- and concentration-dependent manner. The activation of p70 S6K by LPA and AVP was PI 3-kinase-dependent. PKC was necessary in AVP- but not in LPA-induced activation of p70 S6K. Since RSK and p70 S6K have been implicated in the regulation of translational control of protein synthesis, we concluded that AVP and LPA may stimulate the growth of cardiomyocytes through these two protein kinase cascades.
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PMID:Stimulation of 90- and 70-kDa ribosomal protein S6 kinases by arginine vasopressin and lysophosphatidic acid in rat cardiomyocytes. 1070 47

Ribosomal S6 kinases (RSKs) are serine/threonine kinases activated by mitogenic signals through the Mitogen-Activated Protein Kinases/Extracellular Signal-Regulated Kinases (MAPK/ERK). RSKs contain two heterologous complete protein kinase domains. Phosphorylation by ERK of the C-terminal kinase domain allows activation of the N-terminal kinase domain, which mediates substrate phosphorylation. In human, there are three isoforms of RSK (RSK1, RSK2, RSK3), whose functional specificity remains undefined. Importantly, we have shown that mutations in the RSK2 gene lead to the Coffin-Lowry syndrome (CLS). In this study, we characterize two monoclonal antibodies raised against phosphorylated forms of the N- and C-terminal domain of RSK2 (P-S227 and P-T577, respectively). Using these two antibodies, we show that stress signals, such as UV light, induce phosphorylation and activation of the three RSKs to an extent which is comparable to Epidermal Growth Factor (EGF)-mediated activation. The use of specific kinase inhibitors indicates that UV-induced phosphorylation and activation of RSK2 is mediated by the MAPK/ERK pathway, but that the Stress-Activated Protein Kinase 2 (SAPK2)/p38 pathway is also involved. These results modify the view of RSKs as kinases restricted to the mitogenic response and reveal a previously unappreciated role of MAPKs in stress induced signaling. Oncogene (2000) 19, 4221 - 4229
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PMID:Activation of RSK by UV-light: phosphorylation dynamics and involvement of the MAPK pathway. 1098 May 95

Heat shock transcription factor 1(HSF1) activation is a multistep process. The conversion of a latent cytoplasmic form to a nuclear, DNA binding state appears to be activated by nonsteroidal anti-inflammatory drugs. In previous studies, we showed that HSF 1 is phosphorylated by the protein kinase RSK2 in vitro and that this effect is inhibited by nonsteroidal anti-inflammatory drugs at the concentration that leads to the activation of HSF1 in vivo (Stevenson et al 1999). In the present study, using cells from a patient with Coffin-Lowry syndrome (deficient in RSK2), we demonstrate that RSK2 slightly represses activation of HSF1 in vivo at 37 degrees C. In Coffin-Lowry syndrome cells, HSF1-HSE DNA binding activity after treatment with sodium salicylate was slightly higher than that in untreated cells, indicating that although RSK2 is involved in HSF1 regulation, it is not the unique protein kinase that suppresses HSF1-HSE binding activity at 37 degrees C. However, heat shock treatment resulted in significantly higher HSF1-HSE binding activity in Coffin-Lowry syndrome cells as compared with normal controls, suggesting that RSK2 represses HSF1-HSE binding activity during heat shock.
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PMID:RSK2 represses HSF1 activation during heat shock. 1118 48

N-terminal tail phosphorylation of histone H3 plays an important role in gene expression, chromatin remodeling, and chromosome condensation. Phosphorylation of histone H3 at serine 10 was shown to be mediated by RSK2, mitogen- and stress-activated protein kinase-1 (MSK1), and mitogen-activated protein kinases depending on the specific stimulation or stress. Our previous study showed that mitogen-activated protein kinases MAP kinases are involved in ultraviolet B-induced phosphorylation of histone H3 at serine 28 (Zhong, S., Zhong, Z., Jansen, J., Goto, H., Inagaki, M., and Dong, Z., J. Biol. Chem. 276, 12932-12937). However, downstream effectors of MAP kinases remain to be identified. Here, we report that H89, a selective inhibitor of the nucleosomal response, totally inhibits ultraviolet B-induced phosphorylation of histone H3 at serine 28. H89 blocks MSK1 activity but does not inhibit ultraviolet B-induced activation of MAP kinases p70/85(S6K), p90(RSK), Akt, and protein kinase A. Furthermore, MSK1 markedly phosphorylated serine 28 of histone H3 and chromatin in vitro. Transfection experiments showed that an N-terminal mutant MSK1 or a C-terminal mutant MSK1 markedly blocked MSK1 activity. Compared with wild-type MSK1, cells transfected with N-terminal or C-terminal mutant MSK1 strongly blocked ultraviolet B-induced phosphorylation of histone H3 at serine 28 in vivo. These data illustrate that MSK1 mediates ultraviolet B-induced phosphorylation of histone H3 at serine 28.
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PMID:Ultraviolet B-induced phosphorylation of histone H3 at serine 28 is mediated by MSK1. 1144 Oct 12

