Summary: Folliculin C-terminal domain
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Folliculin Edit Wikipedia article
|, BHD, FLCL, Folliculin|
Folliculin also known as FLCN, Birt-Hogg-Dubé syndrome protein or FLCN_HUMAN is a protein that in humans is associated with Birt-Hogg-Dubé syndrome and hereditary spontaneous pneumothorax. It is encoded by the Folliculin (FLCN) gene (alias BHD, FLCL) that acts as a tumor suppressor gene. Tumor suppressors help control the growth and division of cells.
- 1 Gene
- 2 Function
- 2.1 Interactions
- 2.2 FLCN phosphorylation
- 2.3 Proposed functions of FLCN
- 2.3.1 Regulation of the AKT-mTOR pathway
- 2.3.2 mTORC1 activation on the lysosome
- 2.3.3 Control of TFE3/TFEB transcriptional activation
- 2.3.4 Regulation of PGC-1α and mitochondrial biogenesis
- 2.3.5 Maintenance of cell-cell adhesions and regulation of RhoA signaling
- 2.3.6 Ciliogenesis and cilia-dependent flow sensory mechanisms
- 2.3.7 Other potential functions of FLCN
- 3 References
- 4 Further reading
- 5 External links
Molecular Location on chromosome 17: base pairs 17,056,252 to 17,081,230 (NCI Build 36.1)
Germline mutations in the FLCN gene cause Birt-Hogg-Dubé syndrome (BHD), an autosomal dominant disease that predisposes individuals to develop benign tumors of the hair follicle called fibrofolliculomas, lung cysts, spontaneous pneumothorax, and an increased risk for kidney tumors. FLCN mutations have also been found in the germline of patients with inherited spontaneous pneumothorax and no other clinical manifestations. 
In a risk assessment performed in affected and unaffected members of BHD families, the odds ratio for developing kidney tumors in a person affected with BHD was 6.9 times greater than his unaffected siblings. The odds ratio for spontaneous pneumothorax in BHD affected individuals, when adjusted for age, was 50.3 times greater than unaffected family members.
Birt-Hogg-Dubé syndrome was originally described by three Canadian physicians in a family in which 15 of 70 members over 3 generations exhibited a triad of dermatological lesions (fibrofolliculomas, trichodiscomas and acrochordons). Subsequently, cosegregation of kidney neoplasms with BHD cutaneous lesions was observed in 3 families with a family history of kidney tumors, suggesting that kidney tumors may be part of the BHD syndrome phenotype. In order to identify the genetic locus for BHD syndrome, genetic linkage analysis was performed in families recruited on the basis of BHD cutaneous lesions.  A region spanning chromosome 17p11 was identified and mutations in a novel gene, FLCN, were subsequently found in the germline of individuals affected with BHD syndrome.
The FLCN gene encodes a novel 64 kDa protein, FLCN, which is highly conserved across species. The majority of germline FLCN mutations identified in BHD patients are loss-of-function mutations including frameshift mutations (insertion/deletion), nonsense mutations, and splice site mutations that are predicted to inactivate the FLCN protein, although some missense mutations have been reported that exchange one nucleotide for another and consequently result in a different amino acid at the mutation site. Most mutations are identified by DNA sequencing. With the advent of multiplex ligation-dependent probe amplification (MLPA) technology, partial deletions of the FLCN gene have also been identified  permitting a FLCN mutation detection rate in BHD cohorts that approaches 90%. Very few FLCN mutations have been found in association with sporadic kidney tumors indicating that FLCN mutation may play only a minor role in non-inherited kidney cancer.
Experimental evidence supports a role for FLCN as a tumor suppressor gene. In BHD-associated kidney tumors, the inherited FLCN gene with a germline mutation is present in all cells, but the remaining wild type copy is inactivated in the tumor cells through somatic mutation or loss of heterozygosity. Naturally-occurring dog and rat models with germline Flcn mutations develop kidney tumors that retain only the mutant copy of the gene. Homozygous inactivation of Flcn in these animal models is lethal to the embryo. Tumors develop in mice injected with FLCN-deficient kidney cancer cells from BHD-associated human tumors but when wild type FLCN is restored in these cells, tumor development is inhibited. Additionally, injection of kidney tumor cells from the adenocarcinoma cell line ACHN with FLCN inactivation into immunocompromised mice resulted in the growth of significantly larger tumors, further underscoring a tumor suppressor role for FLCN. Based on the presence of FLCN staining by immunohistochemistry, haploinsufficiency, that is mutation of one copy of FLCN with retention of the wild type copy, may be sufficient for the development of fibrofolliculomas and lung cysts.
