Osmotic Stress Regulates Mammalian Target of Rapamycin (mTOR) Complex 1 via c-Jun N-terminal Kinase (JNK)-mediated Raptor Protein Phosphorylation

Kwak, Dongoh; Choi, Sunkyu; Jeong, Heeyoon; Jang, Jin-Wook; Lee, Young-Mi; Jeon, Hyeona; Lee, Mi Nam; Noh, Jungeun; Cho, Kun; Yoo, Jong Shin; Hwang, Daehee; Suh, Pann‐Ghill; Ryu, Sung Ho

doi:10.1074/jbc.m111.326538

Cited by 34 publications

(41 citation statements)

References 34 publications

(51 reference statements)

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“…6A,B). JNK is suggested to induce Raptor-S863 phosphorylation under strong hyperosmotic stress (Kwak et al 2012). Consistently, we observed that, in Nlk knockout cells, a high concentration of sorbitol could still increase Raptor-S863 phosphorylation, which was blocked by JNK inhibitor (Fig.…”

Section: Nlk Inhibits Mtorc1 By Phosphorylating Raptor S863 Residuesupporting

confidence: 85%

“…For example, AMPK might be activated under stress to inhibit mTORC1 (Chen et al 2010). Phosphatase activation upon hyperosmotic stress might also contribute to S6K dephosphorylation (Parrott and Templeton 1999;Kwak et al 2012). Nevertheless, our result indicates that the compromised mTORC1 inhibition, not activation of phosphatase, is responsible for the altered S6K phosphorylation in the Nlk knockout cells (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 69%

“…Raptor S863 has been reported to be a common phosphorylation site by multiple kinases (Wang et al 2009;Foster et al 2010;Carriere et al 2011;Wu et al 2011;Kwak et al 2012), including ERK1/2, JNK, p38β, and mTOR. Therefore, Raptor S863 phosphorylation can occur in response to a number of stimuli.…”

Section: Discussionmentioning

confidence: 99%

“…Phosphatase activation by hyperosmotic stress has been suggested to be responsible for S6K suppression (Parrott and Templeton 1999;Kwak et al 2012). However, the time course of S6K dephosphorylation by Torin1, a specific inhibitor of mTOR, was similar between wild-type and Nlk knockout cells (Supplemental Fig.…”

Section: Nlk Mediates Stress-induced Mtorc1 Inhibitionmentioning

confidence: 98%

“…A previous study has implicated JNK in osmotic stress-induced mTORC1 regulation. Perplexingly, JNK was reported to enhance mTORC1 activity in response to osmotic stress, although hyperosmotic conditions strongly inhibited the phosphorylation of mTORC1 substrates (Kwak et al 2012). It is thus not clear how mTORC1 is regulated under hyperosmotic condition if JNK activates mTORC1 and mediates the osmotic signal.…”

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confidence: 99%

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NLK phosphorylates Raptor to mediate stress-induced mTORC1 inhibition

Yuan¹,

Wang

et al. 2015

Genes Dev.

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The mechanistic target of rapamycin (mTOR) is a central cell growth controller and forms two distinct complexes: mTORC1 and mTORC2. mTORC1 integrates a wide range of upstream signals, both positive and negative, to regulate cell growth. Although mTORC1 activation by positive signals, such as growth factors and nutrients, has been extensively investigated, the mechanism of mTORC1 regulation by stress signals is less understood. In this study, we identified the Nemo-like kinase (NLK) as an mTORC1 regulator in mediating the osmotic and oxidative stress signals. NLK inhibits mTORC1 lysosomal localization and thereby suppresses mTORC1 activation. Mechanistically, NLK phosphorylates Raptor on S863 to disrupt its interaction with the Rag GTPase, which is important for mTORC1 lysosomal recruitment. Cells with Nlk deletion or knock-in of the Raptor S863 phosphorylation mutants are defective in the rapid mTORC1 inhibition upon osmotic stress. Our study reveals a function of NLK in stress-induced mTORC1 modulation and the underlying biochemical mechanism of NLK in mTORC1 inhibition in stress response.

