FLCN_HUMAN
ID FLCN_HUMAN Reviewed; 579 AA.
AC Q8NFG4; A6NJJ8; Q6ZRX1; Q96BD2; Q96BE4;
DT 21-FEB-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2002, sequence version 1.
DT 03-AUG-2022, entry version 160.
DE RecName: Full=Folliculin {ECO:0000303|PubMed:15657874};
DE AltName: Full=BHD skin lesion fibrofolliculoma protein {ECO:0000303|PubMed:12204536};
DE AltName: Full=Birt-Hogg-Dube syndrome protein {ECO:0000303|PubMed:12204536};
GN Name=FLCN {ECO:0000303|PubMed:15657874, ECO:0000312|HGNC:HGNC:27310};
GN Synonyms=BHD {ECO:0000303|PubMed:12204536};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, DEVELOPMENTAL
RP STAGE, AND INVOLVEMENT IN BIRT-HOGG-DUBE SYNDROME.
RC TISSUE=Lung;
RX PubMed=12204536; DOI=10.1016/s1535-6108(02)00104-6;
RA Nickerson M.L., Warren M.B., Toro J.R., Matrosova V., Glenn G.,
RA Turner M.L., Duray P., Merino M., Choyke P.L., Pavlovich C.P., Sharma N.,
RA Walther M.M., Munroe D., Hill R., Maher E., Greenberg C., Lerman M.I.,
RA Linehan W.M., Zbar B., Schmidt L.S.;
RT "Mutations in a novel gene lead to kidney tumors, lung wall defects, and
RT benign tumors of the hair follicle in patients with the Birt-Hogg-Dube
RT syndrome.";
RL Cancer Cell 2:157-164(2002).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Spleen;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT human lineage.";
RL Nature 440:1045-1049(2006).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND NUCLEOTIDE SEQUENCE
RP [LARGE SCALE MRNA] OF 267-579 (ISOFORM 1).
RC TISSUE=Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP POSSIBLE INVOLVEMENT IN COLORECTAL CANCER, AND VARIANTS TRP-79 AND THR-445.
RX PubMed=12843323; DOI=10.1136/jmg.40.7.511;
RA Kahnoski K., Khoo S.K., Nassif N.T., Chen J., Lobo G.P., Segelov E.,
RA Teh B.T.;
RT "Alterations of the Birt-Hogg-Dube gene (BHD) in sporadic colorectal
RT tumours.";
RL J. Med. Genet. 40:511-515(2003).
RN [7]
RP POSSIBLE INVOLVEMENT IN RENAL CELL CARCINOMA AND COLORECTAL CANCER, AND
RP VARIANTS VAL-238; GLN-320; GLY-392 AND SER-444.
RX PubMed=14627671; DOI=10.1136/jmg.40.11.820;
RA da Silva N.F., Gentle D., Hesson L.B., Morton D.G., Latif F., Maher E.R.;
RT "Analysis of the Birt-Hogg-Dube (BHD) tumour suppressor gene in sporadic
RT renal cell carcinoma and colorectal cancer.";
RL J. Med. Genet. 40:820-824(2003).
RN [8]
RP INVOLVEMENT IN PSP.
RX PubMed=15657874; DOI=10.1086/428455;
RA Painter J.N., Tapanainen H., Somer M., Tukiainen P., Aittomaeki K.;
RT "A 4-bp deletion in the Birt-Hogg-Dube gene (FLCN) causes dominantly
RT inherited spontaneous pneumothorax.";
RL Am. J. Hum. Genet. 76:522-527(2005).
RN [9]
RP INVOLVEMENT IN BIRT-HOGG-DUBE SYNDROME.
RX PubMed=15852235; DOI=10.1086/430842;
RA Schmidt L.S., Nickerson M.L., Warren M.B., Glenn G.M., Toro J.R.,
RA Merino M.J., Turner M.L., Choyke P.L., Sharma N., Peterson J., Morrison P.,
RA Maher E.R., Walther M.M., Zbar B., Linehan W.M.;
RT "Germline BHD-mutation spectrum and phenotype analysis of a large cohort of
RT families with Birt-Hogg-Dube syndrome.";
RL Am. J. Hum. Genet. 76:1023-1033(2005).
RN [10]
RP FUNCTION, PHOSPHORYLATION, SUBCELLULAR LOCATION, INTERACTION WITH FNIP1,
RP AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=17028174; DOI=10.1073/pnas.0603781103;
RA Baba M., Hong S.-B., Sharma N., Warren M.B., Nickerson M.L., Iwamatsu A.,
RA Esposito D., Gillette W.K., Hopkins R.F. III, Hartley J.L., Furihata M.,
RA Oishi S., Zhen W., Burke T.R. Jr., Linehan W.M., Schmidt L.S., Zbar B.;
RT "Folliculin encoded by the BHD gene interacts with a binding protein,
RT FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:15552-15557(2006).
RN [11]
RP INVOLVEMENT IN PSP.
RX PubMed=17496196; DOI=10.1136/jmg.2007.049874;
RA Gunji Y., Akiyoshi T., Sato T., Kurihara M., Tominaga S., Takahashi K.,
RA Seyama K.;
RT "Mutations of the Birt Hogg Dube gene in patients with multiple lung cysts
RT and recurrent pneumothorax.";
RL J. Med. Genet. 44:588-593(2007).
RN [12]
RP INTERACTION WITH FNIP2.
RX PubMed=18403135; DOI=10.1016/j.gene.2008.02.022;
RA Hasumi H., Baba M., Hong S.-B., Hasumi Y., Huang Y., Yao M., Valera V.A.,
RA Linehan W.M., Schmidt L.S.;
RT "Identification and characterization of a novel folliculin-interacting
RT protein FNIP2.";
RL Gene 415:60-67(2008).
RN [13]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH FNIP2.
RX PubMed=18663353; DOI=10.1038/onc.2008.261;
RA Takagi Y., Kobayashi T., Shiono M., Wang L., Piao X., Sun G., Zhang D.,
RA Abe M., Hagiwara Y., Takahashi K., Hino O.;
RT "Interaction of folliculin (Birt-Hogg-Dube gene product) with a novel
RT Fnip1-like (FnipL/Fnip2) protein.";
RL Oncogene 27:5339-5347(2008).
RN [14]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-62, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [15]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [16]
RP INVOLVEMENT IN PSP.
RX PubMed=19483054; DOI=10.1183/09031936.00062608;
RA Sundaram S., Tasker A.D., Morrell N.W.;
RT "Familial spontaneous pneumothorax and lung cysts due to a Folliculin exon
RT 10 mutation.";
RL Eur. Respir. J. 33:1510-1512(2009).
RN [17]
RP FUNCTION.
RX PubMed=21209915; DOI=10.1371/journal.pone.0015793;
RA Hong S.B., Oh H., Valera V.A., Baba M., Schmidt L.S., Linehan W.M.;
RT "Inactivation of the FLCN tumor suppressor gene induces TFE3
RT transcriptional activity by increasing its nuclear localization.";
RL PLoS ONE 5:E15793-E15793(2010).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-62, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [19]
RP SUBCELLULAR LOCATION, AND INVOLVEMENT IN BHD.