FLCN has been shown to interact through its C-terminus with two novel proteins, folliculin interacting protein 1 (FNIP1) and folliculin interacting protein 2 (FNIP2/FNIPL) , and indirectly through FNIP1 and FNIP2 with AMP-activated protein kinase (AMPK). AMPK is an important energy sensor in cells and negative regulator of mechanistic target of rapamycin (mTOR)  suggesting that FLCN and FNIP1 may play a role in modulating mTOR activity through energy or nutrient sensing pathways. Coimmunoprecipitation experiments with FNIP1 and FLCN expressed in HEK293 cells and in vitro binding assays have shown that the C-terminus of FLCN and amino acids 300 to 1166 of FNIP1 are required for optimal FLCN-FNIP1 binding. FLCN and FNIP1 colocalized to the cytoplasm in a reticular pattern.
FLCN phosphorylation was diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, suggesting that FLCN phosphorylation may be regulated by mTOR and AMPK signaling. FNIP1 was phosphorylated by AMPK and its phosphorylation was inhibited in a dose-dependent manner by an AMPK inhibitor, resulting in reduced FNIP1 expression. FLCN has multiple phosphorylation sites including serine 62, which are differentially affected by FNIP1 binding and by inhibitors of mTOR and AMPK. The significance of this modification, however, is unknown.
Proposed functions of FLCN
Several pathways in which FLCN plays a role as a tumor suppressor have been identified, but it remains to be determined which of these pathways when dysregulated leads to the cutaneous, lung and kidney phenotypes associated with Birt-Hogg-Dubé syndrome.
Regulation of the AKT-mTOR pathway
Work with Flcn-deficient mouse models suggests a role for FLCN in regulating the AKT-mechanistic target of rapamycin (mTOR) signaling pathway, but the results are conflicting. mTOR activation was seen in the highly cystic kidneys that developed in mice with kidney-targeted inactivation of Flcn.  Elevated AKT and phospho-AKT proteins, and activation of mTORC1 and mTORC2 were observed in late-onset tumors that developed in aged Flcn heterozygous mice subsequent to loss of the remaining Flcn wild type allele, and in FLCN-deficient kidney tumors from BHD patients. On the other hand, mTOR inhibition was demonstrated in smaller cysts (although mTOR activation was seen in larger cysts) that developed in Flcn heterozygous knockout mice generated with a gene trapping approach. N-ethyl-N-nitrosourea (ENU) mutagenesis of another Flcn heterozygous mouse model produced tumors with reduced mTOR activity. Evidence from studies in yeast suggests that the FLCN ortholog Bhd activates the mTOR ortholog Tor2. These opposing effects of FLCN deficiency on the mTOR pathway have led to the hypothesis that FLCN regulation of mTOR activity may be context or cell-type dependent.
mTORC1 activation on the lysosome
Resolution of the crystal structure of the FLCN carboxy-terminal protein domain revealed a structural similarity to the differentially expressed in normal cells and neoplasia (DENN) domain of DENN1B suggesting that they are distantly related proteins. The DENN domain family of proteins are guanine nucleotide exchange factors (GEFs) for Rab proteins, members of the Ras superfamily of G proteins that are involved in vesicular transport suggesting that FLCN may have a similar function.
FLCN acts as a GTPase-activating protein (GAP) toward Rag C/D GTPases, members of another Ras-related GTP-binding protein family, which are necessary for amino acid-dependent mTORC1 activation at the lysosomal membrane. The heterodimeric Rag GTPases (RagA or B in complex with RagC or D) in a lysosome-associated complex with Ragulator and vacuolar adenosine triphosphatase (v-ATPase) interact with mTORC1 in response to amino acids from the lysosomal lumen to promote translocation of mTORC1 to the lysosomal surface for activation by the small GTPase Ras-homolog enriched in brain (Rheb). GTP-loading of RagA/B is a requirement for amino acid signaling to mTORC1. In recent studies, FLCN was shown to localize to the lysosome surface under amino acid starved conditions, where with its binding partners FNIP1/FNIP2, FLCN acts as a GAP to facilitate GDP-loading of Rag C/D, clarifying the role of this Rag GTPase in amino acid-dependent mTORC1 activation. Another report demonstrated that FLCN in association with FNIP1 preferentially binds to GDP-bound /nucleotide free Rag A/B under amino acid deprived conditions suggesting a potential role for FLCN as a GEF for RagA/B. Recently the heterodimeric Lst4-Lst7 complex in yeast, orthologous to the mammalian FLCN-FNIP1 complex, was found to function as a GAP for Gtr2, the yeast ortholog of Rag C/D, and cluster at the vacuolar membrane in amino acid starved cells. Refeeding of amino acids stimulated Lst4-Lst7 binding to and GAP activity towards Gtr2 resulting in mTORC1 activation and demonstrating conservation of a GAP function for FLCN in lower organisms. 
