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:2.7.11.2 (PDK1)
2,238 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

G protein-coupled receptor (GPCR) kinase 2 (GRK2) regulates G protein-coupled receptor signaling via agonist-induced receptor phosphorylation and desensitization. GRK2 can also modulate cellular activation by interacting with downstream signaling molecules. The intracellular GRK2 level changes during inflammatory conditions. We investigated how IL-1beta-induced changes in endogenous GRK2 expression influence chemokine receptor signaling in primary astrocytes. Culturing astrocytes with IL-1beta for 24 h induced a 2-3-fold increase in GRK2 and decreased C-C chemokine ligand 2 (CCL2)-induced ERK1/2 activation. Conversely, the 45% decrease in GRK2 expression in astrocytes from GRK2+/- animals resulted in a more pronounced CCL2-induced ERK1/2 phosphorylation. Increased GRK2 inhibited CCL2-induced Akt phosphorylation at Thr308 and Ser473 as well as pPDK-1 translocation. In contrast, altered GRK2 levels did not change the CCL2-induced increase in intracellular calcium or MEK1/2 phosphorylation. These data suggest that altered GRK2 expression modulates chemokine signaling downstream of the receptor. We found that GRK2 kinase activity was not required to decrease chemokine-induced ERK1/2 phosphorylation, whereas regulation of CCL2-induced Akt phosphorylation did require an active GRK2 kinase domain. Collectively, these data suggest that changes in endogenous GRK2 expression in primary astrocytes regulate chemokine receptor signaling to ERK1/2 and to PDK-1-Akt downstream of receptor coupling via kinase-dependent and kinase-independent mechanisms, respectively.
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PMID:Physiological changes in GRK2 regulate CCL2-induced signaling to ERK1/2 and Akt but not to MEK1/2 and calcium. 1797 Nov 24

beta 1-3-Adrenoreceptor (AR)-deficient mice are unable to regulate energy expenditure and develop diet-induced obesity on a high-fat diet. We determined previously that beta2-AR agonist treatment activated expression of the mRNA encoding the orphan nuclear receptor, NOR-1, in muscle cells and plantaris muscle. Here we show that beta2-AR agonist treatment significantly and transiently activated the expression of NOR-1 (and the other members of the NR4A subgroup) in slow-twitch oxidative soleus muscle and fast-twitch glycolytic tibialis anterior muscle. The activation induced by beta-adrenergic signaling is consistent with the involvement of protein kinase A, MAPK, and phosphorylation of cAMP response element-binding protein. Stable cell lines transfected with a silent interfering RNA targeting NOR-1 displayed decreased palmitate oxidation and lactate accumulation. In concordance with these observations, ATP production in the NOR-1 silent interfering RNA (but not control)-transfected cells was resistant to (azide-mediated) inhibition of oxidative metabolism and expressed significantly higher levels of hypoxia inducible factor-1alpha. In addition, we observed the repression of genes that promote fatty acid oxidation (peroxisomal proliferator-activated receptor-gamma coactivator-1alpha/beta and lipin-1alpha) and trichloroacetic acid cycle-mediated carbohydrate (pyruvate) oxidation [pyruvate dehydrogenase phosphatase 1 regulatory and catalytic subunits (pyruvate dehydrogenase phosphatases-1r and -c)]. Furthermore, we observed that beta2-AR agonist administration in mouse skeletal muscle induced the expression of genes that activate fatty acid oxidation and modulate pyruvate use, including PGC-1alpha, lipin-1alpha, FOXO1, and PDK4. Finally, we demonstrate that NOR-1 is recruited to the lipin-1alpha and PDK-4 promoters, and this is consistent with NOR-1-mediated regulation of these genes. In conclusion, NOR-1 is necessary for oxidative metabolism in skeletal muscle.
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PMID:The orphan nuclear receptor, NOR-1, a target of beta-adrenergic signaling, regulates gene expression that controls oxidative metabolism in skeletal muscle. 1832 99

