REDD1, an inhibitor of mTOR signalling, is regulated by the CUL4A–DDB1 ubiquitin ligase

Katiyar, Samiksha; Liu, Enbo; Knutzen, Christine A.; Lang, Elizabeth S; Lombardo, Christian R.; Sankar, Sabita; Toth, Julia I.; Petroski, Matthew D.; Ronai, Ze’ev A.; Chiang, Gary G.

doi:10.1038/embor.2009.93

Cited by 133 publications

(135 citation statements)

References 22 publications

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“…In serum-starved U2OS cells, MG132 treatment was able to block insulin-stimulated phosphorylation of the mTORC1 substrate S6K1, as judged by the stereotypic mobility shift. This observation was not completely unexpected, because negative regulators of mTORC1, such as TSC2 and REDD1, undergo ubiquitin-mediated degradation (15,16). However, following MG132 treatment, TSC2 levels did not increase, suggesting that TSC2 was not responsible for decreased mTORC1 signaling.…”

Section: Resultsmentioning

confidence: 76%

“…A growing number of E3 ligases that target upstream components of mTORC1 signaling (e.g., PTEN, AKT, TSC2, REDD1), downstream effectors of mTORC1 signaling (e.g., S6K1), as well as mTOR itself have been identified (15,16,(28)(29)(30)(31)(32). Here, we demonstrate that the MID1 E3 ligase affects mTORC1 signaling at the level of mTOR/Raptor complex formation.…”

Section: Discussionmentioning

confidence: 86%

“…In particular, Raptor plays an essential scaffolding role toward mTORC1 substrates such as 4E-BP1 and S6K1 (13,14). Studies in our laboratory have recently focused on the regulation of mTOR signaling by the ubiquitin proteasome system (UPS) (15). Here, we show that proteasome inhibition disrupts mTORC1 formation and signaling in a PP2A-dependent manner.…”

mentioning

confidence: 77%

“…The α-Raptor and α-Rictor antibodies were purchased from Bethyl. The α-PLCγ antibody has been previously described (15). The α-phospho-S6K1 (T389), α-phospho AKT (S473), α-AKT, and α-NBS1 antibodies were purchased from Cell Signaling Technology.…”

Section: Methodsmentioning

confidence: 99%

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Control of mTORC1 signaling by the Opitz syndrome protein MID1

Liu

Knutzen

Krauß

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in the MID1 gene are causally linked to X-linked Opitz BBB/G syndrome (OS), a congenital disorder that primarily affects the formation of diverse ventral midline structures. The MID1 protein has been shown to function as an E3 ligase targeting the catalytic subunit of protein phosphatase 2A (PP2A-C) for ubiquitinmediated degradation. However, the molecular pathways downstream of the MID1/PP2A axis that are dysregulated in OS and that translate dysfunctional MID1 and elevated levels of PP2A-C into the OS phenotype are poorly understood. Here, we show that perturbations in MID1/PP2A affect mTORC1 signaling. Increased PP2A levels, resulting from proteasome inhibition or depletion of MID1, lead to disruption of the mTOR/Raptor complex and downregulated mTORC1 signaling. Congruously, cells derived from OS patients that carry MID1 mutations exhibit decreased mTORC1 formation, S6K1 phosphorylation, cell size, and cap-dependent translation, all of which is rescued by expression of wild-type MID1 or an activated mTOR allele. Our findings define mTORC1 signaling as a downstream pathway regulated by the MID1/PP2A axis, suggesting that mTORC1 plays a key role in OS pathogenesis.ubiquitin ligase | proteasome-mediated degradation M utations in the MID1 gene are causally linked to X-linked Opitz BBB/G syndrome (OS), a congenital disorder that primarily affects the formation of ventral midline structures. The clinical manifestations of Opitz syndrome are characterized by a diverse spectrum of symptoms, including hypertelorism and hypospadias, cleft lip/palate, dysphagia, heart defects, and mental retardation (1).The MID1 protein is a member of the RBCC/TRIM family, which contains a conserved module of the RING domain, followed by B-boxes and a coiled-coil domain (2). MID1 also contains fibronectin type III and B30.2/SPRY domains. The RING domain has been well characterized in ubiquitin-mediated protein degradation, whereas the other domains mediate proteinprotein interactions (3-6). Opitz syndrome-derived mutations in MID1 have been identified throughout the protein and show several functional consequences such as compromised association with microtubules and/or transport along microtubules (4, 7-9). In addition to its microtubule-binding function, MID1 also functions as an E3 ligase that targets the microtubule-associated pool of the catalytic subunit of protein phosphatase 2A (PP2A-C) for ubiquitin-mediated degradation through an interaction with the protein α4 (3). Perturbation of the E3 ligase function of MID1 in OS cells leads to the accumulation of PP2A-C and the dramatic dephosphorylation of microtubule-associated proteins, which is postulated to contribute to OS pathogenesis (3).Signaling from the mammalian target of rapamycin (mTOR) controls diverse cellular processes such as growth, autophagy, stress responses, cytoskeletal reorganization, cell motility, metabolism, and aging (10-12). mTORC1 consists of mTOR and the interacting proteins, Raptor, and mLST8. In particular, Raptor plays an essential scaffolding...