Control of TFE3/TFEB transcriptional activation
TFE3 and TFEB are members of the microphthalmia-associated transcription factor (MiTF) family, which also includes MiTF and TFEC. Gene fusions of TFE3 with a number of different gene partners can arise sporadically and are responsible for Xp11.2 translocation renal cell carcinoma. FLCN-deficient BHD associated renal tumors and tumors that develop in mouse models with Flcn inactivation were found to have elevated expression of transmembrane glycoprotein NMB (GPNMB), a transcriptional target of TFE3. Subsequently, FLCN was shown to regulate TFE3 activity by sequestering TFE3 in the cytoplasm where it is transcriptionally inactive; however, loss of FLCN expression results in localization of TFE3 to the nucleus driving transcriptional activation of its target genes including GPNMB. Another study investigating genes required for mouse embryonic stem cell (ESC) progression from pluripotency to cell lineage differentiation revealed that Flcn in complex with Fnip1/2 was necessary for ESC exit from pluripotency through cytoplasmic sequestering of Tfe3, thereby abrogating expression of its gene target, estrogen-related receptor beta(Esrrb), the core pluripotency factor.
Regulation of PGC-1α and mitochondrial biogenesis
Chromophobe renal carcinoma and hybrid oncocytic tumors with features of chromophobe renal carcinoma and renal oncocytoma, which are the most common renal tumor histologic subtypes associated with BHD, contain large numbers of mitochondria. Comparative gene expression profiling of BHD-associated renal tumors and sporadic counterpart tumors revealed distinct gene expression patterns and cytogenetic differences between the groups. BHD-associated tumors displayed high expression of mitochondrial- and oxidative phosphorylation-associated genes reflecting deregulation of the peroxisome proliferator-activated receptor gamma coactivator 1-alpha / mitochondrial transcription factor A (PGC-1α/TFAM) signaling axis. FLCN expression was inversely correlated with PGC-1α activation, which drives mitochondrial biogenesis. In support of these data, FLCN inactivation was correlated with PGC-1α activation and upregulation of its target genes in BHD-associated renal tumors, and kidney, heart and muscle tissues from genetically engineered mouse models with Flcn inactivation targeted to the respective tissues.
Maintenance of cell-cell adhesions and regulation of RhoA signaling
Yeast two-hybrid screening performed by two independent groups identified p0071 (plakophilin-4) as a FLCN interacting protein. p0071 binds E-cadherin at adherens junctions, which are important for maintenance of cell architecture in epithelial tissues, and regulates RhoA activity. Loss of FLCN function leads to a disruptive effect on cell-cell adhesions and cell polarity, and dysregulation of RhoA signaling. Additional supporting evidence includes reduction in E-cadherin expression and increased alveolar apoptosis in lungs from lung-targeted Flcn-deficient mice, and increased cell-cell adhesions in FLCN-deficient lung cell lines. These studies suggest a potential function of FLCN in maintaining proper cell-cell adhesions for lung cell integrity and support the “stretch hypothesis” as a mechanism of pulmonary cyst pathogenesis in BHD.
Ciliogenesis and cilia-dependent flow sensory mechanisms
Individuals affected with the inherited kidney cancer syndromes von Hippel-Lindau syndrome and tuberous sclerosis complex can develop kidney cysts in addition to kidney tumors, which have been shown to result from defects in primary cilia function. BHD patients also may present with kidney cysts, which led researchers to investigate a potential role for FLCN in regulating primary cilia development and/or function. FLCN protein was found to localize on primary cilia, the basal body and centrosome in different cell types. FLCN siRNA knockdown in nutrient starved kidney cells resulted in delayed cilia development. Both overexpression of FLCN in FLCN-expressing kidney cells and knockdown of FLCN resulted in reduced numbers of cilia and aberrant cell divisions, suggesting that levels of FLCN must be tightly regulated for proper ciliogenesis. Primary cilia play a role in inhibiting the canonical Wnt signaling pathway ( Wnt/β-catenin signaling pathway) by sequestering β-catenin in the basal body, and dysregulated Wnt/β-catenin signaling has been linked to kidney cyst formation. In Flcn-deficient mouse inner medullary collecting duct cells, levels of unphosphorylated (active) β-catenin and its down stream targets were elevated suggesting that improper activation of the canonical Wnt/β-catenin signaling pathway through defective ciliogenesis may lead to kidney, and potentially lung, cyst development in BHD syndrome.
