Non-canonical mTORC1 signaling at the lysosome

Napolitano, Gennaro; Malta, Chiara Di; Ballabio, Andrea

doi:10.1016/j.tcb.2022.04.012

Cited by 75 publications

(73 citation statements)

References 120 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Taken together, FLCN directly and selectively controls mTORC1 regulation of MiT-TFE members but not other substrates ( 10, 11 ). These findings support the existence of separate mechanisms for control of mTORC1-dependent anabolic versus catabolic programs ( 22 ), and highlight a therapeutic potential for FLCN to be targeted as a means of mTOR inhibition for treating LSDs and neurodegenerative diseases, with fewer toxic effects on cell proliferation and translation.…”

supporting

confidence: 73%

See 1 more Smart Citation

Structural basis for FLCN RagC GAP activation in TFEB substrate-selective mTORC1 regulation

Jansen

Peruzzo

Fromm

et al. 2022

Preprint

View full text Add to dashboard Cite

AbstractmTORC1 regulates cell growth and catabolism in response to fluctuations in nutrients through phosphorylation of key substrates. The tumor suppressor FLCN is a RagC/D GTPase activating protein (GAP) that regulates mTORC1 phosphorylation of MiT-TFE family transcription factors, controlling lysosome biogenesis and autophagy. Here, we determined the cryo-EM structure of the active FLCN complex (AFC) containing FLCN, FNIP2, the N-terminal tail of SLC38A9, the RagAGDP:RagCGDP.BeFx- GTPase dimer, and the Ragulator scaffold. Relative to the inactive lysosomal FLCN complex (LFC) structure, FLCN reorients by 90°, breaks its contacts with RagA, and makes new contacts with RagC that position its Arg164 finger for catalysis. Disruption of the AFC-specific interfaces of FLCN and FNIP2 with RagC eliminated GAP activity in vitro and led to nuclear retention of the MiT-TFE family member TFE3, with no effect on mTORC1 phosphorylation of S6K or 4E-BP1. The structure thus provides a structural basis for the regulation of an mTORC1 substrate-specific pathway and a roadmap to discover MiT-TFE family selective mTORC1 antagonists.

show abstract

supporting

confidence: 73%

“…We sought to further explore FLCN specificity for RagC by understanding why GATOR1 does not function as a GAP for RagC. We modelled RagC with GATOR1 and observed residues in GATOR1 (Thr 18 and Pro 19 ) that clashed with RagC at the interface (Fig. S6B).…”

Section: Resultsmentioning

confidence: 99%

Structural basis for FLCN RagC GAP activation in TFEB substrate-selective mTORC1 regulation

Jansen

Peruzzo

Fromm

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…mTORC1 function is highly reliant on its physical recruitment to the lysosomal membrane, which is dependent on the activity of Rag GTPase heterodimeric complexes (RagA/B and RagC/D) and the pentameric lysosomal complex Ragulator. 4 RagA/B must be in the GTP-bound state for mTORC1 to be recruited to the lysosomal surface. RagC/D contributes to dimer formation, although its GTP/GDP-binding state is less important for mTORC1 lysosomal recruitment.…”

mentioning

confidence: 99%

“…Several cytoplasmic amino acid sensors, including Sestrin2, CASTOR1, and SAMTOR, sense intracellular amino-acid levels and transmit their information to mTORC1 via GATOR complexes. The solute carrier SLC38A9 facilitates intralysosomal amino acid level sensing, and the lysosomal v-ATPase complex is necessary for the preservation of the lysosomal proton gradient 4 (Fig. 1 ).…”

mentioning

confidence: 99%

“…Rheb binding to mTORC1 induces profound conformational changes that result in the activation of the canonical mTORC1 substrates S6 kinase (S6K) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). 3 , 4 Briefly, in response to upstream stimulations, activation of mTORC1 and canonical substrate phosphorylation need nutrient-stimulated Rag activity and GF-dependent Rheb activation (Fig. 1 ).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Targeting folliculin to selectively inhibit mTORC1: a promising strategy for treating nonalcoholic fatty liver disease

Ling

2022

Sig Transduct Target Ther

View full text Add to dashboard Cite

Diet predisposes to pancreatic cancer through cellular nutrient sensing pathways

Noè,

Carrer

2024

FEBS Letters

View full text Add to dashboard Cite

Pancreatic cancer is a lethal disease with limited effective treatments. A deeper understanding of its molecular mechanisms is crucial to reduce incidence and mortality. Epidemiological evidence suggests a link between diet and disease risk, though dietary recommendations for at‐risk individuals remain debated. Here, we propose that cell‐intrinsic nutrient sensing pathways respond to specific diet‐derived cues to facilitate oncogenic transformation of pancreatic epithelial cells. This review explores how diet influences pancreatic cancer predisposition through nutrient sensing and downstream consequences for (pre‐)cancer cell biology. We also examine experimental evidence connecting specific food intake to pancreatic cancer progression, highlighting nutrient sensing as a promising target for therapeutic development to mitigate disease risk.

show abstract

Non-canonical mTORC1 signaling at the lysosome

Cited by 75 publications

References 120 publications

Structural basis for FLCN RagC GAP activation in TFEB substrate-selective mTORC1 regulation

Structural basis for FLCN RagC GAP activation in TFEB substrate-selective mTORC1 regulation

Targeting folliculin to selectively inhibit mTORC1: a promising strategy for treating nonalcoholic fatty liver disease

Diet predisposes to pancreatic cancer through cellular nutrient sensing pathways

Contact Info

Product

Resources

About