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Section: Nlk Inhibits Mtorc1 By Phosphorylating Raptor S863 Residuesupporting

confidence: 85%

Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Nlk Mediates Stress-induced Mtorc1 Inhibitionmentioning

confidence: 98%

mentioning

confidence: 99%

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NLK phosphorylates Raptor to mediate stress-induced mTORC1 inhibition

Yuan¹,

Wang

et al. 2015

Genes Dev.

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circ‐016910 sponges miR‐574‐5p to regulate cell physiology and milk synthesis via MAPK and PI3K/AKT–mTOR pathways in GMECs

Liu

Hou

Zhang

et al. 2019

Journal Cellular Physiology

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Incremental proofs demonstrate that miRNAs, the essential regulators of gene expression, are implicated in various biological procedures, including mammary development and milk synthesis. Here, the role of miR-574-5p in milk synthesis, apoptosis, and proliferation of goat mammary epithelial cells (GMECs) are explored without precedent, and the molecular mechanisms for the impacts are elucidated.Small RNA libraries were constructed using GMECs transfected with miR-574-5p mimics and negative control followed by sequencing via Solexa technology. Overall, 332 genes were distinguishingly expressed entre two libraries, with 74 genes upregulated and 258 genes downregulated. This approach revealed mitogenactivated protein kinase kinase kinase 9 (MAP3K9), an upstream activator of MAPK signaling, as a differentially expressed unigene. miR-574-5p targeted seed sequences of the MAP3K9 3′-untranslated region and suppressed its messenger RNA (mRNA) and protein levels, correspondingly. GMECs with miR-574-5p overexpression and MAP3K9 inhibition showed increased cell apoptosis and decreased cell proliferation resulting from sustained suppression of MAPK pathways, while MAP3K9 elevation manifested the opposite results. miR-574-5p repressed the phosphorylation of members of protein kinase B (AKT)-mammalian target of rapamycin pathway via downregulating MAP3K9 and AKT3, resulting in reducing the secretion of β-casein and triglycerides in GMECs. Finally, according to the constructed circular RNA (circRNA) libraries and bioinformatics prediction approach, we selected circ-016910 and found it acted as a sponge for miR-574-5p and blocked its relevant behaviors to undertake biological effects in GMECs. The circRNA-miRNA-mRNA network facilitates further probes on the function of miR-574-5p in mammary development and milk synthesis.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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High glucose induces an early and transient cytoprotective autophagy in retinal Müller cells

et al. 2022

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Purpose We investigated the autophagic response of rat Müller rMC-1 cells during a short-term high glucose challenge. Methods rMC-1 cells were maintained in 5 mM glucose (LG) or exposed to 25 mM glucose (HG). Western blot analysis was used to evaluate the expression levels of markers of autophagy (LC3-II, p62) and glial activation (AQP4), as well as the activation of TRAF2/JNK, ERK and AKT pathways. Autophagic flux assessment was performed using the autophagy inhibitor chloroquine. ROS levels were measured by flow cytometry using dichlorofluorescein diacetate. ERK involvement in autophagy induction was addressed using the ERK inhibitor FR180204. The effect of autophagy inhibition on cell viability was evaluated by SRB assay. Results Activation of autophagy was observed in the first 2–6 h of HG exposure. This early autophagic response was transient, not accompanied by an increase in AQP4 or in the phospho-activation of JNK, a key mediator of cellular response to oxidative stress, and required ERK activity. Cells exposed to HG had a lower viability upon autophagy inhibition by chloroquine, as compared to those maintained in LG. Conclusion A short-term HG challenge triggers in rMC-1 cells a process improving the ability to cope with stressful conditions, which involves ERK and an early and transient autophagy activation.

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Osmotic Stress Regulates Mammalian Target of Rapamycin (mTOR) Complex 1 via c-Jun N-terminal Kinase (JNK)-mediated Raptor Protein Phosphorylation

Cited by 34 publications

References 34 publications

NLK phosphorylates Raptor to mediate stress-induced mTORC1 inhibition

NLK phosphorylates Raptor to mediate stress-induced mTORC1 inhibition

circ‐016910 sponges miR‐574‐5p to regulate cell physiology and milk synthesis via MAPK and PI3K/AKT–mTOR pathways in GMECs

High glucose induces an early and transient cytoprotective autophagy in retinal Müller cells

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