Serum- and glucocorticoid-inducible kinases in microglia

Inoue, Kōichi; Sakuma, Eisuke; Morimoto, Hiroyuki; Asai, Hayato; Koide, Yoshinori; Leng, Tiandong; Wada, Ikuo; Xiong, Zhi‐Gang; Ueki, Takatoshi

doi:10.1016/j.bbrc.2016.07.094

Cited by 19 publications

(16 citation statements)

References 39 publications

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“…In our studies, a strong response of the MR and GR target gene Sgk1 was found in the SHR hippocampus. Although we did not localise the cellular type responsible for the increased Sgk1 mRNA, the kinase has been detected in neurones, oligodendrocytes, astrocytes and microglia . Lang et al .…”

Section: Discussionmentioning

confidence: 59%

Mineralocorticoid receptor associates with pro‐inflammatory bias in the hippocampus of spontaneously hypertensive rats

Brocca

Pietranera

Meyer

et al. 2017

J Neuroendocrinology

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Damage observed in the hippocampus of the adult spontaneously hypertensive rat (SHR) resembles the neuropathology of mineralocorticoid-induced hypertension, supporting a similar endocrine dysfunction in both entities. In the present study, we tested the hypothesis that increased expression of the hippocampal mineralocorticoid receptor (MR) in SHR animals is associated with a prevalent expression of pro-inflammatory over anti-inflammatory factors. Accordingly, in the hippocampus, we measured mRNA expression and immunoreactivity of the MR and glucocorticoid receptor (GR) using a quantitative polymerase chain reaction and histochemistry. We also measured serum-glucocorticoid-activated kinase 1 (Sgk1 mRNA), the number and phenotype of Iba1+ microglia, as well as mRNA expression levels of the pro-inflammatory factors cyclo-oxygenase 2 (Cox2), Nlrp3 inflammasome and tumour necrosis factor α (Tnfα). Expression of anti-inflammatory transforming growth factor (Tgf)β mRNA and the NADPH-diaphorase activity of nitric oxide synthase (NOS) were also determined. The results showed that, in the hippocampus of SHR rats, expression of MR and the number of immunoreactive MR/GR co-expressing cells were increased compared to Wistar-Kyoto control animals. Expression of Sgk1, Cox2, Nlrp3 and the number of ramified glia cells positive for Iba1+ were also increased, whereas Tgfβ mRNA expression and the NADPH-diaphorase activity of NOS were decreased. We propose that, in the SHR hippocampus, increased MR expression causes a bias towards a pro-inflammatory phenotype characteristic for hypertensive encephalopathy.

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Section: Discussionmentioning

confidence: 59%

Mineralocorticoid receptor associates with pro‐inflammatory bias in the hippocampus of spontaneously hypertensive rats

Brocca

Pietranera

Meyer

et al. 2017

J Neuroendocrinology

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“…As a consequence of phosphorylation of Ser507 and/or 750 residues of ULK2 by SGK1, its phosphorylation and association with AMPK1α were decreased, coupled with an increase of an antagonistic effect on its autophagy (Figure 4, Table 1). SGK1, similar to Akt kinase as a downstream effector of PI3K-PDK1 signal pathway for cell survival [13] [19], can inhibit ULK2 autophagy activity by phosphorylation as its authentic substrate proteins until they are active (Figure 4). Therefore, cell survival and autophagy are not antagonistic, but agonistic for cell survival in the transformed cell line [14] [15] [16].…”

Section: Discussionmentioning

confidence: 99%

“…For the cell amount control, the western blot with actin Ab was shown. The autophagy activity which was detected by LC3 Ab western (third lane) was 5 times enhanced by the specific SGK1 inhibitor (GSK-650394) treatment [19] than by the insulin or no treatment control. This is one of four repeated experiment results.…”

Section: Interaction Of Ulk2 With Lc3 Is Enhanced By Sgk1 Inhibitor Tmentioning

confidence: 96%

“…The functional proteins (such as Atg13-AMPK1α) are disassociated. SGK1 activation by insulin inhibits ULK2 autophagy activity through the enhancement of AMPK1α dissociation, while SGK1 inactivation by GSK650394 [19] promotes ULK2 autophagy activity through the enhancement of AMPK1α association. From the action mechanism of ULK1 [20] [21], this picture was redraw by replacing it with ULK2.…”