Additional experimental evidence that FLCN may be involved in primary cilium function was obtained from a yeast two-hybrid screening that identified KIF3A as a FLCN interacting protein. Intraflagellar transport, which is required for primary cilium assembly and maintenance, is driven by kinesin-2 motor made up of subunits KIF3A and KIF3B. Researchers have shown that FLCN could interact with both subunits in a cilium-dependent manner and localize to cilia in FLCN-expressing but not FLCN-deficient cells. Cilia have been shown to act as flow sensors and suppress mTOR signaling by activating the serine/threonine kinase LKB1 located in the basal body of resting cells in response to flow stimuli. LKB1 in turn phosphorylates and activates AMPK, a negative regulator of mTOR activation. Flow stress was able to suppress mTOR signaling in FLCN-expressing human kidney cells but not under FLCN deficient conditions, and required intact cilia. FLCN was shown to recruit LKB1 and facilitate its interaction with AMPK in the basal body in a flow stress-dependent manner. These findings suggest a role for FLCN in the mechanosensory signaling machinery of the cell that controls the cilia-dependent regulation of the LKB1-AMPK-mTOR signaling axis.
Other potential functions of FLCN
Additional potential roles for FLCN in autophagy,    TGF β signaling,  regulation of AMPK activity,   and regulation of HIF-1α transcriptional activity  have been described.
- GRCh38: Ensembl release 89: ENSG00000154803 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000032633 - Ensembl, May 2017
- "Human PubMed Reference:".
- "Mouse PubMed Reference:".
- "Folliculin". Genetics Home Reference. 
- Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, et al. (August 2002). "Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome". Cancer Cell. 2 (2): 157–64. doi:10.1016/S1535-6108(02)00104-6. PMID 12204536.
- Ren HZ, Zhu CC, Yang C, Chen SL, Xie J, Hou YY, et al. (August 2008). "Mutation analysis of the FLCN gene in Chinese patients with sporadic and familial isolated primary spontaneous pneumothorax". Clinical Genetics. 74 (2): 178–83. doi:10.1111/j.1399-0004.2008.01030.x. PMID 18505456.
- Graham RB, Nolasco M, Peterlin B, Garcia CK (July 2005). "Nonsense mutations in folliculin presenting as isolated familial spontaneous pneumothorax in adults". American Journal of Respiratory and Critical Care Medicine. 172 (1): 39–44. doi:10.1164/rccm.200501-143OC. PMID 15805188.
- Zbar B, Alvord WG, Glenn G, Turner M, Pavlovich CP, Schmidt L, et al. (April 2002). "Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome". Cancer Epidemiology, Biomarkers & Prevention. 11 (4): 393–400. PMID 11927500.
- Birt AR, Hogg GR, Dubé WJ (December 1977). "Hereditary multiple fibrofolliculomas with trichodiscomas and acrochordons". Archives of Dermatology. 113 (12): 1674–7. doi:10.1001/archderm.113.12.1674. PMID 596896.
- Toro JR, Glenn G, Duray P, Darling T, Weirich G, Zbar B, Linehan M, Turner ML (October 1999). "Birt-Hogg-Dubé syndrome: a novel marker of kidney neoplasia". Archives of Dermatology. 135 (10): 1195–202. doi:10.1001/archderm.135.10.1195. PMID 10522666.
- Schmidt LS, Warren MB, Nickerson ML, Weirich G, Matrosova V, Toro JR, et al. (October 2001). "Birt-Hogg-Dubé syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2". American Journal of Human Genetics. 69 (4): 876–82. doi:10.1086/323744. PMID 11533913.
- Khoo SK, Bradley M, Wong FK, Hedblad MA, Nordenskjöld M, Teh BT (August 2001). "Birt-Hogg-Dubé syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2". Oncogene. 20 (37): 5239–42. doi:10.1038/sj.onc.1204703. PMID 11526515.
- Toro JR, Wei MH, Glenn GM, Weinreich M, Toure O, Vocke C, et al. (June 2008). "BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports". Journal of Medical Genetics. 45 (6): 321–31. doi:10.1136/jmg.2007.054304. PMID 18234728.
- Benhammou JN, Vocke CD, Santani A, Schmidt LS, Baba M, Seyama K, et al. (June 2011). "Identification of intragenic deletions and duplication in the FLCN gene in Birt-Hogg-Dubé syndrome". Genes, Chromosomes & Cancer. 50 (6): 466–77. doi:10.1002/gcc.20872. PMID 21412933.