RX PubMed=23784378; DOI=10.1093/hmg/ddt288;
RA Luijten M.N., Basten S.G., Claessens T., Vernooij M., Scott C.L.,
RA Janssen R., Easton J.A., Kamps M.A., Vreeburg M., Broers J.L., van Geel M.,
RA Menko F.H., Harbottle R.P., Nookala R.K., Tee A.R., Land S.C., Giles R.H.,
RA Coull B.J., van Steensel M.A.;
RT "Birt-Hogg-Dube syndrome is a novel ciliopathy.";
RL Hum. Mol. Genet. 22:4383-4397(2013).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-62; SER-73; SER-302 AND
RP SER-571, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [21]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=24081491; DOI=10.1083/jcb.201307084;
RA Petit C.S., Roczniak-Ferguson A., Ferguson S.M.;
RT "Recruitment of folliculin to lysosomes supports the amino acid-dependent
RT activation of Rag GTPases.";
RL J. Cell Biol. 202:1107-1122(2013).
RN [22]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=24095279; DOI=10.1016/j.molcel.2013.09.016;
RA Tsun Z.Y., Bar-Peled L., Chantranupong L., Zoncu R., Wang T., Kim C.,
RA Spooner E., Sabatini D.M.;
RT "The folliculin tumor suppressor is a GAP for the RagC/D GTPases that
RT signal amino acid levels to mTORC1.";
RL Mol. Cell 52:495-505(2013).
RN [23]
RP INVOLVEMENT IN RCC.
RX PubMed=23922894; DOI=10.1371/journal.pone.0070030;
RA Bastola P., Stratton Y., Kellner E., Mikhaylova O., Yi Y., Sartor M.A.,
RA Medvedovic M., Biesiada J., Meller J., Czyzyk-Krzeska M.F.;
RT "Folliculin contributes to VHL tumor suppressing activity in renal cancer
RT through regulation of autophagy.";
RL PLoS ONE 8:E70030-E70030(2013).
RN [24]
RP FUNCTION, INTERACTION WITH GABARAP; FNIP1 AND FNIP2, PHOSPHORYLATION AT
RP SER-406; SER-537 AND SER-542, AND MUTAGENESIS OF SER-406; SER-537 AND
RP SER-542.
RX PubMed=25126726; DOI=10.4161/auto.29640;
RA Dunlop E.A., Seifan S., Claessens T., Behrends C., Kamps M.A., Rozycka E.,
RA Kemp A.J., Nookala R.K., Blenis J., Coull B.J., Murray J.T.,
RA van Steensel M.A., Wilkinson S., Tee A.R.;
RT "FLCN, a novel autophagy component, interacts with GABARAP and is regulated
RT by ULK1 phosphorylation.";
RL Autophagy 10:1749-1760(2014).
RN [25]
RP INVOLVEMENT IN PSP.
RX PubMed=25827758; DOI=10.1007/s00408-015-9723-9;
RA Ray A., Paul S., Chattopadhyay E., Kundu S., Roy B.;
RT "Genetic analysis of familial spontaneous pneumothorax in an Indian
RT family.";
RL Lung 193:433-438(2015).
RN [26]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH RILP.
RX PubMed=27113757; DOI=10.15252/embr.201541382;
RA Starling G.P., Yip Y.Y., Sanger A., Morton P.E., Eden E.R., Dodding M.P.;
RT "Folliculin directs the formation of a Rab34-RILP complex to control the
RT nutrient-dependent dynamic distribution of lysosomes.";
RL EMBO Rep. 17:823-841(2016).
RN [27]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH KIF3A AND KIF3B.
RX PubMed=27072130; DOI=10.1074/jbc.m116.719997;
RA Zhong M., Zhao X., Li J., Yuan W., Yan G., Tong M., Guo S., Zhu Y.,
RA Jiang Y., Liu Y., Jiang Y.;
RT "Tumor suppressor folliculin regulates mTORC1 through primary cilia.";
RL J. Biol. Chem. 291:11689-11697(2016).
RN [28]
RP INTERACTION WITH HSP70; HSP90AA1; STUB1; CDC37; AHSA1; CCT2; STIP1; FNIP1;
RP FNIP2; PTGES3 AND PPP5C.
RX PubMed=27353360; DOI=10.1038/ncomms12037;
RA Woodford M.R., Dunn D.M., Blanden A.R., Capriotti D., Loiselle D.,
RA Prodromou C., Panaretou B., Hughes P.F., Smith A., Ackerman W.,
RA Haystead T.A., Loh S.N., Bourboulia D., Schmidt L.S., Marston Linehan W.,
RA Bratslavsky G., Mollapour M.;
RT "The FNIP co-chaperones decelerate the Hsp90 chaperone cycle and enhance
RT drug binding.";
RL Nat. Commun. 7:12037-12037(2016).
RN [29]
RP SUBCELLULAR LOCATION.
RX PubMed=29848618; DOI=10.1083/jcb.201712177;
RA Meng J., Ferguson S.M.;
RT "GATOR1-dependent recruitment of FLCN-FNIP to lysosomes coordinates Rag
RT GTPase heterodimer nucleotide status in response to amino acids.";
RL J. Cell Biol. 217:2765-2776(2018).
RN [30]
RP FUNCTION.
RX PubMed=31272105; DOI=10.1093/hmg/ddz158;
RA Kennedy J.C., Khabibullin D., Hougard T., Nijmeh J., Shi W., Henske E.P.;
RT "Loss of FLCN inhibits canonical WNT signaling via TFE3.";
RL Hum. Mol. Genet. 28:3270-3281(2019).
RN [31]
RP FUNCTION.
RX PubMed=30733432; DOI=10.1038/s41467-018-08020-0;
RA Mathieu J., Detraux D., Kuppers D., Wang Y., Cavanaugh C., Sidhu S.,
RA Levy S., Robitaille A.M., Ferreccio A., Bottorff T., McAlister A.,
RA Somasundaram L., Artoni F., Battle S., Hawkins R.D., Moon R.T., Ware C.B.,
RA Paddison P.J., Ruohola-Baker H.;
RT "Folliculin regulates mTORC1/2 and WNT pathways in early human
RT pluripotency.";
RL Nat. Commun. 10:632-632(2019).
RN [32]
RP FUNCTION, AND INTERACTION WITH LDHA.
RX PubMed=34381247; DOI=10.1038/s41594-021-00633-2;
RA Woodford M.R., Baker-Williams A.J., Sager R.A., Backe S.J., Blanden A.R.,
RA Hashmi F., Kancherla P., Gori A., Loiselle D.R., Castelli M.,
RA Serapian S.A., Colombo G., Haystead T.A., Jensen S.M.,
RA Stetler-Stevenson W.G., Loh S.N., Schmidt L.S., Linehan W.M., Bah A.,
RA Bourboulia D., Bratslavsky G., Mollapour M.;
RT "The tumor suppressor folliculin inhibits lactate dehydrogenase A and
RT regulates the Warburg effect.";
RL Nat. Struct. Mol. Biol. 28:662-670(2021).
RN [33] {ECO:0007744|PDB:3V42}
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 341-566.
RX PubMed=22977732; DOI=10.1098/rsob.120071;
RA Nookala R.K., Langemeyer L., Pacitto A., Ochoa-Montano B., Donaldson J.C.,
RA Blaszczyk B.K., Chirgadze D.Y., Barr F.A., Bazan J.F., Blundell T.L.;
RT "Crystal structure of folliculin reveals a hidDENN function in genetically
RT inherited renal cancer.";
RL Open Biol. 2:120071-120071(2012).
