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Substrate-selective mTORC1 regulation and gene dosage-dependent tissue divergence in Birt-Hogg-Dubé syndrome

Cao ZL, Zhao SC, Lin F, Liu YH, Hong XT, Hong LY, Xu LQ, Li FP, Yu HY, Yao WG, Chen WY · 2026 · Frontiers in Oncology · Atlas ID CAO2026

What this study shows

Reframes Birt-Hogg-Dube (BHD) syndrome beyond the classic 'global mTORC1 hyperactivation' model: FLCN acts as a GAP for RagC/D, giving substrate-selective (not global) mTORC1 control. Biallelic FLCN loss drives kidney tumors via MiT/TFE nuclear accumulation, while haploinsufficiency alone is sufficient for lung and skin lesions -- resolving the 'mTORC1 paradox' via gene dosage and signaling timing. Narrative synthesis of human genetics and mouse mechanistic data.

Abstract

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Birt-Hogg-Dube (BHD) syndrome, caused by mutations in the tumor suppressor gene, has traditionally been classified as a classic 'mTORopathy' characterized by global mTORC1 activation. Recent structural and multi-omic studies have fundamentally challenged this view, revealing that FLCN functions as a GAP for RagC/D to govern substrate-selective mTORC1 regulation.

Read the full abstract on PubMed →

At a glance

Evidence type R Review — secondary literature, not a new result Marked R because it is a review or synthesis of existing evidence rather than a new primary result; that is a different form of writing, not a weaker one.
Study typeNarrative Review
Model systemNarrative synthesis (human genetics + mouse mechanistic data)
JournalFrontiers in Oncology
Year2026
Peer reviewedYes
Record last updated2026-08-22
SourceDOI 10.3389/fonc.2026.1848740 · PMID 42558438 · Free full text (PMC13437482)

Extracted findings

TargetFLCN / RagC-RagD / mTORC1 / MiT-TFE

Cite this paper

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Cao, Z. L., Zhao, S. C., Lin, F., Liu, Y. H., Hong, X. T., Hong, L. Y., Xu, L. Q., Li, F. P., Yu, H. Y., Yao, W. G., & Chen, W. Y. (2026). Substrate-selective mTORC1 regulation and gene dosage-dependent tissue divergence in Birt-Hogg-Dubé syndrome. Frontiers in Oncology. https://doi.org/10.3389/fonc.2026.1848740

@article{CAO2026,
  author       = {Cao, Z. L. and Zhao, S. C. and Lin, F. and Liu, Y. H. and Hong, X. T. and Hong, L. Y. and Xu, L. Q. and Li, F. P. and Yu, H. Y. and Yao, W. G. and Chen, W. Y.},
  title        = {{Substrate-selective mTORC1 regulation and gene dosage-dependent tissue divergence in Birt-Hogg-Dubé syndrome}},
  journal      = {Frontiers in Oncology},
  year         = {2026},
  doi          = {10.3389/fonc.2026.1848740},
  note         = {PMID: 42558438},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper. 

Barton, O. (2026). Oliver's mTOR Atlas (record CAO2026) [Data set]. https://mtor-atlas.org/study/CAO2026/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_CAO2026,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record CAO2026},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/CAO2026/},
  doi          = {10.5281/zenodo.22059963}
}