Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Forkhead transcription factor FoxO3a, also known as DAF-16 in Caenorhabditis elegans, is a key regulator of the insulin receptor (IR)/insulin-like growth factor-I signaling pathway mediated extension of life span in worms and yeast. In this study, we report that calorie restriction (CR)-mediated activation of the IR signaling pathway leads to hyperphosphorylation of FoxO3a transcription factor and, consequently, its exclusion from the nucleus. This inactivation of FoxO3a activity is correlated with attenuation of Alzheimer's disease (AD)-type amyloid neuropathology and with preservation of spatial reference memory in the Tg2576 mouse model of AD. Further, in vitro studies reveal that exogenous expression of viral, triple-mutant, constitutively active FoxO3a resulting in increased nuclear FoxO3a activity in primary neuron cultures derived from Tg2576 mouse embryos, causally promotes AD amyloid-beta peptide (Abeta) levels by inhibiting nonamyloidogenic alpha-secretase activity, indicating the existence of an inverse correlation between FoxO3a activity and cerebral Abeta amyloidosis. Moreover, we report for the first time that the exclusion of the FoxO3a transcription factor from the nucleus in combination with inhibition of nuclear FoxO3a activity by SIRT1-mediated deacetylation in response to CR is a mechanism resulting in the repression of Rho-associated protein kinase-1 gene expression, thereby activating nonamyloidogenic alpha-secretase processing of the amyloid precursor protein and lowering Abeta generation. This study provides a novel metabolic pathway for prevention and/or treatment of AD.
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PMID:Regulation of forkhead transcription factor FoxO3a contributes to calorie restriction-induced prevention of Alzheimer's disease-type amyloid neuropathology and spatial memory deterioration. 1907 55

Pancreatic adenocarcinoma (PCA) is an almost invariably fatal disease. Recently, it has been shown by several groups as well as ours that insulin-like growth factor-I receptor (IGF-IR) overexpression is related to higher proliferation, survival, angiogenesis, and highly invasive pancreatic tumors. Several studies have been carried out to understand the pathways that lead to growth factor-mediated signaling, but the molecular mechanism of receptor overexpression remains mostly unknown. Treatment with neutralizing antibodies or a specific kinase inhibitor against IGF-IR could block the receptor expression in PCA cells. Furthermore, we also showed that insulin receptor substrate (IRS)-2, but not IRS-1, is involved in regulation of IGF-IR expression, which is most likely not transcriptional control. By blocking mammalian target of rapamycin (mTOR) pathway with rapamycin as well as other biochemical analysis, we defined a unique regulation of IGF-IR expression mediated by protein kinase Cdelta (PKCdelta) and mTOR pathway. Moreover, we showed that the down-regulation of IGF-IR expression due to IRS-2 small interfering RNA can be compensated by overexpression of dominant-active mutant of PKCdelta, suggesting that PKCdelta is downstream of IGF-IR/IRS-2 axis. Overall, these findings suggest a novel regulatory role of IRS-2 on the expression of IGF-IR through PKCdelta and mTOR in pancreatic cancer cells.
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PMID:Insulin receptor substrate-2 mediated insulin-like growth factor-I receptor overexpression in pancreatic adenocarcinoma through protein kinase Cdelta. 1919 Mar 47

3'-phosphoinositide-dependent protein kinase-1 (PDK-1) is a crucial serine/threonine kinase in the insulin-like growth factor-I (IGF-I)/AKT signaling pathway, but its function and localization in the nervous system has not been fully characterized. In this study, we compared the localization of PDK-1 in adult neurons and non-neuronal PC-3 cells. We showed that PC-3 cells expressed phosphorylated and nonphosphorylated PDK-1 in the cytoplasm and nucleoplasm. In contrast, neuronal PDK-1 was located in the nucleoplasm and the phosphorylated form was located along the perinuclear region. Furthermore, we found that IGF-I transiently increased phosphorylation of neuronal PDK-1, resulting in its translocation to other cellular compartments. Our findings suggest that IGF-I may regulate neuronal PDK-1 differently than in non-neuronal cells, which may indicate a novel role for PDK-1 in IGF-I-mediated neuroprotective signaling.
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PMID:IGF-I regulated phosphorylation and translocation of PDK-1 in neurons. 1927 99

