ArticleHuman molecular genetics2019
Loss of FLCN inhibits canonical WNT signaling via TFE3.
Article in Human molecular genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 26 citations in OpenAlex.
- Review
- Differential contribution of TFE3 isoforms to cell motility and invasion.EMBO reports · 2026Article
- Familial analysis: pulmonary Birt-Hogg-Dubé syndrome in two siblings.BMJ case reports · 2025Article
- Clinic Examination and Gene Diagnosis for a Birt-Hogg-Dubé Syndrome Family With a NovelHuman mutation · 2025Article
- The Spectrum of Renal "TFEopathies": Flipping the mTOR Switch in Renal Tumorigenesis.Physiology (Bethesda, Md.) · 2024Review
- Familial multiple discoid fibromas is linked to a locus on chromosome 5 including the FNIP1 gene.Journal of human genetics · 2023Article
- Inhibition of nonalcoholic fatty liver disease in mice by selective inhibition of mTORC1.Science (New York, N.Y.) · 2022Article
- Long noncoding RNA LINC01606 protects colon cancer cells from ferroptotic cell death and promotes stemness by SCD1-Wnt/β-catenin-TFE3 feedback loop signalling.Clinical and translational medicine · 2022Article
- Bibliometric Analysis of Birt-Hogg-Dubé Syndrome From 2001 to 2021.Frontiers in medicine · 2022Article
- Folliculin: A Regulator of Transcription Through AMPK and mTOR Signaling Pathways.Frontiers in cell and developmental biology · 2021Review
- Birt-Hogg-Dubé syndrome.European respiratory review : an official journal of the European Respiratory Society · 2020Article
- Ultra-rare cystic disease.European respiratory review : an official journal of the European Respiratory Society · 2020Article
- Folliculin Interacting Protein 1 Maintains Metabolic Homeostasis during B Cell Development by Modulating AMPK, mTORC1, and TFE3.Journal of immunology (Baltimore, Md. : 1950) · 2019Article
- Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex.Science (New York, N.Y.) · 2019Article
- FLCN regulates transferrin receptor 1 transport and iron homeostasis.The Journal of biological chemistryArticle
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Authors and funding
6 authors at 3 institutions in 1 country.
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Abstract
Lower lobe predominant pulmonary cysts occur in up to 90% of patients with Birt-Hogg-Dubé (BHD) syndrome, but the key pathologic cell type and signaling events driving this distinct phenotype remain elusive. Through examination of the LungMAP database, we found that folliculin (FLCN) is highly expressed in neonatal lung mesenchymal cells. Using RNA-Seq, we found that inactivation of Flcn in mouse embryonic fibroblasts leads to changes in multiple Wnt ligands, including a 2.8-fold decrease in Wnt2. This was associated with decreased TCF/LEF activity, a readout of canonical WNT activity, after treatment with a GSK3-α/β inhibitor. Similarly, FLCN deficiency in HEK293T cells decreased WNT pathway activity by 76% post-GSK3-α/β inhibition. Inactivation of FLCN in human fetal lung fibroblasts (MRC-5) led to ~ 100-fold decrease in Wnt2 expression and a 33-fold decrease in Wnt7b expression-two ligands known to be necessary for lung development. Furthermore, canonical WNT activity was decreased by 60%. Classic WNT targets such as AXIN2 and BMP4, and WNT enhanceosome members including TCF4, LEF1 and BCL9 were also decreased after GSK3-α/β inhibition. FLCN-deficient MRC-5 cells failed to upregulate LEF1 in response to GSK3-α/β inhibition. Finally, we found that a constitutively active β-catenin could only partially rescue the decreased WNT activity phenotype seen in FLCN-deficient cells, whereas silencing the transcription factor TFE3 completely reversed this phenotype. In summary, our data establish FLCN as a critical regulator of the WNT pathway via TFE3 and suggest that FLCN-dependent defects in WNT pathway developmental cues may contribute to lung cyst pathogenesis in BHD.
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