RN [34] {ECO:0007744|PDB:6ULG}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.31 ANGSTROMS) IN COMPLEX WITH FNIP2;
RP RRAGA; RRAGC; LAMTOR1; LAMTOR2; LAMTOR3; LAMTOR4 AND LAMTOR5, FUNCTION,
RP IDENTIFICATION IN THE LFC COMPLEX, AND MUTAGENESIS OF ARG-164.
RX PubMed=31704029; DOI=10.1016/j.cell.2019.10.036;
RA Shen K., Rogala K.B., Chou H.T., Huang R.K., Yu Z., Sabatini D.M.;
RT "Cryo-EM structure of the human FLCN-FNIP2-Rag-Ragulator complex.";
RL Cell 179:1319-1329(2019).
RN [35] {ECO:0007744|PDB:6NZD}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.60 ANGSTROMS) IN COMPLEX WITH FNIP2;
RP RRAGA; RRAGC; LAMTOR1; LAMTOR2; LAMTOR3; LAMTOR4 AND LAMTOR5, FUNCTION,
RP ACTIVITY REGULATION, SUBCELLULAR LOCATION, IDENTIFICATION IN THE LFC
RP COMPLEX, AND MUTAGENESIS OF PHE-118 AND ARG-164.
RX PubMed=31672913; DOI=10.1126/science.aax0364;
RA Lawrence R.E., Fromm S.A., Fu Y., Yokom A.L., Kim D.J., Thelen A.M.,
RA Young L.N., Lim C.Y., Samelson A.J., Hurley J.H., Zoncu R.;
RT "Structural mechanism of a Rag GTPase activation checkpoint by the
RT lysosomal folliculin complex.";
RL Science 366:971-977(2019).
RN [36]
RP VARIANTS PSP 315-GLU--ASN-579 DEL AND 477-ARG--ASN-579 DEL.
RX PubMed=15805188; DOI=10.1164/rccm.200501-143oc;
RA Graham R.B., Nolasco M., Peterlin B., Garcia C.K.;
RT "Nonsense mutations in folliculin presenting as isolated familial
RT spontaneous pneumothorax in adults.";
RL Am. J. Respir. Crit. Care Med. 172:39-44(2005).
RN [37]
RP VARIANT RCC CYS-239.
RX PubMed=18794106; DOI=10.1158/1078-0432.ccr-08-0608;
RA Woodward E.R., Ricketts C., Killick P., Gad S., Morris M.R., Kavalier F.,
RA Hodgson S.V., Giraud S., Bressac-de Paillerets B., Chapman C., Escudier B.,
RA Latif F., Richard S., Maher E.R.;
RT "Familial non-VHL clear cell (conventional) renal cell carcinoma: clinical
RT features, segregation analysis, and mutation analysis of FLCN.";
RL Clin. Cancer Res. 14:5925-5930(2008).
RN [38]
RP VARIANTS PSP PHE-157 DEL AND TYR-429.
RX PubMed=18505456; DOI=10.1111/j.1399-0004.2008.01030.x;
RA Ren H.Z., Zhu C.C., Yang C., Chen S.L., Xie J., Hou Y.Y., Xu Z.F.,
RA Wang D.J., Mu D.K., Ma D.H., Wang Y., Ye M.H., Ye Z.R., Chen B.F.,
RA Wang C.G., Lin J., Qiao D., Yi L.;
RT "Mutation analysis of the FLCN gene in Chinese patients with sporadic and
RT familial isolated primary spontaneous pneumothorax.";
RL Clin. Genet. 74:178-183(2008).
RN [39]
RP VARIANT PSP LYS-132.
RX PubMed=18579543; DOI=10.1183/09031936.00132707;
RA Frohlich B.A., Zeitz C., Matyas G., Alkadhi H., Tuor C., Berger W.,
RA Russi E.W.;
RT "Novel mutations in the folliculin gene associated with spontaneous
RT pneumothorax.";
RL Eur. Respir. J. 32:1316-1320(2008).
RN [40]
RP VARIANT BHD ARG-508.
RX PubMed=18234728; DOI=10.1136/jmg.2007.054304;
RA Toro J.R., Wei M.H., Glenn G.M., Weinreich M., Toure O., Vocke C.,
RA Turner M., Choyke P., Merino M.J., Pinto P.A., Steinberg S.M.,
RA Schmidt L.S., Linehan W.M.;
RT "BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-
RT Dube syndrome: a new series of 50 families and a review of published
RT reports.";
RL J. Med. Genet. 45:321-331(2008).
RN [41]
RP VARIANT BHD ILE-108.
RX PubMed=19785621; DOI=10.1111/j.1365-2133.2009.09517.x;
RA Kluger N., Giraud S., Coupier I., Avril M.F., Dereure O., Guillot B.,
RA Richard S., Bessis D.;
RT "Birt-Hogg-Dube syndrome: clinical and genetic studies of 10 French
RT families.";
RL Br. J. Dermatol. 162:527-537(2010).
RN [42]
RP VARIANT CYS-362, AND CHARACTERIZATION OF VARIANTS PHE-157 DEL; CYS-239;
RP CYS-362 AND ARG-508.
RX PubMed=21538689; DOI=10.1002/humu.21519;
RA Nahorski M.S., Reiman A., Lim D.H., Nookala R.K., Seabra L., Lu X.,
RA Fenton J., Boora U., Nordenskjold M., Latif F., Hurst L.D., Maher E.R.;
RT "Birt Hogg-Dube syndrome-associated FLCN mutations disrupt protein
RT stability.";
RL Hum. Mutat. 32:921-929(2011).
RN [43]
RP VARIANT PSP 170-TYR--ASN-579 DEL.
RX PubMed=27486260; DOI=10.1093/qjmed/hcw109;
RA Zhu J.F., Shen X.Q., Zhu F., Tian L.;
RT "Novel folliculin (FLCN) mutation and familial spontaneous pneumothorax.";
RL QJM 110:23-26(2017).
RN [44]
RP VARIANT PSP 425-GLN--ASN-579 DEL.
RX PubMed=31625278; DOI=10.1002/mgg3.1003;
RA Genc Yavuz B., Guzel Tanoglu E., Salman Yilmaz S., Colak S.;
RT "A novel FLCN mutation in family members diagnosed with primary spontaneous
RT pneumothorax.";
RL Mol. Genet. Genomic Med. 7:E1003-E1003(2019).
RN [45]
RP VARIANTS BHD PHE-157 DEL; 220-GLN--ASN-579 DEL; 339-GLN--ASN-579 DEL;
RP 409-TYR--ASN-579 DEL; 511-TRP--ASN-579 DEL AND 533-GLN--ASN-579 DEL.
RX PubMed=31615547; DOI=10.1186/s13023-019-1198-y;
RA Liu K., Xu W., Tian X., Xiao M., Zhao X., Zhang Q., Qu T., Song J., Liu Y.,
RA Xu K.F., Zhang X.;
RT "Genotypic characteristics of Chinese patients with BHD syndrome and
RT functional analysis of FLCN variants.";
RL Orphanet J. Rare Dis. 14:223-223(2019).