Insulin-like growth factor-I (IGF-I) exerts beneficial effects on cognitive function. The selective acetylcholinesterase inhibitor donepezil increases serum IGF-I levels in elderly subjects. Because stimulation of sensory neurons induces IGF-I production by releasing calcitonin gene-related peptide (CGRP) in the mouse brain, we hypothesized that donepezil increases IGF-I production by sensory neuron stimulation to improve the cognitive function in mice. Donepezil, but not tacrine, increased the CGRP release from dorsal root ganglion neurons isolated from wild-type (WT) mice. Pretreatment with the protein kinase A inhibitor KT5720 [(9S,10S,12R)-2,3,9,10,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg: 3',2',1'-kl]pyrrolo[3,4-i][1,6]-benzo-diazocine-10-carboxylic acid hexyl ester] reversed the effects induced by donepezil. Increase in tissue levels of CGRP, IGF-I, and IGF-I mRNA in the hippocampus was observed at 4 weeks after oral administration of donepezil in WT mice. In these animals, c-fos expression in spinal dorsal horns, parabrachial nuclei, the solitary tract nucleus, and the hippocampus was increased. Enhancement in angiogenesis and neurogenesis was observed in the dentate gyrus of the hippocampus of WT mice after donepezil administration. Improvement of spatial learning was observed in WT mice after donepezil administration. Oral administration of tacrine for 4 weeks produced none of the aforementioned effects induced by donepezil in WT mice. However, none of the effects observed in WT mice was seen after donepezil administration in CGRP-knockout mice and WT mice subjected to functional denervation. These observations suggest that donepezil may improve cognitive function in mice by increasing the hippocampal production of IGF-I through sensory neuron stimulation. These effects of donepezil may not be dependent on its acetylcholinesterase inhibitory activity.
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PMID:Donepezil improves cognitive function in mice by increasing the production of insulin-like growth factor-I in the hippocampus. 1931 94

Previously, we observed that in vitro germinal vesicle breakdown (GVBD) in Cyprinus carpio oocytes was induced by recombinant human insulin-like growth factor-I (IGF-I) and bovine insulin (b-insulin) and this induction was steroid-independent. To investigate further the early signal transduction components involved in this process, the possible role of phosphatidylinositol 3-kinase (PI3 kinase) during oocyte maturation was examined. IGF-I- and b-insulin-induced oocyte maturation was significantly inhibited by Wortmannin and LY294002, two mechanistically different specific inhibitors of PI3 kinase. IGF-I and b-insulin were shown to activate PI3 kinase after 90 min of their treatment. Both IGF-I and b-insulin were found to activate cdc2 kinase at 21h of treatment. We examined the relative involvement of PI3 kinase, MAP kinase and cdc2 kinase in IGF-I- and b-insulin-induced oocyte maturation in C. carpio. MAP kinase was rapidly phosphorylated and activated (30-150 min) in response to exposure of the oocytes with IGF-I and b-insulin. This response preceded the phosphorylation and activation of cdc2 by several hours (almost 19h). A potent and selective inhibitor of MEK, PD98059, the protein kinase that phosphorylates and activate MAP kinase, blocked the phosphorylation and activation of MAP kinase and cdc2 kinase and GVBD induction. Likewise, PI3 kinase inhibitors strongly inhibited phosphorylation and activation of MAP kinase, which was increased during oocyte maturation. Taken together, these results suggest that PI3 kinase is an initial component of the signal transduction pathway which precedes MAP kinase, and MPF activation during IGF-I- and b-insulin-induced oocyte maturation in C. carpio.
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PMID:Involvement of PI3 kinase and MAP kinase in IGF-I- and insulin-induced oocyte maturation in Cyprinus carpio. 1948 57