Section: The Effect Of Ulk2 Wt S507as750a or S507ds750d On Hek293 Cmentioning

confidence: 99%

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SGK1 Inhibits ULK2 Autophagy Activity

Sein¹,

Lee²,

Hyun³

et al. 2020

AJMB

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Serum-and glucocorticoid-induced kinase 1 (SGK1) is known to have consensus sequence of phosphorylation site R-x-R-x-x-(S/T)-Φ, where Φ is any hydrophobic amino acid and arginine residues are conserved at positions −5 and −3 relative to positions of Ser/Thr residues that are phosphorylated in the presence of SGK1. UNC-21-like kinase 2 (ULK2) also harbors putative SGK1 phosphorylation sites at both Ser507 (502 RsRnsSG 508) and Ser750 (745 RtRttSV 751) residues. Thus, the objective of this study was to determine whether Ser507 and Ser750 residues of ULK2 could be phosphorylation sites of SGK1 as one of its authentic substrate proteins. Using ULK2 507 and 750 serine residue un-or phosphorylation analog (S507AS750A or 507DS750D), we observed that modification of Ser507 or Ser750 residue was required to activate the kinase activity of ULK2 and sensitize ULK2 to stress or starvation while simultaneously enhancing its active state and autophagy characteristics, suggesting that phosphorylation at Ser750 or Ser507 residue could modulate its subcellular localization and protein interaction with AMPK1α to activate ULK2. We also observed that ULK2 autophagy activity was enhanced by GSK650394 (an SGK1 inhibitor) to compensate survival capacity through increasing its association with LC3 and phosphorylation. When SGK1 known to be associated with cell survival was inhibited by GSK650394, ULK2 autophagy pathway was activated to avoid cell death alternatively. Thus, our observations indicate that phosphorylation of ULK2 by SGK1 can regulate cell survival as an alternative modulation of ULK2 functions.

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“…Blocking of SGK2 activity was assessed by inhibiting SGK2 expression using iRNA (Dharmacon Accell siRNA assay: #E-004673-00-0005, GE Healthcare, Chicago, IL) (see Fig. S2) [18] or blocking its kinase activity using the SGK-1/2 inhibitor GSK650394 (Tocris Biosciences, Bristol, UK: catalog # 3572; 2 μM) [19]. Dexamethasone (1 μM) was used as a positive control.…”

Section: Sgk Blocking Assaysmentioning

confidence: 99%

Axonal and Myelin Neuroprotection by the Peptoid BN201 in Brain Inflammation

et al. 2019

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The development of neuroprotective therapies is a sought-after goal. By screening combinatorial chemical libraries using in vitro assays, we identified the small molecule BN201 that promotes the survival of cultured neural cells when subjected to oxidative stress or when deprived of trophic factors. Moreover, BN201 promotes neuronal differentiation, the differentiation of precursor cells to mature oligodendrocytes in vitro, and the myelination of new axons. BN201 modulates several kinases participating in the insulin growth factor 1 pathway including serum-glucocorticoid kinase and midkine, inducing the phosphorylation of NDRG1 and the translocation of the transcription factor Foxo3 to the cytoplasm. In vivo, BN201 prevents axonal and neuronal loss, and it promotes remyelination in models of multiple sclerosis, chemically induced demyelination, and glaucoma. In summary, we provide a new promising strategy to promote neuroaxonal survival and remyelination, potentially preventing disability in brain diseases.

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Serum- and glucocorticoid-inducible kinases in microglia

Cited by 19 publications

References 39 publications

Mineralocorticoid receptor associates with pro‐inflammatory bias in the hippocampus of spontaneously hypertensive rats

Mineralocorticoid receptor associates with pro‐inflammatory bias in the hippocampus of spontaneously hypertensive rats

SGK1 Inhibits ULK2 Autophagy Activity

Axonal and Myelin Neuroprotection by the Peptoid BN201 in Brain Inflammation

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