Insulin-like modulation of Akt/FoxO signaling by copper ions is independent of insulin receptor

Hamann, Ingrit; Petroll, Kerstin; Grimm, Larson; Hartwig, Andrea; Klotz, Lars‐Oliver

doi:10.1016/j.abb.2014.06.004

Cited by 19 publications

(13 citation statements)

References 38 publications

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“…The insulin-mimetic ability of Cu 2+ and Zn 2+ to activate the PI3K/Akt pathway by the interaction with insulin-receptor (IR) and IGF1-receptor (IGF1R) in HepG2 human hepatoma cells (Walter et al, 2006), which result in the phosphorylation and nuclear exclusion of transcription factor FoxO1a, has been recently questioned (Hamann et al, 2014). In this work copper affected overall tyrosine phosphorylation and, more specifically, tyrosine phosphorylation involved in Akt/FoxO signaling, by the inactivation of phosphatases [PTPase(s)], according to previous findings (Kim et al, 2000; Barthel et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

The Inorganic Side of NGF: Copper(II) and Zinc(II) Affect the NGF Mimicking Signaling of the N-Terminus Peptides Encompassing the Recognition Domain of TrkA Receptor

Pandini

Satriano

Pietropaolo³

et al. 2016

Front. Neurosci.

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The nerve growth factor (NGF) N-terminus peptide, NGF(1–14), and its acetylated form, Ac-NGF(1–14), were investigated to scrutinize the ability of this neurotrophin domain to mimic the whole protein. Theoretical calculations demonstrated that non-covalent forces assist the molecular recognition of TrkA receptor by both peptides. Combined parallel tempering/docking simulations discriminated the effect of the N-terminal acetylation on the recognition of NGF(1–14) by the domain 5 of TrkA (TrkA-D5). Experimental findings demonstrated that both NGF(1–14) and Ac-NGF(1–14) activate TrkA signaling pathways essential for neuronal survival. The NGF-induced TrkA internalization was slightly inhibited in the presence of Cu2+ and Zn2+ ions, whereas the metal ions elicited the NGF(1–14)-induced internalization of TrkA and no significant differences were found in the weak Ac-NGF(1–14)-induced receptor internalization. The crucial role of the metals was confirmed by experiments with the metal-chelator bathocuproine disulfonic acid, which showed different inhibitory effects in the signaling cascade, due to different metal affinity of NGF, NGF(1–14) and Ac-NGF(1–14). The NGF signaling cascade, activated by the two peptides, induced CREB phosphorylation, but the copper addition further stimulated the Akt, ERK and CREB phosphorylation in the presence of NGF and NGF(1–14) only. A dynamic and quick influx of both peptides into PC12 cells was tracked by live cell imaging with confocal microscopy. A significant role of copper ions was found in the modulation of peptide sub-cellular localization, especially at the nuclear level. Furthermore, a strong copper ionophoric ability of NGF(1–14) was measured. The Ac-NGF(1–14) peptide, which binds copper ions with a lower stability constant than NGF(1–14), exhibited a lower nuclear localization with respect to the total cellular uptake. These findings were correlated to the metal-induced increase of CREB and BDNF expression caused by NGF(1–14) stimulation. In summary, we here validated NGF(1–14) and Ac-NGF(1–14) as first examples of monomer and linear peptides able to activate the NGF-TrkA signaling cascade. Metal ions modulated the activity of both NGF protein and the NGF-mimicking peptides. Such findings demonstrated that NGF(1–14) sequence can reproduce the signal transduction of whole protein, therefore representing a very promising drug candidate for further pre-clinical studies.

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Section: Discussionmentioning

confidence: 99%

The Inorganic Side of NGF: Copper(II) and Zinc(II) Affect the NGF Mimicking Signaling of the N-Terminus Peptides Encompassing the Recognition Domain of TrkA Receptor

Pandini

Satriano

Pietropaolo³

et al. 2016

Front. Neurosci.