Insulin-like growth factor-I receptor (IGF-IR) overexpression may play a role in prostate cancer progression. We found previously that, in prostate cancer cells, IGF-IR is up-regulated by both androgens and estrogens via a nongenotropic pathway. We now show that, in prostate cancer cells, stimulation with either androgens or estrogens up-regulates IGF-IR by inducing cyclic AMP response element-binding protein (CREB) activation. Both sex steroids phosphorylated CREB at Ser(133) in a dose-dependent manner in androgen receptor (AR)-positive LNCaP cells, whereas only estrogens phosphorylated CREB in AR-negative PC3 cells. CREB phosphorylation involved c-Src-dependent extracellular signal-regulated kinase 1/2 activation, but not protein kinase A, protein kinase C, or calmodulin-dependent kinase II, and occurred also in cells transfected with AR or estrogen receptor mutants that do not localize into the nucleus. CREB silencing abrogated IGF-IR up-regulation and promoter activation. We also showed that CREB binds to IGF-IR promoter region and identified the relevant CREB-binding site at the 5'-untranslated region fragment of IGF-IR promoter. In conclusion, we describe a novel mechanism of IGF-IR up-regulation and promoter activity by CREB activation, induced by sex steroids, through a nongenotropic signaling.
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PMID:Role of cyclic AMP response element-binding protein in insulin-like growth factor-i receptor up-regulation by sex steroids in prostate cancer cells. 1973 69

Our previous studies found that insulin-like growth factor-I receptor (IGF1R) signaling blockade caused cardiac hypertrophy, and that apoptosis is required for upregulating the IGF-II and the IGF-II/ mannose 6-phosphate receptor (IGF2R) gene. However, the role of IGF-II in the regulation of cell apoptosis through IGF2R is little known. In this study, we hypothesized that IGF-II may induce cell apoptosis through IGF2R but is dependent on IGF1R activity. Western blots and TUNEL assay revealed that in the presence of IGF1R, exogenous IGF-II acts, like IGF-I, would increase phospho-Akt through IGF1R, but does not affect the caspase 3 activation and apoptotic induction in H9c2 cardiomyoblast cells. Conversely, AG1024, an inhibitor of IGF1R activity, causes cell apoptosis, and the treatment with IGF-II further enhances this process, implying that it occurs through IGF2R. Moreover, immunoprecipitation assay revealed that treatment with IGF-II could enhance the interaction of IGF2R with Galphai and Galphaq but reduce its binding with Galphas, resulting in the reduction of phospho-PKA and the activation of PLC-beta. Taken together, these data provide new insight into the dual role of IGF-II in the control of IGF1R dependent cell apoptosis and involved activation of IGF2R signaling. Improving IGF1R activity and suppressing IGF2R may be a good strategy to prevent the progression of heart disease with cardiomyocyte apoptosis.
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PMID:Enhancement of AG1024-induced H9c2 cardiomyoblast cell apoptosis via the interaction of IGF2R with Galpha proteins and its downstream PKA and PLC-beta modulators by IGF-II. 1976 51

In cultured bovine adrenal chromaffin cells, approximately 24 h-treatment with insulin-like growth factor-I (IGF-I) decreased cell surface (125)I-IGF-I binding capacity and IGF-I receptor protein level by approximately 64% (EC(50) = 5.0 nM; t(1/2) = approximately 7 h). IGF-I-induced IGF-I receptor decrease was abolished by LY294002 (phosphoinositide 3-kinase inhibitor) and partially attenuated by rapamycin (an inhibitor of mammalian target of rapamycin [mTOR]). SB216763 (an inhibitor of glycogen synthase kinase-3 [GSK-3]) down-regulated IGF-I receptor, which was further decreased by IGF-I. IGF-I increased inhibitory Ser(9)-phosphorylation of GSK-3beta and stimulatory Ser(2448)-phosphorylation of mTOR. l-leucine increased phosphorylation of mTOR (but not GSK-3beta), and down-regulated IGF-I receptor, both events being abolished by rapamycin. IGF-I-induced IGF-I receptor decrease was not prevented by proteolysis inhibitors. Pulse-label with [(35)S]methionine/cysteine followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that SB216763 or L-leucine retarded synthesis of IGF-I receptor and its precursor molecule. SB216763 (but not l-leucine) destabilized IGF-I receptor mRNA and decreased its level, without changing IGF-I receptor gene transcription. In SB216763-treated cells, IGF-I-induced Tyr-autophosphorylation of IGF-I receptor was decreased by 36%, compared to nontreated cells. IGF-I attenuated constitutive Ser(396)-phosphorylation of tau by 30% in nontreated cells, but not in SB216763-treated cells. IGF-I-induced down-regulations of (125)I-IGF-I binding and IGF-I receptor, as well as IGF-I-induced phosphorylations of GSK-3beta and mTOR were restored to the control levels of nontreated cells after washout of IGF-I (10 nM for 12 h)-treated cells. Thus, IGF-I down-regulated functional IGF-I receptor via GSK-3beta inhibition and mTOR activation; constitutive activity of GSK-3beta maintained IGF-I receptor level in nonstimulated cells.
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PMID:Homologous posttranscriptional regulation of insulin-like growth factor-I receptor level via glycogen synthase kinase-3beta and mammalian target of rapamycin in adrenal chromaffin cells: effect on tau phosphorylation. 2014 29