CC -!- FUNCTION: Multi-functional protein, involved in both the cellular
CC response to amino acid availability and in the regulation of glycolysis
CC (PubMed:17028174, PubMed:18663353, PubMed:21209915, PubMed:24081491,
CC PubMed:24095279, PubMed:31704029, PubMed:31672913, PubMed:34381247).
CC GTPase-activating protein that plays a key role in the cellular
CC response to amino acid availability through regulation of the mTORC1
CC signaling cascade controlling the MiT/TFE factors TFEB and TFE3
CC (PubMed:17028174, PubMed:18663353, PubMed:21209915, PubMed:24081491,
CC PubMed:24095279, PubMed:31704029, PubMed:31672913). Regulates
CC glycolysis by binding to lactate dehydrogenase LDHA, acting as an
CC uncompetitive inhibitor (PubMed:34381247). Activates mTORC1 by acting
CC as a GTPase-activating protein: specifically stimulates GTP hydrolysis
CC by RRAGC/RagC or RRAGD/RagD, promoting the conversion to the GDP-bound
CC state of RRAGC/RagC or RRAGD/RagD, and thereby activating the kinase
CC activity of mTORC1 (PubMed:24095279, PubMed:31704029, PubMed:31672913).
CC The GTPase-activating activity is inhibited during starvation and
CC activated in presence of nutrients (PubMed:31672913). Acts as a key
CC component for mTORC1-dependent control of the MiT/TFE factors TFEB and
CC TFE3, while it is not involved in mTORC1-dependent phosphorylation of
CC canonical RPS6KB1/S6K1 and EIF4EBP1/4E-BP1 (PubMed:21209915,
CC PubMed:24081491, PubMed:31672913). In low-amino acid conditions, the
CC lysosomal folliculin complex (LFC) is formed on the membrane of
CC lysosomes, which inhibits the GTPase-activating activity of FLCN,
CC inactivates mTORC1 and maximizes nuclear translocation of TFEB and TFE3
CC (PubMed:31672913). Upon amino acid restimulation, RRAGA/RagA (or
CC RRAGB/RagB) nucleotide exchange promotes disassembly of the LFC complex
CC and liberates the GTPase-activating activity of FLCN, leading to
CC activation of mTORC1 and subsequent cytoplasmic retention of TFEB and
CC TFE3 (PubMed:31672913). Indirectly acts as a positive regulator of Wnt
CC signaling by promoting mTOR-dependent cytoplasmic retention of MiT/TFE
CC factor TFE3 (PubMed:31272105). Required for the exit of hematopoietic
CC stem cell from pluripotency by promoting mTOR-dependent cytoplasmic
CC retention of TFE3, thereby increasing Wnt signaling (PubMed:30733432).
CC Acts as an inhibitor of browning of adipose tissue by regulating mTOR-
CC dependent cytoplasmic retention of TFE3 (By similarity). Involved in
CC the control of embryonic stem cells differentiation; together with
CC LAMTOR1 it is necessary to recruit and activate RRAGC/RagC and
CC RRAGD/RagD at the lysosomes, and to induce exit of embryonic stem cells
CC from pluripotency via non-canonical, mTOR-independent TFE3 inactivation
CC (By similarity). In response to flow stress, regulates STK11/LKB1
CC accumulation and mTORC1 activation through primary cilia: may act by
CC recruiting STK11/LKB1 to primary cilia for activation of AMPK resided
CC at basal bodies, causing mTORC1 down-regulation (PubMed:27072130).
CC Together with FNIP1 and/or FNIP2, regulates autophagy: following
CC phosphorylation by ULK1, interacts with GABARAP and promotes autophagy
CC (PubMed:25126726). Required for starvation-induced perinuclear
CC clustering of lysosomes by promoting association of RILP with its
CC effector RAB34 (PubMed:27113757). {ECO:0000250|UniProtKB:Q8QZS3,
CC ECO:0000269|PubMed:17028174, ECO:0000269|PubMed:18663353,
CC ECO:0000269|PubMed:21209915, ECO:0000269|PubMed:24081491,
CC ECO:0000269|PubMed:24095279, ECO:0000269|PubMed:25126726,
CC ECO:0000269|PubMed:27072130, ECO:0000269|PubMed:27113757,
CC ECO:0000269|PubMed:30733432, ECO:0000269|PubMed:31272105,
CC ECO:0000269|PubMed:31672913, ECO:0000269|PubMed:31704029,
CC ECO:0000269|PubMed:34381247}.
CC -!- ACTIVITY REGULATION: GTPase-activating activity is inhibited in the
CC folliculin complex (LFC), which stabilizes the GDP-bound state of
CC RRAGA/RagA (or RRAGB/RagB), because Arg-164 is located far from the
CC RRAGC/RagC or RRAGD/RagD nucleotide pocket (PubMed:31672913).
CC Disassembly of the LFC complex upon amino acid restimulation liberates
CC the GTPase-activating activity (PubMed:31672913).
CC {ECO:0000269|PubMed:31672913}.
CC -!- SUBUNIT: Interacts (via C-terminus) with FNIP1 or FNIP2 (via C-
CC terminus) (PubMed:17028174, PubMed:18403135, PubMed:18663353,
CC PubMed:27353360). Component of the lysosomal folliculin complex (LFC),
CC composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound,
CC RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029,
CC PubMed:31672913). Interaction with FNIP1 or FNIP2 mediates indirect
CC interaction with the PRKAA1, PRKAB1 and PRKAG1 subunits of 5'-AMP-
CC activated protein kinase (AMPK) (PubMed:17028174). Interacts with
CC HSP90AA1 in the presence of FNIP1 (PubMed:27353360). Interacts with
CC HSP70, STUB1, CDC37, AHSA1, CCT2, STIP1, PTGES3 and PPP5C
CC (PubMed:27353360). Interacts with GABARAP; interaction takes place in
CC the presence of FNIP1 and/or FNIP2 (PubMed:25126726). Interacts with
CC RILP; the interaction is direct and promotes association between RILP
CC and RAB34 (PubMed:27113757). Interacts with KIF3A and KIF3B
CC (PubMed:27072130). Interacts with lactate dehydrogenase LDHA, but not
CC LDHB; the interaction is direct, may preferentially bind LDHA dimers
CC rather than tetramers, and regulates LDHA activity, acting as an
CC uncompetitive inhibitor (PubMed:34381247).
CC {ECO:0000269|PubMed:17028174, ECO:0000269|PubMed:18403135,
CC ECO:0000269|PubMed:18663353, ECO:0000269|PubMed:25126726,
CC ECO:0000269|PubMed:27072130, ECO:0000269|PubMed:27113757,
CC ECO:0000269|PubMed:27353360, ECO:0000269|PubMed:31672913,
CC ECO:0000269|PubMed:31704029, ECO:0000269|PubMed:34381247}.