- Kunogi M, Kurihara M, Ikegami TS, Kobayashi T, Shindo N, Kumasaka T, et al. (April 2010). "Clinical and genetic spectrum of Birt-Hogg-Dube syndrome patients in whom pneumothorax and/or multiple lung cysts are the presenting feature". Journal of Medical Genetics. 47 (4): 281–7. doi:10.1136/jmg.2009.070565. PMID 20413710.
- Khoo SK, Kahnoski K, Sugimura J, Petillo D, Chen J, Shockley K, et al. (August 2003). "Inactivation of BHD in sporadic renal tumors". Cancer Research. 63 (15): 4583–7. PMID 12907635.
- Murakami T, Sano F, Huang Y, Komiya A, Baba M, Osada Y, et al. (April 2007). "Identification and characterization of Birt-Hogg-Dubé associated renal carcinoma". The Journal of Pathology. 211 (5): 524–31. doi:10.1002/path.2139. PMID 17323425.
- Davis CF, Ricketts CJ, Wang M, Yang L, Cherniack AD, Shen H, et al. (September 2014). "The somatic genomic landscape of chromophobe renal cell carcinoma". Cancer Cell. 26 (3): 319–30. doi:10.1016/j.ccr.2014.07.014. PMID 25155756.
- Vocke CD, Yang Y, Pavlovich CP, Schmidt LS, Nickerson ML, Torres-Cabala CA, et al. (June 2005). "High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors". Journal of the National Cancer Institute. 97 (12): 931–5. doi:10.1093/jnci/dji154. PMID 15956655.
- Lingaas F, Comstock KE, Kirkness EF, Sørensen A, Aarskaug T, Hitte C, et al. (December 2003). "A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog". Human Molecular Genetics. 12 (23): 3043–53. doi:10.1093/hmg/ddg336. PMID 14532326.
- Okimoto K, Sakurai J, Kobayashi T, Mitani H, Hirayama Y, Nickerson ML, et al. (February 2004). "A germ-line insertion in the Birt-Hogg-Dubé (BHD) gene gives rise to the Nihon rat model of inherited renal cancer". Proceedings of the National Academy of Sciences of the United States of America. 101 (7): 2023–7. doi:10.1073/pnas.0308071100. PMID 14769940.
- Hong SB, Oh H, Valera VA, Stull J, Ngo DT, Baba M, Merino MJ, Linehan WM, Schmidt LS (June 2010). "Tumor suppressor FLCN inhibits tumorigenesis of a FLCN-null renal cancer cell line and regulates expression of key molecules in TGF-beta signaling". Molecular Cancer. 9: 160. doi:10.1186/1476-4598-9-160. PMID 20573232.
- Hudon V, Sabourin S, Dydensborg AB, Kottis V, Ghazi A, Paquet M, et al. (March 2010). "Renal tumour suppressor function of the Birt-Hogg-Dubé syndrome gene product folliculin". Journal of Medical Genetics. 47 (3): 182–9. doi:10.1136/jmg.2009.072009. PMID 19843504.
- van Steensel MA, Verstraeten VL, Frank J, Kelleners-Smeets NW, Poblete-Gutiérrez P, Marcus-Soekarman D, et al. (March 2007). "Novel mutations in the BHD gene and absence of loss of heterozygosity in fibrofolliculomas of Birt-Hogg-Dubé patients". The Journal of Investigative Dermatology. 127 (3): 588–93. doi:10.1038/sj.jid.5700592. PMID 17124507.
- Koga S, Furuya M, Takahashi Y, Tanaka R, Yamaguchi A, Yasufuku K, et al. (October 2009). "Lung cysts in Birt-Hogg-Dubé syndrome: histopathological characteristics and aberrant sequence repeats". Pathology International. 59 (10): 720–8. doi:10.1111/j.1440-1827.2009.02434.x. PMID 19788617.
- Baba M, Hong SB, Sharma N, Warren MB, Nickerson ML, Iwamatsu A, et al. (October 2006). "Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling". Proceedings of the National Academy of Sciences of the United States of America. 103 (42): 15552–7. doi:10.1073/pnas.0603781103. PMC . PMID 17028174.
- Hasumi H, Baba M, Hong SB, Hasumi Y, Huang Y, Yao M, Valera VA, Linehan WM, Schmidt LS (May 2008). "Identification and characterization of a novel folliculin-interacting protein FNIP2". Gene. 415 (1-2): 60–7. doi:10.1016/j.gene.2008.02.022. PMID 18403135.