IGF-II, a potent stimulator of cellular proliferation, differentiation, and development, regulates uterine function and conceptus growth in several species. In situ hybridization analyses found that IGF-II mRNA was most abundant in the caruncular endometrial stroma of both cyclical and pregnant ewes. In the intercaruncular endometrium, IGF-II mRNA transitioned from stroma to luminal epithelium between d 14 and 20 of pregnancy. IGF-II mRNA was present in all cells of the conceptus but was particularly abundant in the yolk sac. Immunohistochemical analyses revealed that phosphorylated (p)-protooncogenic protein kinase 1, p-ribosomal protein S6 kinase, p-ERK1/2, and p-P38 MAPK proteins were present at low levels in a majority of endometrial cells but were most abundant in the nuclei of endometrial luminal epithelium and conceptus trophectoderm of pregnant ewes. In mononuclear trophectoderm cells isolated from d-15 conceptuses, IGF-II increased the abundance of p-pyruvate dehydrogenase kinase 1, p-protooncogenic protein kinase 1, p-glycogen synthase kinase 3B, p-FK506 binding protein 12-rapamycin associated protein 1, and p-ribosomal protein S6 kinase protein within 15 min, and the increase was maintained for 90 min. IGF-II also elicited a rapid increase in p-ERK1/2 and p-P38 MAPK proteins that was maximal at 15 or 30 min posttreatment. Moreover, IGF-II increased migration of trophectoderm cells. Collectively, these results support the hypothesis that IGF-II coordinately activates multiple cell signaling pathways critical to survival, growth, and differentiation of the ovine conceptus during early pregnancy.
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PMID:Insulin-like growth factor II activates phosphatidylinositol 3-kinase-protooncogenic protein kinase 1 and mitogen-activated protein kinase cell Signaling pathways, and stimulates migration of ovine trophectoderm cells. 1833 15

cAMP regulates a wide range of processes through its downstream effectors including PKA, and the family of guanine nucleotide exchange factors. Depending on the cell type, cAMP inhibits or stimulates growth and proliferation in a PKA-dependent or independent manner. PKA-independent effects are mediated by PI 3-kinases-Akt signaling and EPAC1 (exchange protein directly activated by cAMP) activation. Recently, we reported PKA-independent activation of the protein kinase Akt as well co-immunoprecipitation of Epac1 with Rap1, p-Akt(Thr-308), and p-Akt(Ser-473) in forskolin-stimulated macrophages. To further probe the role of Epac1 in Akt protein kinase activation and cellular proliferation, we employed the cAMP analog 8-CPT-2-O-Me-cAMP, which selectively binds to Epac1 and triggers Epac1 signaling. We show the association of Epac1 with activated Akt kinases by co-immunoprecipitation and GST-pulldown assays. Silencing Epac1 gene expression by RNA interference significantly reduced levels of Epac1 mRNA, Epac protein, Rap1 GTP, p-ERK1/2, p-B-Raf, p110alpha catalytic subunit of PI 3-kinase, p-PDK, and p-p(70s6k). Silencing Epac1 gene expression by RNA interference also suppressed 8-CPT-2-O-Me-cAMP-upregulated protein and DNA synthesis. Concomitantly, 8-CPT-2-O-Me-cAMP-mediated upregulation of Akt(Thr-308) protein kinase activity and p-Akt(Thr-308) levels was prevented in plasma membranes and nuclei of the cells. In contrast, silencing Epac1 gene expression reduced Akt(Ser-473) kinase activity and p-Akt(Ser-473) levels in plasma membranes, but showed negligible effects on nuclear activity. In conclusion, we show that cAMP-induced Akt kinase activation and cellular proliferation is mediated by Epac1 which appears to function as an accessory protein for Akt activation.
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PMID:The cAMP-activated GTP exchange factor, Epac1 upregulates plasma membrane and nuclear Akt kinase activities in 8-CPT-2-O-Me-cAMP-stimulated macrophages: Gene silencing of the cAMP-activated GTP exchange Epac1 prevents 8-CPT-2-O-Me-cAMP activation of Akt activity in macrophages. 1849 29