CC -!- INTERACTION:
CC Q8NFG4; Q8TF40: FNIP1; NbExp=5; IntAct=EBI-2970160, EBI-2946919;
CC Q8NFG4; Q9P278: FNIP2; NbExp=7; IntAct=EBI-2970160, EBI-7597109;
CC Q8NFG4-1; Q8TF40-1: FNIP1; NbExp=7; IntAct=EBI-15604776, EBI-15604805;
CC -!- SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:24081491,
CC ECO:0000269|PubMed:24095279, ECO:0000269|PubMed:27113757,
CC ECO:0000269|PubMed:29848618, ECO:0000269|PubMed:31672913}. Cytoplasm,
CC cytosol {ECO:0000269|PubMed:17028174, ECO:0000269|PubMed:18663353,
CC ECO:0000269|PubMed:24081491, ECO:0000269|PubMed:24095279,
CC ECO:0000269|PubMed:29848618, ECO:0000269|PubMed:31672913}. Cell
CC projection, cilium {ECO:0000269|PubMed:23784378,
CC ECO:0000269|PubMed:27072130}. Cytoplasm, cytoskeleton, microtubule
CC organizing center, centrosome {ECO:0000269|PubMed:23784378}. Cytoplasm,
CC cytoskeleton, spindle {ECO:0000269|PubMed:23784378}. Nucleus
CC {ECO:0000269|PubMed:17028174, ECO:0000269|PubMed:18663353}.
CC Note=Localizes to lysosome membrane in amino acid-depleted conditions
CC and relocalizes to the cytosol upon refeeding (PubMed:24095279,
CC PubMed:29848618, PubMed:31672913). Colocalizes with FNIP1 and FNIP2 in
CC the cytoplasm (PubMed:17028174, PubMed:18663353). Also localizes to
CC motile and non-motile cilia, centrosomes and the mitotic spindle
CC (PubMed:23784378). {ECO:0000269|PubMed:17028174,
CC ECO:0000269|PubMed:18663353, ECO:0000269|PubMed:23784378,
CC ECO:0000269|PubMed:24095279, ECO:0000269|PubMed:29848618,
CC ECO:0000269|PubMed:31672913}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q8NFG4-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8NFG4-2; Sequence=VSP_017314, VSP_017315;
CC Name=3;
CC IsoId=Q8NFG4-3; Sequence=VSP_017312, VSP_017313;
CC -!- TISSUE SPECIFICITY: Expressed in most tissues tested, including skin,
CC lung, kidney, heart, testis and stomach. {ECO:0000269|PubMed:12204536}.
CC -!- DEVELOPMENTAL STAGE: Expressed in fetal lung, kidney, liver, and brain.
CC {ECO:0000269|PubMed:12204536}.
CC -!- PTM: Phosphorylation by ULK1 modulates the interaction with GABARAP and
CC is required to regulate autophagy. {ECO:0000269|PubMed:25126726}.
CC -!- DISEASE: Birt-Hogg-Dube syndrome (BHD) [MIM:135150]: A rare autosomal
CC dominant genodermatosis characterized by hair follicle hamartomas
CC (fibrofolliculomas), kidney tumors, and spontaneous pneumothorax.
CC Fibrofolliculomas are part of the triad of Birt-Hogg-Dube syndrome skin
CC lesions that also includes trichodiscomas and acrochordons. Onset of
CC this dermatologic condition is invariably in adulthood. Birt-Hogg-Dube
CC syndrome is associated with a variety of histologic types of renal
CC tumors, including chromophobe renal cell carcinoma (RCC), benign renal
CC oncocytoma, clear-cell RCC and papillary type I RCC. Multiple lipomas,
CC angiolipomas, and parathyroid adenomas are also seen in Birt-Hogg-Dube
CC syndrome patients. {ECO:0000269|PubMed:12204536,
CC ECO:0000269|PubMed:15852235, ECO:0000269|PubMed:18234728,
CC ECO:0000269|PubMed:19785621, ECO:0000269|PubMed:23784378,
CC ECO:0000269|PubMed:31615547}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Primary spontaneous pneumothorax (PSP) [MIM:173600]: Condition
CC in which air is present in the pleural space in the absence of a
CC precipitating event, such as trauma or lung disease. This results in
CC secondary collapse of the lung, either partially or completely, and
CC some degree of hypoxia. PSP is relatively common, with an incidence
CC between 7.4-18/100'000 for men and 1.2-6/100'000 for women and a dose-
CC dependent, increased risk among smokers. Most cases are sporadic,
CC typically occurring in tall, thin men aged 10-30 years and generally
CC while at rest. Familial PSP is rarer and usually is inherited as an
CC autosomal dominant condition with reduced penetrance, although X-linked
CC recessive and autosomal recessive inheritance have also been suggested.
CC {ECO:0000269|PubMed:15657874, ECO:0000269|PubMed:15805188,
CC ECO:0000269|PubMed:17496196, ECO:0000269|PubMed:18505456,
CC ECO:0000269|PubMed:18579543, ECO:0000269|PubMed:19483054,
CC ECO:0000269|PubMed:25827758, ECO:0000269|PubMed:27486260,
CC ECO:0000269|PubMed:31625278}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Renal cell carcinoma (RCC) [MIM:144700]: Renal cell carcinoma
CC is a heterogeneous group of sporadic or hereditary carcinoma derived
CC from cells of the proximal renal tubular epithelium. It is
CC subclassified into clear cell renal carcinoma (non-papillary
CC carcinoma), papillary renal cell carcinoma, chromophobe renal cell
CC carcinoma, collecting duct carcinoma with medullary carcinoma of the
CC kidney, and unclassified renal cell carcinoma. Clear cell renal cell
CC carcinoma is the most common subtype. {ECO:0000269|PubMed:18794106,
CC ECO:0000269|PubMed:23922894}. Note=The gene represented in this entry
CC may be involved in disease pathogenesis.
CC -!- SIMILARITY: Belongs to the folliculin family. {ECO:0000305}.
CC -!- CAUTION: Based on its structure and in vitro assays, was initially
CC thought to have guanine nucleotide exchange factor (GEF) activity
CC (PubMed:22977732). However, subsequent studies showed that it does not
CC act as GEF in vivo (PubMed:24095279). {ECO:0000269|PubMed:22977732,
CC ECO:0000269|PubMed:24095279}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/FLCNID789ch17p11.html";
CC -!- WEB RESOURCE: Name=Leiden Open Variation Database; Note=Folliculin
CC (FLCN);
CC URL="https://databases.lovd.nl/shared/genes/FLCN";
CC ---------------------------------------------------------------------------
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DR EMBL; AF517523; AAM94803.1; -; mRNA.
DR EMBL; AK127912; BAC87186.1; -; mRNA.
DR EMBL; AK126951; BAC86760.1; -; mRNA.
DR EMBL; AC055811; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471196; EAW55716.1; -; Genomic_DNA.
DR EMBL; BC015687; AAH15687.1; -; mRNA.
DR EMBL; BC015725; AAH15725.2; -; mRNA.
DR CCDS; CCDS32579.1; -. [Q8NFG4-1]
DR CCDS; CCDS32580.1; -. [Q8NFG4-2]
DR RefSeq; NP_653207.1; NM_144606.5. [Q8NFG4-2]
DR RefSeq; NP_659434.2; NM_144997.5. [Q8NFG4-1]
DR RefSeq; XP_016879795.1; XM_017024306.1.
DR RefSeq; XP_016879796.1; XM_017024307.1.
DR RefSeq; XP_016879797.1; XM_017024308.1. [Q8NFG4-1]
DR PDB; 3V42; X-ray; 2.00 A; A/B=341-566.
DR PDB; 6NZD; EM; 3.60 A; H=1-579.
DR PDB; 6ULG; EM; 3.31 A; L=1-579.
DR PDBsum; 3V42; -.