- Takagi Y, Kobayashi T, Shiono M, Wang L, Piao X, Sun G, et al. (September 2008). "Interaction of folliculin (Birt-Hogg-Dubé gene product) with a novel Fnip1-like (FnipL/Fnip2) protein". Oncogene. 27 (40): 5339–47. doi:10.1038/onc.2008.261. PMID 18663353.
- Shackelford DB, Shaw RJ (August 2009). "The LKB1-AMPK pathway: metabolism and growth control in tumour suppression". Nature Reviews. Cancer. 9 (8): 563–75. doi:10.1038/nrc2676. PMID 19629071.
- Wang L, Kobayashi T, Piao X, Shiono M, Takagi Y, Mineki R, et al. (January 2010). "Serine 62 is a phosphorylation site in folliculin, the Birt-Hogg-Dubé gene product". FEBS Letters. 584 (1): 39–43. doi:10.1016/j.febslet.2009.11.033. PMID 19914239.
- Baba M, Furihata M, Hong SB, Tessarollo L, Haines DC, Southon E, et al. (January 2008). "Kidney-targeted Birt-Hogg-Dube gene inactivation in a mouse model: Erk1/2 and Akt-mTOR activation, cell hyperproliferation, and polycystic kidneys". Journal of the National Cancer Institute. 100 (2): 140–54. doi:10.1093/jnci/djm288. PMID 18182616.
- Chen J, Futami K, Petillo D, Peng J, Wang P, Knol J, et al. (2008). "Deficiency of FLCN in mouse kidney led to development of polycystic kidneys and renal neoplasia". PloS One. 3 (10): e3581. doi:10.1371/journal.pone.0003581. PMID 18974783.
- Hasumi Y, Baba M, Ajima R, Hasumi H, Valera VA, Klein ME, Haines DC, Merino MJ, Hong SB, Yamaguchi TP, Schmidt LS, Linehan WM (November 2009). "Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2". Proceedings of the National Academy of Sciences of the United States of America. 106 (44): 18722–7. doi:10.1073/pnas.0908853106. PMID 19850877.
- Hartman TR, Nicolas E, Klein-Szanto A, Al-Saleem T, Cash TP, Simon MC, Henske EP (April 2009). "The role of the Birt-Hogg-Dubé protein in mTOR activation and renal tumorigenesis". Oncogene. 28 (13): 1594–604. doi:10.1038/onc.2009.14. PMID 19234517.
- van Slegtenhorst M, Khabibullin D, Hartman TR, Nicolas E, Kruger WD, Henske EP (August 2007). "The Birt-Hogg-Dube and tuberous sclerosis complex homologs have opposing roles in amino acid homeostasis in Schizosaccharomyces pombe". The Journal of Biological Chemistry. 282 (34): 24583–90. doi:10.1074/jbc.M700857200. PMID 17556368.
- Nookala RK, Langemeyer L, Pacitto A, Ochoa-Montaño B, Donaldson JC, Blaszczyk BK, et al. (August 2012). "Crystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer". Open Biology. 2 (8): 120071. doi:10.1098/rsob.120071. PMID 22977732.
- Tsun ZY, Bar-Peled L, Chantranupong L, Zoncu R, Wang T, Kim C, Spooner E, Sabatini DM (November 2013). "The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1". Molecular Cell. 52 (4): 495–505. doi:10.1016/j.molcel.2013.09.016. PMID 24095279.
- Bar-Peled L, Sabatini DM (July 2014). "Regulation of mTORC1 by amino acids". Trends in Cell Biology. 24 (7): 400–6. doi:10.1016/j.tcb.2014.03.003. PMID 24698685.
- Petit CS, Roczniak-Ferguson A, Ferguson SM (September 2013). "Recruitment of folliculin to lysosomes supports the amino acid-dependent activation of Rag GTPases". The Journal of Cell Biology. 202 (7): 1107–22. doi:10.1083/jcb.201307084. PMID 24081491.
- Péli-Gulli MP, Sardu A, Panchaud N, Raucci S, De Virgilio C (October 2015). "Amino Acids Stimulate TORC1 through Lst4-Lst7, a GTPase-Activating Protein Complex for the Rag Family GTPase Gtr2". Cell Reports. 13 (1): 1–7. doi:10.1016/j.celrep.2015.08.059. PMID 26387955.
- Armah HB, Parwani AV (January 2010). "Xp11.2 translocation renal cell carcinoma". Archives of Pathology & Laboratory Medicine. 134 (1): 124–9. doi:10.1043/2008-0391-RSR.1. PMID 20073616.
