The TMEM127 human tumor suppressor is a component of the mTORC1 lysosomal nutrient-sensing complex
Open accessAbstract
The TMEM127 tumor suppressor gene encodes a transmembrane protein of unknown function mutated in pheochromocytomas and, rarely, in renal cancers. Tumors with inactivating TMEM127 mutations have increased mTORC1 signaling by undefined mechanisms. Here we report that TMEM127 interacts with the lysosome-anchored complex comprised of Rag GTPases, the LAMTOR pentamer (or 'ragulator') and vATPase, which controls amino acid-mediated mTORC1 activation. We found that under nutrient-rich conditions TMEM127 expression reduces mTORC1 recruitment to Rags. In addition, TMEM127 interacts with LAMTOR in an amino acid-dependent manner and decreases the LAMTOR1-vATPase association, while TMEM127-vATPase binding requires intact lysosomal acidification but is amino acid independent. Conversely, both murine and human cells lacking TMEM127 accumulate LAMTOR proteins in the lysosome. Consistent with these findings, pheochromocytomas with TMEM127 mutations have increased levels of LAMTOR proteins. These results suggest that TMEM127 interactions with ragulator and vATPase at the lysosome contribute to restrain mTORC1 signaling in response to amino acids, thus explaining the increased mTORC1 activation seen in TMEM127-deficient tumors.
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TMEM55B and TMEM127 appear to support the stability of the Ragulator-v-ATPase assembly.
“TMEM55B and TMEM127 appear to support the stability of the Ragulator-v-ATPase assembly (Hashimoto et al., 2018; Deng et al., 2018)”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Deng et al., 2018
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Signal integration in the (m)TORC1 growth pathway
Ramlaul, K., & Aylett, C. H. S. (2018) · Frontiers in Biology · doi:10.1007/s11515-018-1501-7 · Cited by 12 · see citing works
- Authors
- Deng, Y., Qin, Y., Srikantan, S., Luo, A., Cheng, Z.-M., Flores, S. K., Vogel, K. S., Wang, E., & Dahia, P. L. M.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Dahia, Patricia L M
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-03-14
- Volume
- 27
- Issue
- 10
- Pages
- 1794-1808
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC5932569
- OpenAlex
- W2790915104
- Cited by
- 25
- References
- 51
- Citations by year
- 2025: 1 · 2024: 5 · 2023: 6 · 2022: 2 · 2021: 2 · 2020: 5 · 2019: 3 · 2018: 1
- FWCI
- 0.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Prevention and Research Institute of Texas (RP101202 and RP140473)
- CPRIT (RP140105)
- Department of Defense (W81XWH-12-1-0508)
- NIH (GM114102, P01-AG19316)
- NIA (T32AG021890)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- TMEM127, tumor suppressor, mTORC1 signaling, lysosomes, Ragulator complex, amino acid sensing, nutrient sensing, pheochromocytoma, kidney cancer, lysosomal acidification, protein-protein interaction
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Adrenal Gland Neoplasms, Amino Acids, Animals, Carrier Proteins, Gene Expression Regulation, Humans, Lysosomes, Membrane Proteins, Mutation, Pheochromocytoma, Signal Transduction, Genes, Tumor Suppressor, Multiprotein Complexes, Intracellular Signaling Peptides and Proteins, Mice
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