The ability of calcineurin to regulate IRS-1 and IRS-2 levels has not been examined in any given cells, although calcineurin inhibition by therapeutic immunosuppressants produced cytoprotective and cytotoxic effects (e.g., new-onset of diabetes mellitus, seizure). Chronic (>or=3h) treatment of cultured bovine adrenal chromaffin cells with cyclosporin A or FK506 decreased IRS-2 protein level by approximately 50% (IC(50)=200 or 10nM), without changing IRS-2 mRNA level, and insulin receptor, insulin-like growth factor-I (IGF-I) receptor, IRS-1, PI3K/PDK-1/Akt/GSK-3beta and ERK1/ERK2 protein levels. When the cells were washed to remove the test drug, the decreased IRS-2 level restored to the control level. Cyclosporin A or FK506 treatment inhibited calcineurin activity (IC(50)=500 or 40 nM, in vitro assay). Rapamycin, an FK506-binding protein ligand unable to inhibit calcineurin, failed to decrease IRS-2, but reversed FK506-induced decreases of calcineurin activity and IRS-2 level. Pulse-label followed by polyacrylamide gel electrophoresis revealed that cyclosporin A or FK506 accelerated IRS-2 degradation rate (t(1/2)) from >24 to approximately 4.2h, without altering IRS-2 synthesis. IRS-2 reduction by cyclosporin A or FK506 was prevented by lactacystin (proteasome inhibitor), but not by calpeptin (calpain inhibitor) or leupeptin (lysosome inhibitor). Cyclosporin A or FK506 increased serine-phosphorylation and ubiquitination of IRS-2. Cell surface (125)I-IGF-I binding capacity was not changed in cyclosporin A- or FK506-treated cells; however, IGF-I-induced phosphorylations of GSK-3beta and ERK1/ERK2 were attenuated by approximately 50%, which were prevented by rapamycin or lactacystin. Thus, calcineurin inhibition decreased IRS-2 level via proteasomal IRS-2 degradation, attenuating IGF-I-induced GSK-3beta and ERK pathways.
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PMID:Proteasomal degradation of IRS-2, but not IRS-1 by calcineurin inhibition: attenuation of insulin-like growth factor-I-induced GSK-3beta and ERK pathways in adrenal chromaffin cells. 1853 59

Macrophage migration inhibitory factor (MIF) is a pluripotent cytokine that is involved in host immune and inflammatory responses, as well as tumorigenesis. However, the regulatory mechanism of MIF function is unclear. Here we report that the NM23-H1 interacts with MIF in cells, as demonstrated by cotransfection and coimmunoprecipitation experiments. Analysis of cysteine (Cys) to serine (Ser) substitution mutants of NM23-H1 (C4S, C109S, and C145S) and MIF (C57S, C60S, and C81S) revealed that Cys(145) of NM23-H1 and Cys(60) of MIF are responsible for complex formation. NM23-H1-MIF complexes were dependent on reducing conditions, such as the presence of dithiothreitol or beta-mercaptoethanol, but not H(2)O(2). NM23-H1 alleviated the MIF-mediated suppression of p53-induced apoptosis and cell cycle arrest by promoting the dissociation of MIF from MIF-p53 complexes. In addition, NM23-H1 significantly inhibited the MIF-induced proliferation of quiescent NIH 3T3 cells through a direct interaction with MIF, and decreased the MIF-induced activation of phosphatidylinositol 3-kinase/PDK1 and p44/p42 extracellular signal-regulated (ERK) mitogen-activated protein kinase. The results of the current study suggest that the NM23-H1 functions as a negative regulator of MIF.
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PMID:Direct interaction between NM23-H1 and macrophage migration inhibitory factor (MIF) is critical for alleviation of MIF-mediated suppression of p53 activity. 1881 36