DR PDBsum; 6NZD; -.
DR PDBsum; 6ULG; -.
DR AlphaFoldDB; Q8NFG4; -.
DR SMR; Q8NFG4; -.
DR BioGRID; 128366; 98.
DR CORUM; Q8NFG4; -.
DR DIP; DIP-61287N; -.
DR IntAct; Q8NFG4; 27.
DR MINT; Q8NFG4; -.
DR STRING; 9606.ENSP00000285071; -.
DR iPTMnet; Q8NFG4; -.
DR MetOSite; Q8NFG4; -.
DR PhosphoSitePlus; Q8NFG4; -.
DR BioMuta; FLCN; -.
DR DMDM; 74751276; -.
DR EPD; Q8NFG4; -.
DR jPOST; Q8NFG4; -.
DR MassIVE; Q8NFG4; -.
DR MaxQB; Q8NFG4; -.
DR PaxDb; Q8NFG4; -.
DR PeptideAtlas; Q8NFG4; -.
DR PRIDE; Q8NFG4; -.
DR ProteomicsDB; 73302; -. [Q8NFG4-1]
DR ProteomicsDB; 73303; -. [Q8NFG4-2]
DR ProteomicsDB; 73304; -. [Q8NFG4-3]
DR Antibodypedia; 4192; 319 antibodies from 37 providers.
DR DNASU; 201163; -.
DR Ensembl; ENST00000285071.9; ENSP00000285071.4; ENSG00000154803.13. [Q8NFG4-1]
DR Ensembl; ENST00000389169.9; ENSP00000373821.5; ENSG00000154803.13. [Q8NFG4-2]
DR GeneID; 201163; -.
DR KEGG; hsa:201163; -.
DR MANE-Select; ENST00000285071.9; ENSP00000285071.4; NM_144997.7; NP_659434.2.
DR UCSC; uc002gra.5; human. [Q8NFG4-1]
DR CTD; 201163; -.
DR DisGeNET; 201163; -.
DR GeneCards; FLCN; -.
DR GeneReviews; FLCN; -.
DR HGNC; HGNC:27310; FLCN.
DR HPA; ENSG00000154803; Low tissue specificity.
DR MalaCards; FLCN; -.
DR MIM; 135150; phenotype.
DR MIM; 144700; phenotype.
DR MIM; 173600; phenotype.
DR MIM; 607273; gene.
DR neXtProt; NX_Q8NFG4; -.
DR OpenTargets; ENSG00000154803; -.
DR Orphanet; 122; Birt-Hogg-Dube syndrome.
DR Orphanet; 2903; Familial spontaneous pneumothorax.
DR Orphanet; 422526; Hereditary clear cell renal cell carcinoma.
DR PharmGKB; PA134901005; -.
DR VEuPathDB; HostDB:ENSG00000154803; -.
DR eggNOG; KOG3715; Eukaryota.
DR GeneTree; ENSGT00390000009864; -.
DR HOGENOM; CLU_035854_2_0_1; -.
DR InParanoid; Q8NFG4; -.
DR OMA; WKNKVTC; -.
DR OrthoDB; 188544at2759; -.
DR PhylomeDB; Q8NFG4; -.
DR TreeFam; TF315084; -.
DR PathwayCommons; Q8NFG4; -.
DR Reactome; R-HSA-9639288; Amino acids regulate mTORC1.
DR SignaLink; Q8NFG4; -.
DR SIGNOR; Q8NFG4; -.
DR BioGRID-ORCS; 201163; 88 hits in 1077 CRISPR screens.
DR ChiTaRS; FLCN; human.
DR GeneWiki; Folliculin; -.
DR GenomeRNAi; 201163; -.
DR Pharos; Q8NFG4; Tbio.
DR PRO; PR:Q8NFG4; -.
DR Proteomes; UP000005640; Chromosome 17.
DR RNAct; Q8NFG4; protein.
DR Bgee; ENSG00000154803; Expressed in buccal mucosa cell and 179 other tissues.
DR ExpressionAtlas; Q8NFG4; baseline and differential.
DR Genevisible; Q8NFG4; HS.
DR GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR GO; GO:0005929; C:cilium; IDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; IDA:UniProtKB.
DR GO; GO:0005764; C:lysosome; TAS:ParkinsonsUK-UCL.
DR GO; GO:0072686; C:mitotic spindle; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB.
DR GO; GO:0004857; F:enzyme inhibitor activity; IDA:UniProtKB.
DR GO; GO:0005096; F:GTPase activator activity; IDA:UniProtKB.
DR GO; GO:0044877; F:protein-containing complex binding; IDA:UniProtKB.
DR GO; GO:0072111; P:cell proliferation involved in kidney development; IEA:Ensembl.
DR GO; GO:0007043; P:cell-cell junction assembly; ISS:UniProtKB.
DR GO; GO:0034198; P:cellular response to amino acid starvation; IDA:UniProtKB.
DR GO; GO:0009267; P:cellular response to starvation; IDA:UniProtKB.
DR GO; GO:0097009; P:energy homeostasis; ISS:UniProtKB.
DR GO; GO:0050673; P:epithelial cell proliferation; IEA:Ensembl.
DR GO; GO:0070371; P:ERK1 and ERK2 cascade; IEA:Ensembl.
DR GO; GO:0030097; P:hemopoiesis; ISS:UniProtKB.
DR GO; GO:0001701; P:in utero embryonic development; ISS:UniProtKB.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; IEA:Ensembl.
DR GO; GO:0032418; P:lysosome localization; IDA:UniProtKB.
DR GO; GO:2001170; P:negative regulation of ATP biosynthetic process; ISS:UniProtKB.
DR GO; GO:1903444; P:negative regulation of brown fat cell differentiation; ISS:UniProtKB.
DR GO; GO:0030308; P:negative regulation of cell growth; IDA:UniProtKB.
DR GO; GO:0030336; P:negative regulation of cell migration; IMP:UniProtKB.
DR GO; GO:1901723; P:negative regulation of cell proliferation involved in kidney development; ISS:UniProtKB.
DR GO; GO:1901856; P:negative regulation of cellular respiration; IEA:Ensembl.
DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; ISS:YuBioLab.
DR GO; GO:0050680; P:negative regulation of epithelial cell proliferation; IEA:Ensembl.
DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; ISS:UniProtKB.
DR GO; GO:0010629; P:negative regulation of gene expression; ISS:UniProtKB.
DR GO; GO:0045820; P:negative regulation of glycolytic process; IDA:UniProtKB.
DR GO; GO:1901859; P:negative regulation of mitochondrial DNA metabolic process; IEA:Ensembl.
DR GO; GO:0010823; P:negative regulation of mitochondrion organization; ISS:UniProtKB.
DR GO; GO:1901862; P:negative regulation of muscle tissue development; IEA:Ensembl.
DR GO; GO:1901874; P:negative regulation of post-translational protein modification; IEA:Ensembl.
DR GO; GO:0051898; P:negative regulation of protein kinase B signaling; ISS:UniProtKB.
DR GO; GO:1900181; P:negative regulation of protein localization to nucleus; IDA:UniProtKB.
DR GO; GO:0035024; P:negative regulation of Rho protein signal transduction; IMP:UniProtKB.
DR GO; GO:0032007; P:negative regulation of TOR signaling; ISS:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0010508; P:positive regulation of autophagy; IDA:UniProtKB.