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“…PI3K/AKT signaling pathway plays a vital role in osteoblast differentiation and mineralization (27). Not only does PI3K regulate the differentiation of osteoblasts by interacting with Runx2 (28-31), but also could inhibit osteoblast apoptosis by inactivating FoxO (forkhead proteins) (32)(33)(34)(35). Apart from these, the PI3K/ AKT signaling pathway promotes the proliferation and differentiation of osteoblasts through associated signaling molecules such as ALP and BMP (36,37).…”

Section: Discussionmentioning

confidence: 99%

Dioscin improves postmenopausal osteoporosis through inducing bone formation and inhibiting apoptosis in ovariectomized rats

Zhao

et al. 2019

BST

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Postmenopausal osteoporosis (PMO) has become a public health problem worldwide. Hormonal replacement therapy (HRT) is the most popular treatment for PMO at present, but the side effects, including increased risk of endometrial cancer and breast cancer, limit its clinical use. Therefore, finding a new medication with high efficiency and less side-effects is urgently required. Dioscin is the main ingredient of some medicinal plants such as Dioscorea nipponica Makino and Dioscorea zingiberensis Wrigh. It is reported that dioscin has anti-tumoral and anti-atherosclerotic activity as well as an inhibitory effect on hepatic fibrosis. In this study, the effects of dioscin on PMO were examined and the mechanisms were analyzed. The results indicated that the bone mineral density and ultimate load of PMO rats were increased after being treated with dioscin. H&E staining and immunohistochemical staining showed the bone trabeculae formation and bone differentiation of PMO rats were promoted by dioscin. Western blots revealed that dioscin could activate the PI3K/P38/AKT signaling pathway and inhibit the apoptosis signaling pathway in bone tissue cells of PMO rats. In addition, MTT assays showed that MC3T3-E1 cell viability could be improved by dioscin. These results suggest dioscin is a potential therapeutic reagent for osteoporosis and deserves further investigation.

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“…Insulin, through phosphoinositide 3′-kinase (PI3K)-dependent stimulation of FOXO phosphorylation by the Ser/Thr-kinase Akt, causes inactivation and nuclear exclusion of three of the four mammalian FOXO isoforms (FOXOs 1, 3 and 4) [8] . As FOXOs were previously demonstrated in mammalian cells to be regulated not only by insulin, but also by stressful stimuli, such as by hydrogen peroxide [9] or the thiophilic agents Cu 2+ and arsenite [10] , [11] , we asked whether exposure to the thiol depleting agent DEM would result in a similar modulation of FOXO signaling in mammalian cells, and whether this occurs with consequences for FOXO target gene expression that are similar to the observations in C. elegans .…”

Section: Introductionmentioning

confidence: 91%

Nuclear trapping of inactive FOXO1 by the Nrf2 activator diethyl maleate

et al. 2019

Self Cite

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Diethyl maleate (DEM), a thiol-reactive α,β-unsaturated carbonyl compound, depletes glutathione (GSH) in exposed cells and was previously shown by us to elicit a stress response in Caenorhabditis elegans that, at lower concentrations, results in enhanced stress resistance and longer lifespan. This hormetic response was mediated through both the Nrf2 ortholog, SKN-1, and the forkhead box O (FOXO) family transcription factor DAF-16. As FOXO signaling is evolutionarily conserved, we analyzed here the effects of DEM exposure on FOXO in cultured human cells (HepG2, HEK293). DEM elicited nuclear accumulation of GFP-coupled wild-type human FOXO1, as well as of a cysteine-deficient FOXO1 mutant. Despite the nuclear accumulation of FOXO1, neither FOXO1 DNA binding nor FOXO target gene expression were stimulated, suggesting that DEM causes nuclear accumulation but not activation of FOXO1. FOXO1 nuclear exclusion elicited by insulin or xenobiotics such as arsenite or copper ions was attenuated by DEM, suggesting that DEM interfered with nuclear export. In addition, insulin-induced FOXO1 phosphorylation at Thr-24, which is associated with FOXO1 nuclear exclusion, was attenuated upon exposure to DEM. Different from FOXO-dependent expression of genes, Nrf2 target gene mRNAs were elevated upon exposure to DEM. These data suggest that, different from C. elegans, DEM elicits opposing effects on the two stress-responsive transcription factors, Nrf2 and FOXO1, in cultured human cells.

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Insulin-like modulation of Akt/FoxO signaling by copper ions is independent of insulin receptor

Cited by 19 publications

References 38 publications

The Inorganic Side of NGF: Copper(II) and Zinc(II) Affect the NGF Mimicking Signaling of the N-Terminus Peptides Encompassing the Recognition Domain of TrkA Receptor

The Inorganic Side of NGF: Copper(II) and Zinc(II) Affect the NGF Mimicking Signaling of the N-Terminus Peptides Encompassing the Recognition Domain of TrkA Receptor

Dioscin improves postmenopausal osteoporosis through inducing bone formation and inhibiting apoptosis in ovariectomized rats

Nuclear trapping of inactive FOXO1 by the Nrf2 activator diethyl maleate

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