Postnatal growth of the mouse adrenal gland shows a characteristic gender-dependent pattern, resulting in an almost 2-fold higher adrenal weight in 11-wk-old female vs. male mice. We demonstrated that the higher weight of the adrenal glands in female mice is due to a significantly (P < 0.05) increased growth rate in female mice and a shorter growth phase of the adrenal glands in male mice (P < 0.05). To address the signaling mechanisms underlying these differential growth patterns, we evaluated the phosphorylation levels of p44/42 and p38 MAPK. In female mice, age-dependent reductions of p38 MAPK phosphorylation were found between wk 3 and 9 (47% reduction; P < 0.05). At the age of 11 wk, the p38 MAPK phosphorylation level in female adrenal glands was about 60% lower than in the male counterparts (P < 0.01). Similarly, the phosphorylation level of p44/42 MAPK was 50% lower in female adrenal glands (P < 0.001). Reduced activation of p44/42 MAPK was also observed after growth stimulation of the adrenal glands in male mice after ACTH treatment (-36%; P < 0.001) or by expression of a GH transgene (-34%; P < 0.001), whereas p38 MAPK, JNK, or PDK1 activation was unaffected. From our findings in three independent mouse models where partial deactivation of p44/42 MAPK was observed under conditions of elevated growth, we suggest a function of p44/42 MAPK for adrenal growth and a role of p44/42 MAPK for the integration of different endocrine stimuli.
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PMID:Decreased p44/42 mitogen-activated protein kinase phosphorylation in gender- or hormone-related but not during age-related adrenal gland growth in mice. 1894 1

Although PDK1 regulates several signaling pathways that respond to neurotrophins, direct evidence for its involvement in neurotrophin-mediated survival has not yet been reported. Here we show high neuronal expression of active PDK1 in the rat cortex and hippocampus at the developmental stages with pronounced dependence on extracellular survival signals. Also, in cultured cortical neurons from newborn rats, BDNF resulted in PDK1- and extracellular signal-regulated kinase-1/2 (ERK1/2)-mediated activation of their direct target, the p90 ribosomal S6 kinase 1/2 (RSK1/2). In trophic-deprived cortical neurons, knockdown of endogenous PDK1 attenuated the antiapoptotic survival response to 10 ng/ml BDNF, whereas an overexpressed active mutant form of PDK1 reduced apoptosis. The neuroprotection by BDNF or active PDK1 required RSK1/2. Conversely, PDK1 knockdown reversed the survival effects of combining the overexpressed RSK1 with a low, subprotective BDNF concentration of 2 ng/ml. Likewise, the protection by the overexpressed, active PDK1 was enhanced by coexpression of an active RSK1 mutant. Consistent with the observations that in BDNF-stimulated neurons RSK1/2 activation required both PDK1 and ERK1/2, ERK1/2 knockdown removed BDNF-mediated survival. Selective activation of ERK1/2 with an overexpressed active mutant form of MKK1 resulted in RSK1/2- and PDK1-dependent neuroprotection. Finally, at subprotective plasmid DNA dosage, overexpression of the active MKK1 and PDK1 mutants produced synergistic effect on survival. Our findings indicate a critical role for PDK1-RSK1/2 signaling in BDNF-mediated neuronal survival. Thus, the PDK1 is indispensable for the antiapoptotic effects of the ERK1/2 pathway offering previously unrecognized layer of survival signal processing and integration.
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PMID:Requirement of 3-phosphoinositide-dependent protein kinase-1 for BDNF-mediated neuronal survival. 1897 83