- Hong SB, Oh H, Valera VA, Baba M, Schmidt LS, Linehan WM (December 2010). "Inactivation of the FLCN tumor suppressor gene induces TFE3 transcriptional activity by increasing its nuclear localization". PloS One. 5 (12): e15793. doi:10.1371/journal.pone.0015793. PMID 21209915.
- Betschinger J, Nichols J, Dietmann S, Corrin PD, Paddison PJ, Smith A (April 2013). "Exit from pluripotency is gated by intracellular redistribution of the bHLH transcription factor Tfe3". Cell. 153 (2): 335–47. doi:10.1016/j.cell.2013.03.012. PMID 23582324.
- Klomp JA, Petillo D, Niemi NM, Dykema KJ, Chen J, Yang XJ, et al. (December 2010). "Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression". BMC Medical Genomics. 3: 59. doi:10.1186/1755-8794-3-59. PMID 21162720.
- Hasumi H, Baba M, Hasumi Y, Huang Y, Oh H, Hughes RM, et al. (November 2012). "Regulation of mitochondrial oxidative metabolism by tumor suppressor FLCN". Journal of the National Cancer Institute. 104 (22): 1750–64. doi:10.1093/jnci/djs418. PMID 23150719.
- Hasumi Y, Baba M, Hasumi H, Huang Y, Lang M, Reindorf R, et al. (November 2014). "Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation". Human Molecular Genetics. 23 (21): 5706–19. doi:10.1093/hmg/ddu286. PMID 24908670.
- Medvetz DA, Khabibullin D, Hariharan V, Ongusaha PP, Goncharova EA, Schlechter T, Darling TN, Hofmann I, Krymskaya VP, Liao JK, Huang H, Henske EP (2012). "Folliculin, the product of the Birt-Hogg-Dube tumor suppressor gene, interacts with the adherens junction protein p0071 to regulate cell-cell adhesion". PloS One. 7 (11): e47842. doi:10.1371/journal.pone.0047842. PMID 23139756.
- Nahorski MS, Seabra L, Straatman-Iwanowska A, Wingenfeld A, Reiman A, Lu X, et al. (December 2012). "Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis". Human Molecular Genetics. 21 (24): 5268–79. doi:10.1093/hmg/dds378. PMID 22965878.
- Goncharova EA, Goncharov DA, James ML, Atochina-Vasserman EN, Stepanova V, Hong SB, et al. (April 2014). "Folliculin controls lung alveolar enlargement and epithelial cell survival through E-cadherin, LKB1, and AMPK". Cell Reports. 7 (2): 412–23. doi:10.1016/j.celrep.2014.03.025. PMID 24726356.
- Khabibullin D, Medvetz DA, Pinilla M, Hariharan V, Li C, Hergrueter A, et al. (August 2014). "Folliculin regulates cell-cell adhesion, AMPK, and mTORC1 in a cell-type-specific manner in lung-derived cells". Physiological Reports. 2 (8). doi:10.14814/phy2.12107. PMID 25121506.
- Kennedy JC, Khabibullin D, Henske EP (April 2016). "Mechanisms of pulmonary cyst pathogenesis in Birt-Hogg-Dube syndrome: The stretch hypothesis". Seminars in Cell & Developmental Biology. 52: 47–52. doi:10.1016/j.semcdb.2016.02.014. PMID 26877139.
- Esteban MA, Harten SK, Tran MG, Maxwell PH (July 2006). "Formation of primary cilia in the renal epithelium is regulated by the von Hippel-Lindau tumor suppressor protein". Journal of the American Society of Nephrology. 17 (7): 1801–6. doi:10.1681/ASN.2006020181. PMID 16775032.
- Hartman TR, Liu D, Zilfou JT, Robb V, Morrison T, Watnick T, Henske EP (January 2009). "The tuberous sclerosis proteins regulate formation of the primary cilium via a rapamycin-insensitive and polycystin 1-independent pathway". Human Molecular Genetics. 18 (1): 151–63. doi:10.1093/hmg/ddn325. PMID 18845692.
- Luijten MN, Basten SG, Claessens T, Vernooij M, Scott CL, Janssen R, Easton JA, Kamps MA, Vreeburg M, Broers JL, van Geel M, Menko FH, Harbottle RP, Nookala RK, Tee AR, Land SC, Giles RH, Coull BJ, van Steensel MA (November 2013). "Birt-Hogg-Dube syndrome is a novel ciliopathy". Human Molecular Genetics. 22 (21): 4383–97. doi:10.1093/hmg/ddt288. PMID 23784378.
