Phosphorylation of TXNIP by AKT Mediates Acute Influx of Glucose in Response to Insulin

Waldhart, Althea N.; Dykstra, Holly; Peck, Anderson; Boguslawski, Elissa A.; Madaj, Zachary; Wen, Jennifer; Veldkamp, Kelsey; Hollowell, Matthew T.; Zheng, Bin; Cantley, Lewis C.; McGraw, Timothy E.; Wu, Ning

doi:10.1016/j.celrep.2017.05.041

Cited by 197 publications

(207 citation statements)

References 32 publications

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“…Other groups have previously shown that TXNIP deficiency induces AKT activation via oxidative inactivation of PTEN in the soleus muscle and heart, and TXNIP is phosphorylated by AKT in response to insulin (Hui et al, 2008; Waldhart et al, 2017). To elucidate the correlation between TXNIP and AKT, we examined whether TXNIP interacts with AKT in cells.…”

Section: Resultsmentioning

confidence: 99%

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

et al. 2018

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Aging is associated with an inevitable and universal loss of cell homeostasis and restricts an organism's lifespan by an increased susceptibility to diseases and tissue degeneration. The glucose uptake associated with producing energy for cell survival is one of the major causes of ROS production under physiological conditions. However, the overall mechanisms by which glucose uptake results in cellular senescence remain mysterious. In this study, we found that TXNIP deficiency accelerated the senescent phenotypes of MEF cells under high glucose condition. TXNIP‐/‐ MEF cells showed greater induced glucose uptake and ROS levels than wild‐type cells, and N‐acetylcysteine (NAC) treatment rescued the cellular senescence of TXNIP‐/‐ MEF cells. Interestingly, TXNIP‐/‐ MEF cells showed continuous activation of AKT during long‐term subculture, and AKT signaling inhibition completely blocked the cellular senescence of TXNIP‐/‐ MEF cells. In addition, we found that TXNIP interacted with AKT via the PH domain of AKT, and their interaction was increased by high glucose or H2O2 treatment. The inhibition of AKT activity by TXNIP was confirmed using western blotting and an in vitro kinase assay. TXNIP deficiency in type 1 diabetes mice (Akita) efficiently decreased the blood glucose levels and finally increased mouse survival. However, in normal mice, TXNIP deficiency induced metabolic aging of mice and cellular senescence of kidney cells by inducing AKT activity and aging‐associated gene expression. Altogether, these results suggest that TXNIP regulates cellular senescence by inhibiting AKT pathways via a direct interaction under conditions of glucose‐derived metabolic stress.

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Section: Resultsmentioning

confidence: 99%

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

et al. 2018

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“…Furthermore, USP6NL is mainly localized to the PM (19), a location where the PI3K/AKT signaling axis is generally considered to initiate (39). Finally, AKT phosphorylates the GLUT1 endocytic adaptor TXNIP at the PM, inhibiting the endocytosis of glucose transporters (40). Thus, the concerted action of USP6NL and AKT, acting at the cell surface, might link EGFR signaling to glucose uptake.…”

Section: Discussionmentioning

confidence: 99%

High USP6NL Levels in Breast Cancer Sustain Chronic AKT Phosphorylation and GLUT1 Stability Fueling Aerobic Glycolysis

et al. 2018

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USP6NL, also named RN-tre, is a GTPase-activating protein involved in control of endocytosis and signal transduction. Here we report that USP6NL is overexpressed in breast cancer, mainly of the basal-like/integrative cluster 10 subtype. Increased USP6NL levels were accompanied by gene amplification and were associated with worse prognosis in the METABRIC dataset, retaining prognostic value in multivariable analysis. High levels of USP6NL in breast cancer cells delayed endocytosis and degradation of the EGFR, causing chronic AKT (protein kinase B) activation. In turn, AKT stabilized the glucose transporter GLUT1 at the plasma membrane, increasing aerobic glycolysis. In agreement, elevated USP6NL sensitized breast cancer cells to glucose deprivation, indicating that their glycolytic capacity relies on this protein. Depletion of USP6NL accelerated EGFR/AKT downregulation and GLUT1 degradation, impairing cell proliferation exclusively in breast cancer cells that harbored increased levels of USP6NL. Overall, these findings argue that USP6NL overexpression generates a metabolic rewiring that is essential to foster the glycolytic demand of breast cancer cells and promote their proliferation. Significance: USP6NL overexpression leads to glycolysis addiction of breast cancer cells and presents a point of metabolic vulnerability for therapeutic targeting in a subset of aggressive basal-like breast tumors. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3432/F1.large.jpg. Cancer Res; 78(13); 3432–44. ©2018 AACR.

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“…Nevertheless, recent research has revealed that TXNIP plays a crucial role in redox-independent signaling [21]. TXNIP was found to inhibit glucose uptake independent of thioredoxin binding, which was important for the survival of thyroid cancer cells [34]. Interestingly, several studies have also shown that the overexpression of TXNIP inhibited HIF-mediated reporter activity in various cancer cells [20,33,35].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-224 Promotes Pancreatic Cancer Cell Proliferation and Migration by Targeting the TXNIP-Mediated HIF1α Pathway

Zhu

Zhou

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: MicroRNAs (miRNAs) have been shown to participate in the development of pancreatic ductal adenocarcinoma (PDAC) by modulating multiple cellular processes. Increased miR-224 expression enhances proliferation and metastasis in human cancers. This study aimed to investigate the role of miR-224 and its underlying mechanism of action in PDAC. Methods: BrdU, MTT, and cell migration assays were performed to determine cell proliferation, viability, and migration, respectively. The binding sites of miR-224 were identified using a luciferase reporter system, whereas protein expression of target genes was determined by immunoblotting and immunofluorescence analyses. A BALB/c nude mouse xenograft model was used to evaluate the role of miR-224 in vivo. Results: We demonstrated that miR-224 expression was enhanced in PDAC cells and tissues, and was related to migration and proliferation. Noticeably, miR-224 overexpression promoted the proliferation, migration, and metastasis of Panc1 cells, while miR-224 inhibition had the reverse effect on PDAC cells. Moreover, we found that thioredoxin-interacting protein (TXNIP) is a target of miR-224. The results also indicated that miR-224 inversely regulated TXNIP by binding directly to its 3′-untranslated region, which resulted in the activation of hypoxia-inducible factor 1α (HIF1α). Further, either TXNIP re-expression or HIF1α depletion abolished the effects of miR-224 on the proliferation and migration of PDAC cells in vitro and in vivo. Regarding the relationship of TXNIP and HIF1α, we found that TXNIP mediated the nuclear export of HIF1α and its degradation by forming a complex with HIF1α. Conclusion: The miR-224-TXNIP-HIF1α axis may be useful in developing novel therapies for PDAC.

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Phosphorylation of TXNIP by AKT Mediates Acute Influx of Glucose in Response to Insulin

Cited by 197 publications

References 32 publications

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

TXNIP regulates AKT‐mediated cellular senescence by direct interaction under glucose‐mediated metabolic stress

High USP6NL Levels in Breast Cancer Sustain Chronic AKT Phosphorylation and GLUT1 Stability Fueling Aerobic Glycolysis

MicroRNA-224 Promotes Pancreatic Cancer Cell Proliferation and Migration by Targeting the TXNIP-Mediated HIF1α Pathway

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