The protein kinase C (PKC) family is the most prominent target of tumor-promoting phorbol esters. For the PKCepsilon isozyme, different intracellular localizations and oncogenic potential in several but not all experimental systems have been reported. To obtain information about PKCepsilon-signaling, we investigated the effects of constitutively active rat PKCepsilon (PKCepsilonA/E, alanine 159 is replaced by glutamic acid) in HeLa cells in a doxycycline-inducible vector. Upon induction of PKCepsilonA/E expression by doxycycline, the major part of PKCepsilonA/E was localized to the Golgi. This led (i) to phosphorylations of PKCepsilon(S729), Elk-1(S383), PDK1(S241) and Rb(S807/S811), (ii) to elevated expression of receptor of activated C kinase 2 (RACK2) after 12 h, and (iii) increased colony formation in soft agar, increased cell migration and invasion, but not to decreased doubling time. Following induction of PKCepsilonA/E-expression by doxycycline for 24 h and additional short-term treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA), PKCepsilonA/E translocated to the plasma membrane and increased phosphorylation of MARCKS(S152/156). Treatment with doxycycline/TPA or TPA alone increased phosphorylations of Elk-1(S383), PDK1(S241), Rb(S807/S811), PKCdelta(T505), p38MAPK(T180/Y182), MEK1/2(S217/S221) and ERK2(T185/T187). MARCKS was not phosphorylated after treatment with TPA alone, demonstrating that in this system it is phosphorylated only by PKCepsilon localized to the plasma membrane but not by PKCalpha or delta, the other TPA-responsive PKC isozymes in HeLa cells. These results demonstrate that PKCepsilon can induce distinctly different signaling from the Golgi and from the plasma membrane.
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PMID:Signal transduction of constitutively active protein kinase C epsilon. 1916 30

In formyl-Met-Leu-Phe (fMLP)-stimulated rat neutrophils, 2-benzyl-3-(4-hydroxymethylphenyl)indazole (CHS-111) inhibited superoxide anion (O(2)(-)) generation, which was not mediated by scavenging the generated O(2)(-) or by a cytotoxic effect, and attenuated migration. CHS-111 had no effect on the arachidonic acid-induced NADPH oxidase activation or the GTPgammaS-stimulated Rac2 membrane translocation in cell-free systems, whereas it effectively attenuated the membrane recruitment of p40(phox), p47(phox) and p67(phox), phosphorylation of Ser residues in p47(phox), association between p47(phox) and p22(phox), and Rac activation in fMLP-stimulated neutrophils. Moreover, the phosphorylation and membrane recruitment of p21-activated kinase (PAK), PAK kinase activity and the interaction of PAK with p47(phox) were inhibited by CHS-111. CHS-111 effectively reduced Akt kinase activity and the association between Akt and p47(phox), moderately inhibited the membrane recruitment of Akt and phospho-PDK1, and slightly attenuated Akt (Thr308) phosphorylation, whereas it had no effect on Akt (Ser473) phosphorylation or p110gamma membrane translocation. The membrane recruitment of protein kinase C (PKC)-alpha, -betaI, -betaII, -delta and -zeta, PKC phosphorylation and PKC kinase activity was attenuated by CHS-111, whereas CHS-111 did not affect the phosphorylation of p38 mitogen-activated protein kinase (MAPK) or downstream MAPK-activated protein kinase-2. Higher concentrations of CHS-111 were required to decrease fMLP-stimulated intracellular free Ca(2+) concentration ([Ca(2+)](i)) elevation in the presence but not in the absence of extracellular Ca(2+), and to reduce cellular cyclic AMP but slightly increase cyclic GMP levels. Taken together, these results suggest that CHS-111 inhibits fMLP-stimulated O(2)(-) generation in rat neutrophils through the blockade of PAK, Akt and PKC signaling pathways.
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PMID:Inhibition of superoxide anion generation by CHS-111 via blockade of the p21-activated kinase, protein kinase B/Akt and protein kinase C signaling pathways in rat neutrophils. 1944 20


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