Rapamycin-induced apoptosis in sarcoma cells is inhibited by insulin-like growth factor-I (IGF-I) through a signaling pathway independent of Ras-extracellular signal-regulated kinase 1/2 and Akt. IGF-I induces Bad phosphorylation (Ser112, Ser136, and Ser155) in a pathway involving phosphoinositide 3' kinase (PI3K) and protein kinase C (PKC; mu, epsilon, or theta) resulting in sequestering Bad from mitochondria and subsequently interacting with 14-3-3gamma in the cytosol. Gene knockdown of Bad, Bid, Akt1, Akt2, PKC-mu, PKC-epsilon, or PKC-theta was achieved by transient transfection using small interfering RNAs. Results indicate that IGF-I signaling to Bad requires activation of PI3K and PKC (mu, theta, epsilon) but not mTOR, Ras-extracellular signal-regulated kinase 1/2, protein kinase A, or p90(RSK). Wortmannin blocked the phosphorylation of PKC-mu (Ser744/Ser748), suggesting that PI3K is required for the activation of PKCs. PKCs phosphorylate Bad under in vitro conditions, and the association of phosphorylated Bad with PKC-mu or PKC-epsilon, as shown by immunoprecipitation, indicated direct involvement of PKCs in Bad phosphorylation. To confirm these results, cells overexpressing pEGFP-N1, wt-Bad, or Bad with a single site mutated (Ser112Ala; Ser136Ala; Ser155Ala), two sites mutated (Ser(112/136)Ala; Ser(112/155)Ala; Ser(136/155)Ala), or the triple mutant were tested. IGF-I protected completely against rapamycin-induced apoptosis in cells overexpressing wt-Bad and mutants having either one or two sites of phosphorylation mutated. Knockdown of Bid using small interfering RNA showed that Bid is not required for rapamycin-induced cell death. Collectively, these data suggest that IGF-I-induced phosphorylation of Bad at multiple sites via a pathway involving PI3K and PKCs is important for protecting sarcoma cells from rapamycin-induced apoptosis.
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PMID:Protection from rapamycin-induced apoptosis by insulin-like growth factor-I is partially dependent on protein kinase C signaling. 2017 9

Sensory neurons release calcitonin-gene related peptide (CGRP) on stimulation. We have reported that topical application of capsaicin increases facial skin elasticity by increasing the production of dermal insulin-like growth factor-I (IGF-I) through stimulation of sensory neurons in mice and humans. In this study, we examined whether topical application of alpha-D-glucosylglycerol (GG), a compound found in Japanese traditional brewed foods such as sake (Japanese rice wine), increases the dermal production of IGF-I in mice and increases the facial skin elasticity in females. GG increased CGRP release and cAMP levels in dorsal root ganglion (DRG) neurons isolated from wild-type mice. Pretreatment with capsazepine, an inhibitor of vanilloid receptor-1 activation, and with KT5720, an inhibitor of protein kinase A, reversed GG-induced increases in CGRP release from DRG neurons. Topical application of GG increased dermal levels of IGF-I, IGF-I mRNA, and collagen in wild-type mice, but not in CGRP-knockout mice. Topical application of GG increased cheek-skin elasticity in 13 female volunteers. These observations strongly suggest that GG increases the production of IGF-I in the skin through sensory neuron stimulation, thereby increasing skin elasticity.
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PMID:Effects of topical application of alpha-D-glucosylglycerol on dermal levels of insulin-like growth factor-i in mice and on facial skin elasticity in humans. 2037 88


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