- Zhong M, Zhao X, Li J, Yuan W, Yan G, Tong M, Guo S, Zhu Y, Jiang Y, Liu Y, Jiang Y (May 2016). "Tumor Suppressor Folliculin Regulates mTORC1 through Primary Cilia". The Journal of Biological Chemistry. 291 (22): 11689–97. doi:10.1074/jbc.M116.719997. PMID 27072130.
- Boehlke C, Kotsis F, Patel V, Braeg S, Voelker H, Bredt S, et al. (November 2010). "Primary cilia regulate mTORC1 activity and cell size through Lkb1". Nature Cell Biology. 12 (11): 1115–22. doi:10.1038/ncb2117. PMID 20972424.
- Possik E, Jalali Z, Nouët Y, Yan M, Gingras MC, Schmeisser K, Panaite L, Dupuy F, Kharitidi D, Chotard L, Jones RG, Hall DH, Pause A (April 2014). "Folliculin regulates ampk-dependent autophagy and metabolic stress survival". PLoS Genetics. 10 (4): e1004273. doi:10.1371/journal.pgen.1004273. PMID 24763318.
- Dunlop EA, Seifan S, Claessens T, Behrends C, Kamps MA, Rozycka E, et al. (October 2014). "FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation". Autophagy. 10 (10): 1749–60. doi:10.4161/auto.29640. PMID 25126726.
- Bastola P, Stratton Y, Kellner E, Mikhaylova O, Yi Y, Sartor MA, Medvedovic M, Biesiada J, Meller J, Czyzyk-Krzeska MF (2013). "Folliculin contributes to VHL tumor suppressing activity in renal cancer through regulation of autophagy". PloS One. 8 (7): e70030. doi:10.1371/journal.pone.0070030. PMID 23922894.
- Cash TP, Gruber JJ, Hartman TR, Henske EP, Simon MC (June 2011). "Loss of the Birt-Hogg-Dubé tumor suppressor results in apoptotic resistance due to aberrant TGFβ-mediated transcription". Oncogene. 30 (22): 2534–46. doi:10.1038/onc.2010.628. PMID 21258407.
- Yan M, Gingras MC, Dunlop EA, Nouët Y, Dupuy F, Jalali Z, et al. (June 2014). "The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation". The Journal of Clinical Investigation. 124 (6): 2640–50. doi:10.1172/JCI71749. PMID 24762438.
- Yan M, Audet-Walsh É, Manteghi S, Dufour CR, Walker B, Baba M, St-Pierre J, Giguère V, Pause A (May 2016). "Chronic AMPK activation via loss of FLCN induces functional beige adipose tissue through PGC-1α/ERRα". Genes & Development. 30 (9): 1034–46. doi:10.1101/gad.281410.116. PMID 27151976.
- Preston RS, Philp A, Claessens T, Gijezen L, Dydensborg AB, Dunlop EA, et al. (March 2011). "Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility". Oncogene. 30 (10): 1159–73. doi:10.1038/onc.2010.497. PMID 21057536.
- Schmidt LS, Linehan WM (October 2015). "Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome". Nature Reviews. Urology. 12 (10): 558–69. doi:10.1038/nrurol.2015.206. PMID 26334087.
- Tee AR, Pause A (September 2013). "Birt-Hogg-Dubé: tumour suppressor function and signalling dynamics central to folliculin". Familial Cancer. 12 (3): 367–72. doi:10.1007/s10689-012-9576-9. PMID 23096221.
- FLCN protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
- The BHD Foundation supports research into BHD syndrome and maintains the world's first website dedicated to BHD syndrome - BHDSyndrome.org
- Human Folliculin variants, listing maintained by the European Birt-Hogg-Dube Consortium.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Folliculin C-terminal domain Provide feedback
This is the C-terminal domain of folliculin. It has guanine nucleotide exchange factor (GEF) activity .
Nookala RK, Langemeyer L, Pacitto A, Ochoa-Montano B, Donaldson JC, Blaszczyk BK, Chirgadze DY, Barr FA, Bazan JF, Blundell TL;, Open Biol. 2012;2:120071.: Crystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer. PUBMED:22977732 EPMC:22977732
This tab holds annotation information from the InterPro database.
InterPro entry IPR032035
This is the C-terminal domain of folliculin. This domain shares structural similarity with DENN domain of DENN1B (a Rab GEF), and has guanine nucleotide exchange factor (GEF) activity [PUBMED:22977732].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||guanyl-nucleotide exchange factor activity (GO:0005085)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Number in seed:||15|
|Number in full:||230|
|Average length of the domain:||201.70 aa|
|Average identity of full alignment:||30 %|
|Average coverage of the sequence by the domain:||38.46 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||4|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Folliculin_C domain has been found. There are 2 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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