VWCE modulates amino acid-dependent mTOR signaling and coordinates with KICSTOR to recruit GATOR1 to the lysosomes

Zhao, Tianyu; Guan, Yuanyuan; Xu, Chenchen; Wang, Dong; Guan, Jialiang; Liu, Ying

doi:10.1038/s41467-023-44241-8

Cited by 2 publications

(1 citation statement)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, there exist studies associating this gene with diverse types of neoplasms [ 25 ]. For instance, it was found to be downregulated in breast and prostate cancers, where it functions as a tumor suppressor [ 26 , 27 ]. Interestingly, another project report mentioned the observation of VWCE overexpression in cervical cancer [ 28 ], which aligns with our findings.…”

Section: Resultsmentioning

confidence: 99%

Gene Expression Analysis for Uterine Cervix and Corpus Cancer Characterization

Almorox,

Antequera,

Rojas

et al. 2024

Genes

View full text Add to dashboard Cite

The analysis of gene expression quantification data is a powerful and widely used approach in cancer research. This work provides new insights into the transcriptomic changes that occur in healthy uterine tissue compared to those in cancerous tissues and explores the differences associated with uterine cancer localizations and histological subtypes. To achieve this, RNA-Seq data from the TCGA database were preprocessed and analyzed using the KnowSeq package. Firstly, a kNN model was applied to classify uterine cervix cancer, uterine corpus cancer, and healthy uterine samples. Through variable selection, a three-gene signature was identified (VWCE, CLDN15, ADCYAP1R1), achieving consistent 100% test accuracy across 20 repetitions of a 5-fold cross-validation. A supplementary similar analysis using miRNA-Seq data from the same samples identified an optimal two-gene miRNA-coding signature potentially regulating the three-gene signature previously mentioned, which attained optimal classification performance with an 82% F1-macro score. Subsequently, a kNN model was implemented for the classification of cervical cancer samples into their two main histological subtypes (adenocarcinoma and squamous cell carcinoma). A uni-gene signature (ICA1L) was identified, achieving 100% test accuracy through 20 repetitions of a 5-fold cross-validation and externally validated through the CGCI program. Finally, an examination of six cervical adenosquamous carcinoma (mixed) samples revealed a pattern where the gene expression value in the mixed class aligned closer to the histological subtype with lower expression, prompting a reconsideration of the diagnosis for these mixed samples. In summary, this study provides valuable insights into the molecular mechanisms of uterine cervix and corpus cancers. The newly identified gene signatures demonstrate robust predictive capabilities, guiding future research in cancer diagnosis and treatment methodologies.

show abstract

Section: Resultsmentioning

confidence: 99%

Gene Expression Analysis for Uterine Cervix and Corpus Cancer Characterization

Almorox,

Antequera,

Rojas

et al. 2024

Genes

View full text Add to dashboard Cite

show abstract

Rag–Ragulator is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway

Valenstein,

Lalgudi,

et al. 2024

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

View full text Add to dashboard Cite

The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates cell growth and metabolism in response to many environmental cues, including nutrients. Amino acids signal to mTORC1 by modulating the guanine nucleotide loading states of the heterodimeric Rag GTPases, which bind and recruit mTORC1 to the lysosomal surface, its site of activation. The Rag GTPases are tethered to the lysosome by the Ragulator complex and regulated by the GATOR1, GATOR2, and KICSTOR multiprotein complexes that localize to the lysosomal surface through an unknown mechanism(s). Here, we show that mTORC1 is completely insensitive to amino acids in cells lacking the Rag GTPases or the Ragulator component p18. Moreover, not only are the Rag GTPases and Ragulator required for amino acids to regulate mTORC1, they are also essential for the lysosomal recruitment of the GATOR1, GATOR2, and KICSTOR complexes, which stably associate and traffic to the lysosome as the “GATOR” supercomplex. The nucleotide state of RagA/B controls the lysosomal association of GATOR, in a fashion competitively antagonized by the N terminus of the amino acid transporter SLC38A9. Targeting of Ragulator to the surface of mitochondria is sufficient to relocalize the Rags and GATOR to this organelle, but not to enable the nutrient-regulated recruitment of mTORC1 to mitochondria. Thus, our results reveal that the Rag–Ragulator complex is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway and underscore that mTORC1 activation requires signal transduction on the lysosomal surface.

show abstract

VWCE modulates amino acid-dependent mTOR signaling and coordinates with KICSTOR to recruit GATOR1 to the lysosomes

Cited by 2 publications

References 17 publications

Gene Expression Analysis for Uterine Cervix and Corpus Cancer Characterization

Gene Expression Analysis for Uterine Cervix and Corpus Cancer Characterization

Rag–Ragulator is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway

Contact Info

Product

Resources

About