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Section: Resultsmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 77%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Control of mTORC1 signaling by the Opitz syndrome protein MID1

Liu

Knutzen

Krauß

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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“…REDD1-mRNA and protein-turnover are heavily regulated by several miRNAs [18,19] and by ubiquitin-dependent proteasomal degradation [20] or caspase-mediated cleavage [21], respectively.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner

Jessica

Bongartz

Klepsch

et al. 2016

Cellular Signalling

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Abstract:Interleukin 6 is a pleiotropic cytokine and a strong activator of Mammalian Target of Rapamycin (mTOR). In contrast, mTOR activity is negatively regulated by Regulated in Development and DNA Damage Responses 1 (REDD1). Expression of REDD1 is induced by cellular stressors such as glucocorticoids and DNA damaging agents. We show that the expression of basal as well as stress-induced REDD1 is reduced by IL-6. The reduction of REDD1 expression by IL-6 is independent of proteasomal or caspase-mediated degradation of REDD1 protein. Instead, induction of REDD1 mRNA is reduced by IL-6. The regulation of REDD1 expression by interleukin 6 (IL-6) is independent of Phosphatidylinositide-3-Kinase (PI3K) and Mitogen-Activated Protein Kinase (MAPK) signalling but depends on the expression and activation of Signal Transducer and Activator of Transcription 3 (STAT3). Furthermore, the reduction of basal REDD1 expression by IL-6 correlates with IL-6-induced activation of mTOR signalling. Inhibition of STAT3 activation blocks IL-6-induced mTOR activation. In summary, we present a novel STAT3-dependent mechanism of both IL-6-induced activation of mTOR and IL-6-dependent reversion of stress-induced inhibition of mTOR activity.

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Time‐dependent effects of hypoxia on cell metabolism, signaling, and iron homeostasis in the hematopoietic progenitor model KG1a

et al. 2023

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Lowered availability of oxygen in the micro‐environment of cells perturbs metabolic and signaling pathways. It affects proliferation, tissue morphology, and differentiation. Leukemia impairs maturation of hematopoietic progenitors: the immune system, healing, and erythropoiesis are weakened, thereby perturbing iron homeostasis and further lowering oxygen provision to tissues. Here, the time‐dependent molecular consequences of sudden hypoxia were studied in the KG1a model of immature hematopoietic progenitors. The oxygen tension of KG1a cells was abruptly lowered from the experimentally usual ca. 20 to 1%. Growth and key hubs of signaling, metabolism, and iron homeostasis were monitored by a combination of immunological methods and functional assays. The collapse of oxygen availability stopped proliferation after one generation. The number of cells then remained approximately constant over several days, including after anaerobic changes in the culture medium. Lowered oxygen resulted in transient increase of the hypoxia‐inducible factor 1α and of its REDD1 target, inhibition of mechanistic (or mammalian) target of rapamycin, decreased autophagy, altered cap‐dependent translation, and minimal repression of the already weak oxidative phosphorylation. These adjustments did not trigger important cellular iron fluxes since the cells relied on their internal iron stores to survive. In conclusion, the response of the KG1a cells to stringent hypoxia is varied, with some established hypoxia‐sensitive pathways exhibiting activation whereas others were unaffected. The results draw attention to the flexibility of the environmental adaptation of cancer cells. They suggest that thorough characterization of early leukemic blasts is warranted to propose informed treatments to patients.

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REDD1, an inhibitor of mTOR signalling, is regulated by the CUL4A–DDB1 ubiquitin ligase

Cited by 133 publications

References 22 publications

Control of mTORC1 signaling by the Opitz syndrome protein MID1

Control of mTORC1 signaling by the Opitz syndrome protein MID1

Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner

Time‐dependent effects of hypoxia on cell metabolism, signaling, and iron homeostasis in the hematopoietic progenitor model KG1a

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