DR GO; GO:0045785; P:positive regulation of cell adhesion; IMP:UniProtKB.
DR GO; GO:0043547; P:positive regulation of GTPase activity; IBA:GO_Central.
DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IEA:Ensembl.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0032008; P:positive regulation of TOR signaling; IDA:UniProtKB.
DR GO; GO:1904263; P:positive regulation of TORC1 signaling; IBA:GO_Central.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0043491; P:protein kinase B signaling; IEA:Ensembl.
DR GO; GO:0032465; P:regulation of cytokinesis; IMP:UniProtKB.
DR GO; GO:0035065; P:regulation of histone acetylation; ISS:UniProtKB.
DR GO; GO:2000973; P:regulation of pro-B cell differentiation; ISS:UniProtKB.
DR GO; GO:0001932; P:regulation of protein phosphorylation; IDA:UniProtKB.
DR GO; GO:0046578; P:regulation of Ras protein signal transduction; IDA:UniProtKB.
DR GO; GO:0032006; P:regulation of TOR signaling; ISS:UniProtKB.
DR GO; GO:0031929; P:TOR signaling; IMP:UniProtKB.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; IEA:Ensembl.
DR Gene3D; 1.10.10.1730; -; 1.
DR InterPro; IPR037521; FLCN/SMCR8_DENN.
DR InterPro; IPR044886; FLCN_DENN_C_sf.
DR InterPro; IPR021713; Folliculin.
DR InterPro; IPR037520; Folliculin/SMCR8_longin.
DR InterPro; IPR032035; Folliculin_DENN.
DR PANTHER; PTHR31441; PTHR31441; 1.
DR Pfam; PF11704; Folliculin; 1.
DR Pfam; PF16692; Folliculin_C; 1.
DR PROSITE; PS51834; DENN_FLCN_SMCR8; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell projection; Coiled coil;
KW Cytoplasm; Cytoskeleton; Disease variant; GTPase activation; Lysosome;
KW Membrane; Nucleus; Phosphoprotein; Reference proteome; Tumor suppressor.
FT CHAIN 1..579
FT /note="Folliculin"
FT /id="PRO_0000223940"
FT DOMAIN 86..242
FT /note="uDENN FLCN/SMCR8-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01178"
FT DOMAIN 339..491
FT /note="cDENN FLCN/SMCR8-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01178"
FT DOMAIN 493..558
FT /note="dDENN FLCN/SMCR8-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01178"
FT REGION 30..81
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 210..220
FT /note="Essential for interaction with LDHA"
FT /evidence="ECO:0000269|PubMed:34381247"
FT REGION 294..337
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 287..310
FT /evidence="ECO:0000255"
FT COMPBIAS 322..337
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 164
FT /note="Essential for GTPase activation (GAP) activity"
FT /evidence="ECO:0000269|PubMed:31672913,
FT ECO:0000269|PubMed:31704029"
FT MOD_RES 62
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:18669648,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT MOD_RES 73
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 302
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 406
FT /note="Phosphoserine; by ULK1"
FT /evidence="ECO:0000269|PubMed:25126726"
FT MOD_RES 537
FT /note="Phosphoserine; by ULK1"
FT /evidence="ECO:0000269|PubMed:25126726"
FT MOD_RES 542
FT /note="Phosphoserine; by ULK1"
FT /evidence="ECO:0000269|PubMed:25126726"
FT MOD_RES 571
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 134..197
FT /note="CPGREGPIFFGDEQHGFVFSHTFFIKDSLARGFQRWYSIITIMMDRIYLINS
FT WPFLLGKVRGII -> SLVATEPVSVGAHMLPGALGGLGASIAQGGRHWSSLRADPQIS
FT TAQGTGRLPCPELREESCWTC (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_017312"
FT VAR_SEQ 198..579
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_017313"
FT VAR_SEQ 291..342
FT /note="DLEEESESWDNSEAEEEEKAPVLPESTEGRELTQGPAESSSLSGCGSWQPRK
FT -> GEAGVLLPGPWPGWPWGGTSCLLSWQESLREGNAALNQPRTSLREAHPPISV (in
FT isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_017314"
FT VAR_SEQ 343..579
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_017315"
FT VARIANT 79
FT /note="S -> W (in a sporadic colorectal carcinoma; somatic
FT mutation; dbSNP:rs137852930)"
FT /evidence="ECO:0000269|PubMed:12843323"
FT /id="VAR_025356"
FT VARIANT 108
FT /note="S -> I (in BHD)"
FT /evidence="ECO:0000269|PubMed:19785621"
FT /id="VAR_066023"
FT VARIANT 132
FT /note="E -> K (in PSP)"
FT /evidence="ECO:0000269|PubMed:18579543"
FT /id="VAR_066024"
FT VARIANT 157
FT /note="Missing (in PSP and BHD; impaired protein stability;
FT dbSNP:rs786203218)"
FT /evidence="ECO:0000269|PubMed:18505456,
FT ECO:0000269|PubMed:21538689, ECO:0000269|PubMed:31615547"
FT /id="VAR_066025"
FT VARIANT 170..579
FT /note="Missing (in PSP)"
FT /evidence="ECO:0000269|PubMed:27486260"
FT /id="VAR_083268"
FT VARIANT 220..579
FT /note="Missing (in BHD)"
FT /evidence="ECO:0000269|PubMed:31615547"
FT /id="VAR_083269"
FT VARIANT 238
FT /note="A -> V (in a renal cell carcinoma cell line)"
FT /evidence="ECO:0000269|PubMed:14627671"
FT /id="VAR_025357"
FT VARIANT 239
FT /note="R -> C (in RCC; impaired protein stability;
FT dbSNP:rs78683075)"
FT /evidence="ECO:0000269|PubMed:18794106,
FT ECO:0000269|PubMed:21538689"
FT /id="VAR_066026"
FT VARIANT 315..579
FT /note="Missing (in PSP)"
FT /evidence="ECO:0000269|PubMed:15805188"
FT /id="VAR_083270"
FT VARIANT 320
FT /note="R -> Q (in a primary colorectal cancer;
FT dbSNP:rs143483053)"
FT /evidence="ECO:0000269|PubMed:14627671"
FT /id="VAR_025358"
FT VARIANT 339..579
FT /note="Missing (in BHD)"
FT /evidence="ECO:0000269|PubMed:31615547"
FT /id="VAR_083271"
FT VARIANT 362
FT /note="R -> C (found in a colorectal cell line; impaired
FT protein stability; dbSNP:rs557336321)"
FT /evidence="ECO:0000269|PubMed:21538689"
FT /id="VAR_066027"
FT VARIANT 392
FT /note="R -> G (in a primary colorectal cancer; somatic
FT mutation; dbSNP:rs1060502374)"
FT /evidence="ECO:0000269|PubMed:14627671"
FT /id="VAR_025359"
FT VARIANT 409..579
FT /note="Missing (in BHD)"
FT /evidence="ECO:0000269|PubMed:31615547"
FT /id="VAR_083272"
FT VARIANT 425..579
FT /note="Missing (in PSP)"
FT /evidence="ECO:0000269|PubMed:31625278"
FT /id="VAR_083273"
FT VARIANT 429
FT /note="H -> Y (in PSP; dbSNP:rs375082054)"
FT /evidence="ECO:0000269|PubMed:18505456"
FT /id="VAR_066028"
FT VARIANT 444
FT /note="A -> S (in a primary clear-cell renal cell
FT carcinoma; somatic mutation)"
FT /evidence="ECO:0000269|PubMed:14627671"
FT /id="VAR_025360"
FT VARIANT 445
FT /note="A -> T (in a sporadic colorectal carcinoma; somatic
FT mutation; dbSNP:rs41419545)"
FT /evidence="ECO:0000269|PubMed:12843323"
FT /id="VAR_025361"
FT VARIANT 477..579
FT /note="Missing (in PSP)"
FT /evidence="ECO:0000269|PubMed:15805188"
FT /id="VAR_083274"
FT VARIANT 508
FT /note="K -> R (in BHD; does not impair protein stability,
FT growth suppression activity or intracellular localization
FT of folliculin; dbSNP:rs199643834)"
FT /evidence="ECO:0000269|PubMed:18234728,
FT ECO:0000269|PubMed:21538689"
FT /id="VAR_066029"
FT VARIANT 511..579
FT /note="Missing (in BHD)"
FT /evidence="ECO:0000269|PubMed:31615547"
FT /id="VAR_083275"
FT VARIANT 533..579
FT /note="Missing (in BHD)"
FT /evidence="ECO:0000269|PubMed:31615547"
FT /id="VAR_083276"
FT MUTAGEN 118
FT /note="F->D: Does not assemble into a stable folliculin
FT complex (LFC), preventing localization to the lysosomal
FT membrane upon amino acid starvation."
