Amino acid-dependent NPRL2 interaction with Raptor determines mTOR Complex 1 activation

Kwak, Sang Su; Kang, Kyung‐Hwa; Kim, Se-Yun; Lee, Seoeun; Lee, Jeung‐Hoon; Kim, Jin Woo; Byun, Boohyeong; Meadows, Gary G.; Joe, Cheol O.

doi:10.1016/j.cellsig.2015.11.008

Cited by 11 publications

(9 citation statements)

References 27 publications

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“…Given that NPRL2 can cause the acidification of the mTORC1 complex on the lysosomal surface, we tested whether NPLR2 can regulate the mTOR signaling in PC3 and LNPER cells. In comparison with that the control (non‐lentivirus treated, NV, or EV), NPRL2 silencing significantly increased the relative levels of mTOR and S6K phosphorylation while NPRL2 over‐expression dramatically decreased their phosphorylation in PC3 and LNPER cells (Figure ).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, the enhanced autophagy by NPRL2 may be mediated by its inhibition of the mTOR activation as the mTOR signaling is a negative regulator of autophagy, but the precise mechanism of NPRL2 enhancing autophagy through m‐TOR signaling warrant further exploration. Alternatively, the enhanced autophagy may stem from NPRL2‐dependent TFEB‐mediated lysosomal biogenesis in PCa cells . More importantly, the growth inhibition effect of NPRL2 in vitro and in vivo (Figure C and Figure B) suggests that NPRL2 may be a new therapeutic target for intervention of CRPC.…”

Section: Discussionmentioning

confidence: 99%

“…Nitrogen permease regulator‐like 2 (NPRL2) is known as tumor‐suppressor candidate 4 (TUSC4) . Previous studies have shown that NPRL2 in the GATOR1 complex inhibits the mTOR signaling . It is well known that the mTORC1 negatively regulates autophagy, a conserved process to maintain homeostasis by recycling macromolecules and organelles to form double‐membrane autophagosome vesicles .…”

Section: Introductionmentioning

confidence: 99%

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NPRL2 enhances autophagy and the resistance to Everolimus in castration‐resistant prostate cancer

et al. 2018

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NPRL2 enhances autophagy and the resistance to Everolimus in castration‐resistant prostate cancer

et al. 2018

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“…A recent study in tissue culture has found that dependent on the phosphorylation status of NPRL2 and amino acid availability, NPLR2 binds either to Raptor, which will activate mTORC1 when there are plentiful amino acids and NPRL2 is phosphorylated. When NPRL2 is dephosphorylated and amino acids are scarce, it will bind to RagGTPases, which will inhibit mTORC1 leading to activation of ULK1 and therefore autophagy (Kwak et al, 2016). Furthermore, we and others have found an important role for S-adenosyl-methionine (SAM) in this regard, as SAM is used as methyl group donor in the methylation catalyzed by LCMT1 (Sutter et al, 2013; Schmeisser and Parker, 2018).…”

Section: Pleiotropic Effects Of Mtor-dependent Autophagy In Neurodegementioning

confidence: 99%

“…mTORC1 consists of three major components – mTOR, Raptor (regulatory protein associated with mTOR), and mLST8 (mammalian lethal with Sec13 protein 8, also known as GßL) (Hara et al, 2002; Kim et al, 2002, 2003). Raptor binds to the TOR signaling motif on several mTORC1 substrates (such as S6 kinase, 4E-BP1, and NPRL2, as described later), therefore facilitating substrate recruitment to mTORC1 (Nojima et al, 2003; Kwak et al, 2016). mLST8, however, is associated with the catalytic domain of mTORC1 and may stabilize the kinase activation loop (Yang et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Pleiotropic Effects of mTOR and Autophagy During Development and Aging

Schmeißer

Parker

2019

Front. Cell Dev. Biol.

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Autophagy as a ubiquitous catabolic process causes degradation of cytoplasmic components and is generally considered to have beneficial effects on health and lifespan. In contrast, inefficient autophagy has been linked with detrimental effects on the organism and various diseases, such as Parkinson’s disease. Previous research, however, showed that this paradigm is far from being black and white. For instance, it has been reported that increased levels of autophagy during development can be harmful, but become advantageous in the aging cell or organism, causing enhanced healthspan and even longevity. The antagonistic pleiotropy hypothesis postulates that genes, which control various traits in an organism, can be fitness-promoting in early life, but subsequently trigger aging processes later. Autophagy is controlled by the mechanistic target of rapamycin (mTOR), a key player of nutrient sensing and signaling and classic example of a pleiotropic gene. mTOR acts upstream of transcription factors such as FOXO, NRF, and TFEB, controlling protein synthesis, degradation, and cellular growth, thereby regulating fertility as well as aging. Here, we review recent findings about the pleiotropic role of autophagy during development and aging, examine the upstream factors, and contemplate specific mechanisms leading to disease, especially neurodegeneration.

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RAPTOR promotes colorectal cancer proliferation by inducing mTORC1 and upregulating ribosome assembly factor URB1

et al. 2019

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Mammalian target of rapamycin complex 1 (mTORC1) is evolutionally conserved and frequently activated in various tumors, including colorectal cancer (CRC). It has been reported that the ribosome assembly factor Urb1 acts downstream of mTORC1/raptor signaling and contributes to digestive organ development in zebrafish. Previously, we highlighted that URB1 was overexpressed in CRC. Here, we assessed the mTORC1/regulatory associated protein with mTOR (RAPTOR)‐URB1 axis in CRC tumorigenesis. We found that RAPTOR was overexpressed in CRC tissues and cell lines, was a favorable predictor in patients with CRC, and positively correlated with URB1. Silencing of RAPTOR suppressed CRC cell proliferation and migration and induced cell cycle arrest and apoptosis in vitro and inhibited xenograft growth in vivo. Moreover, ectopic overexpression of RAPTOR exerted an inverse biological phenotype. Knockdown of RAPTOR quenched mTORC1 activity and reduced the expression of URB1 and cyclinA2 (CCNA2). In contrast, overexpression of RAPTOR activated mTORC1 and upregulated URB1 and CCNA2. Furthermore, URB1 and CCNA2 expression were also impeded by rapamycin, which is a specific inhibitor of mTORC1. Thus, RAPTOR promoted CRC proliferation, migration, and cell cycle progression by inducing mTORC1 signaling and transcriptional activation of both URB1 and CCNA2. Taken together, we concluded that RAPTOR has the potential to serve as a novel biomarker and therapeutic target for CRC.

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Amino acid-dependent NPRL2 interaction with Raptor determines mTOR Complex 1 activation

Cited by 11 publications

References 27 publications

NPRL2 enhances autophagy and the resistance to Everolimus in castration‐resistant prostate cancer

NPRL2 enhances autophagy and the resistance to Everolimus in castration‐resistant prostate cancer

Pleiotropic Effects of mTOR and Autophagy During Development and Aging

RAPTOR promotes colorectal cancer proliferation by inducing mTORC1 and upregulating ribosome assembly factor URB1

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