The mitogen-activated protein (MAP) kinase pathway has been implicated in cell cycle control for some time. Several reports have suggested a role for this pathway in growth factor stimulation of DNA synthesis, while other reports have proposed a role in the transition of cells through mitosis. Here, we have examined the potential involvement of the extracellular signal-related kinase (ERK)1/2 MAP kinases, their upstream regulators, and downstream effectors in the regulation of mitosis. Inhibition of MAP kinase/ERK kinase (MEK) activity reduced the serum-stimulated DNA synthesis and proliferation of Swiss 3T3 cells. To study the potential mechanisms of this effect, we examined the subcellular localization of members of the MAP kinase pathway including regulators (MEK1/2), substrates (90-kDa ribosomal S6 kinases (RSKs): RSK1, RSK2 and RSK3), and ERK itself. We show that there is enrichment of ERK, MEK, and the RSK enzymes on both the spindle and midbody tubulin of dividing cells. Inhibition of MEK1/2 activity in cells released from mitotic arrest results in an inability of cells to complete mitosis. This failure to exit mitosis correlated with altered cyclin-dependent kinase (cdk) activities. Thus, the MAP kinase pathway may act to coordinate passage through mitosis in Swiss 3T3 fibroblasts by regulation of cdk activity.
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PMID:MEK, ERK, and p90RSK are present on mitotic tubulin in Swiss 3T3 cells: a role for the MAP kinase pathway in regulating mitotic exit. 1149 23

The vasoconstrictor peptide endothelin (ET-1) exerts its physiological and pathological effects via activation of ET(A) and ET(B) receptor (ET-R) subtypes. In this study, we demonstrate that both ET-R subtypes are highly expressed in rat astrocytes in vivo, indicating that these cells are potential targets of the biological effects of ET-1 in the brain. In cultured cortical astrocytes, both ET-R subtypes are expressed, and selective stimulation of ET(B)-R with ET-1 induces phosphorylation of cAMP response element-binding protein (CREB). The signal transduction pathway activated by ET-1 includes the Rap1/B-Raf and the Ras/Raf-1 complexes, protein kinase C (PKC) together with extracellular signal-regulated kinases (ERK), and the ribosomal S6 kinase (RSK) isoforms RSK2 and RSK3, two kinases that lie immediately downstream of ERK and are able to phosphorylate CREB. Moreover, ET-1 activates the p38 mitogen-activated protein kinase (MAPK)-dependent, but not the c-jun N-terminal kinase (JNK)-dependent pathway. By using selective protein kinase inhibitors and expression of dominant-negative Rap1 protein, we also found that the Rap1/PKC/ERK-dependent pathway induces the phosphorylation of activating transcription factor-1, CREB, and Elk-1, whereas the p38MAPK-dependent pathway only causes CREB phosphorylation. ET-1-induced transcription of the immediate early gene c-fos requires the concomitant activation of both the PKC/ERK- and p38MAPK-dependent pathways, because inhibitors of either pathway block the ET-1-induced increase of c-fos mRNA. Our findings indicate that changes in the expression of cAMP response element-dependent immediate and delayed response genes could play a pivotal role in the physiological effects elicited by ET-1 in astrocytes.
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PMID:Stimulation of endothelin B receptors in astrocytes induces cAMP response element-binding protein phosphorylation and c-fos expression via multiple mitogen-activated protein kinase signaling pathways. 1169 96


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