FT /evidence="ECO:0000269|PubMed:31672913"
FT MUTAGEN 164
FT /note="R->A: Abolished GTPase activation (GAP) activity."
FT /evidence="ECO:0000269|PubMed:31672913,
FT ECO:0000269|PubMed:31704029"
FT MUTAGEN 406
FT /note="S->A: Impaired ability to regulate autophagy; when
FT associated with A-537 and A-542."
FT /evidence="ECO:0000269|PubMed:25126726"
FT MUTAGEN 537
FT /note="S->A: Impaired ability to regulate autophagy; when
FT associated with A-406 and A-542."
FT /evidence="ECO:0000269|PubMed:25126726"
FT MUTAGEN 542
FT /note="S->A: Impaired ability to regulate autophagy; when
FT associated with A-406 and A-537."
FT /evidence="ECO:0000269|PubMed:25126726"
FT STRAND 4..10
FT /evidence="ECO:0007829|PDB:6ULG"
FT STRAND 12..14
FT /evidence="ECO:0007829|PDB:6ULG"
FT STRAND 16..22
FT /evidence="ECO:0007829|PDB:6ULG"
FT STRAND 95..98
FT /evidence="ECO:0007829|PDB:6ULG"
FT TURN 100..102
FT /evidence="ECO:0007829|PDB:6ULG"
FT STRAND 105..108
FT /evidence="ECO:0007829|PDB:6ULG"
FT HELIX 115..129
FT /evidence="ECO:0007829|PDB:6ULG"
FT STRAND 135..137
FT /evidence="ECO:0007829|PDB:6ULG"
FT STRAND 139..144
FT /evidence="ECO:0007829|PDB:6ULG"
FT STRAND 150..159
FT /evidence="ECO:0007829|PDB:6ULG"
FT STRAND 161..177
FT /evidence="ECO:0007829|PDB:6ULG"
FT HELIX 179..183
FT /evidence="ECO:0007829|PDB:6ULG"
FT HELIX 186..214
FT /evidence="ECO:0007829|PDB:6ULG"
FT STRAND 243..245
FT /evidence="ECO:0007829|PDB:6ULG"
FT HELIX 250..266
FT /evidence="ECO:0007829|PDB:6ULG"
FT STRAND 267..269
FT /evidence="ECO:0007829|PDB:6ULG"
FT HELIX 283..290
FT /evidence="ECO:0007829|PDB:6ULG"
FT STRAND 340..343
FT /evidence="ECO:0007829|PDB:6ULG"
FT HELIX 349..356
FT /evidence="ECO:0007829|PDB:3V42"
FT HELIX 358..370
FT /evidence="ECO:0007829|PDB:3V42"
FT STRAND 373..377
FT /evidence="ECO:0007829|PDB:3V42"
FT HELIX 381..391
FT /evidence="ECO:0007829|PDB:3V42"
FT HELIX 392..394
FT /evidence="ECO:0007829|PDB:3V42"
FT HELIX 397..399
FT /evidence="ECO:0007829|PDB:3V42"
FT STRAND 402..408
FT /evidence="ECO:0007829|PDB:3V42"
FT TURN 412..414
FT /evidence="ECO:0007829|PDB:3V42"
FT STRAND 416..420
FT /evidence="ECO:0007829|PDB:3V42"
FT HELIX 428..431
FT /evidence="ECO:0007829|PDB:3V42"
FT STRAND 436..443
FT /evidence="ECO:0007829|PDB:3V42"
FT STRAND 463..469
FT /evidence="ECO:0007829|PDB:3V42"
FT TURN 473..476
FT /evidence="ECO:0007829|PDB:3V42"
FT HELIX 481..491
FT /evidence="ECO:0007829|PDB:3V42"
FT STRAND 493..495
FT /evidence="ECO:0007829|PDB:6ULG"
FT HELIX 497..521
FT /evidence="ECO:0007829|PDB:3V42"
FT HELIX 530..538
FT /evidence="ECO:0007829|PDB:3V42"
FT HELIX 544..553
FT /evidence="ECO:0007829|PDB:3V42"
FT HELIX 554..556
FT /evidence="ECO:0007829|PDB:3V42"
FT HELIX 559..567
FT /evidence="ECO:0007829|PDB:6ULG"
SQ SEQUENCE 579 AA; 64473 MW; E168EB34544C6336 CRC64;
MNAIVALCHF CELHGPRTLF CTEVLHAPLP QGDGNEDSPG QGEQAEEEEG GIQMNSRMRA
HSPAEGASVE SSSPGPKKSD MCEGCRSLAA GHPGYISHDK ETSIKYVSHQ HPSHPQLFSI
VRQACVRSLS CEVCPGREGP IFFGDEQHGF VFSHTFFIKD SLARGFQRWY SIITIMMDRI
YLINSWPFLL GKVRGIIDEL QGKALKVFEA EQFGCPQRAQ RMNTAFTPFL HQRNGNAARS
LTSLTSDDNL WACLHTSFAW LLKACGSRLT EKLLEGAPTE DTLVQMEKLA DLEEESESWD
NSEAEEEEKA PVLPESTEGR ELTQGPAESS SLSGCGSWQP RKLPVFKSLR HMRQVLGAPS
FRMLAWHVLM GNQVIWKSRD VDLVQSAFEV LRTMLPVGCV RIIPYSSQYE EAYRCNFLGL
SPHVQIPPHV LSSEFAVIVE VHAAARSTLH PVGCEDDQSL SKYEFVVTSG SPVAADRVGP
TILNKIEAAL TNQNLSVDVV DQCLVCLKEE WMNKVKVLFK FTKVDSRPKE DTQKLLSILG
ASEEDNVKLL KFWMTGLSKT YKSHLMSTVR SPTASESRN
