Ubiquitination of Rheb governs growth factor-induced mTORC1 activation

Deng, Lu; Chen, Lei; Zhao, Linlin; Yan, Xu; Peng, Xiao-Ping; Wang, Xinbo; Ding, Lin; Jin, Jiali; Teng, Hongqi; Wang, Yanming; Pan, Weijuan; Yu, Fei; Liao, Lujian; Li, Li; Ge, Xin; Wang, Ping

doi:10.1038/s41422-018-0120-9

Cited by 88 publications

(87 citation statements)

References 59 publications

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“…The results showed that serum‐starved MEF cells treated with lactate disrupted the TSC2 and Rheb interaction in a dose‐dependent manner (Fig EV3D), which is consistent with the dose‐dependent effects of lactate on mTORC1 activation (Fig EV2F). The level of the Rheb‐GTP response to growth factor withdrawal and insulin stimulation and the interaction of TSC2 with Rheb under serum‐starved conditions are consistent with previous findings (Fig EV3E and F). We further confirmed that 20 mM lactate disrupted the TSC2 and Rheb interaction in serum‐starved HCT116 cells (Figs C and EV3G).…”

Section: Resultssupporting

confidence: 92%

Oncogenic KRAS signaling activates mTORC1 through COUP‐TFII‐mediated lactate production

et al. 2019

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Oncogenic signals contribute to enhanced glycolysis and mTORC1 activity, leading to rapid cell proliferation in cancer. Regulation of glycolysis and mTORC1 by PI3K/Akt signaling is well established, but how KRAS‐induced MEK signaling regulates these pathways remains poorly understood. Here, we report a role for MEK‐driven lactate production in mTORC1 activation in KRAS‐activated cells. KRAS/MEK‐induced upregulation of the chicken ovalbumin upstream promoter transcriptional factor II (COUP‐TFII) increases the expression of lactate dehydrogenase A (LDHA), resulting in lactate production and mTORC1 activation. Further, lactate inhibits the interaction of TSC2 and Rheb, leading to the cellular activation of mTORC1 irrespective of growth factor stimulation. These findings suggest that COUP‐TFII is a novel oncogenic mediator, connecting KRAS signaling and glycolysis, and leading to mTORC1 activation and cellular growth.

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Section: Resultssupporting

confidence: 92%

Oncogenic KRAS signaling activates mTORC1 through COUP‐TFII‐mediated lactate production

et al. 2019

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“…2a). 150 Ubiquitination in the adenylate-activated protein kinase signaling pathway Adenylate-activated protein kinase (AMPK), the master sensor of energy in cells and organisms, is the core in regulating intracellular metabolic homeostasis, and its mutation is associated with tumorigenesis. 151,152 When the cellular level of ATP decreases and AMP/ATP increases, the activation of AMPK increases.…”

Section: Ubiquitination In Tumor Metabolism Regulationmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

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464

308

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Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI-219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.Signal Transduction and Targeted Therapy (2020) 5:11; https://doi.

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“…The results showed that expression of most of the genes was not affected by the presence or absence of Shh (Figure 4A). However, RNF152 , which encodes an E3 ubiquitin ligase (Deng et al, 2019; Deng et al, 2015), was strongly induced in Shh H explants with a weaker induction with Shh L , suggesting that RNF152 was expressed preferentially in the FP.…”

Section: Resultsmentioning

confidence: 99%

“…The RNF152 gene encodes an E3 ubiquitin ligase targeting the small GTPase RagA (Deng et al, 2019; Deng et al, 2015; Kim et al, 2008), and the GTP-bound active form of RagA positively regulates the mTOR signalling pathway (Efeyan et al, 2014; Shaw, 2008). Actually the expression of the dominant-negative RagA (DN-RagA) blocks cell proliferation in the electroporated cells while the constitutively-active RagA (CA-RagA) activates it, without changing the FP cell fate (Supplementary Figure 2).…”

Section: Resultsmentioning

confidence: 99%

“…RNF152, a lysosome-anchored E3 ubiquitin ligase (Deng et al, 2019; Zhang et al, 2010) containing RING-finger and transmembrane domains, was initially thought to induce apoptosis (Zhang et al, 2010). Further study showed that RNF152 ubiquitinates and targets the GDP-bound form of RagA for degradation, thereby negatively regulates mTOR signalling (Deng et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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RNF152 Negatively Regulates mTOR Signalling and Blocks Cell Proliferation in the Floor Plate

Kadoya

Sasai

2019

Preprint

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21The neural tube is composed of a number of neural progenitors and postmitotic neurons 22 distributed in a quantitatively and spatially precise manner. The floor plate, located in the ventral-23 most region of the neural tube, has a lot of unique characteristics, including a low cell proliferation 24 rate. The mechanisms by which this region-specific proliferation rate is regulated remain elusive. 25Here we show that the activity of the mTOR signalling pathway, which regulates the 26 proliferation of the neural progenitor cells, is significantly lower in the floor plate than in other 27 domains of the embryonic neural tube. We identified the forkhead-type transcription factor FoxA2 as 28 a negative regulator of mTOR signalling in the floor plate. We demonstrate that FoxA2 29 transcriptionally induces the expression of the E3 ubiquitin ligase RNF152, which together with its 30 substrate RagA, regulates cell proliferation via the mTOR pathway. Silencing of RNF152 led to the 31 aberrant upregulation of the mTOR signal and aberrant cell division in the floor plate. Taken together, 32 the present findings suggest that floor plate cell number is controlled by the negative regulation of 33 mTOR signalling through the activity of FoxA2 and its downstream effector RNF152.34 35

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Ubiquitination of Rheb governs growth factor-induced mTORC1 activation

Cited by 88 publications

References 59 publications

Oncogenic KRAS signaling activates mTORC1 through COUP‐TFII‐mediated lactate production

Oncogenic KRAS signaling activates mTORC1 through COUP‐TFII‐mediated lactate production

The role of ubiquitination in tumorigenesis and targeted drug discovery

RNF152 Negatively Regulates mTOR Signalling and Blocks Cell Proliferation in the Floor Plate

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