ID FLCN_MOUSE Reviewed; 579 AA. AC Q8QZS3; Q3U4U8; Q3UFZ1; Q5SWZ2; Q5SX01; Q5SX02; Q8CAC0; DT 21-FEB-2006, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2002, sequence version 1. DT 02-SEP-2026, entry version 156. DE RecName: Full=Folliculin {ECO:0000303|PubMed:18974783}; DE AltName: Full=Birt-Hogg-Dube syndrome protein homolog {ECO:0000303|PubMed:19850877}; GN Name=Flcn {ECO:0000303|PubMed:18974783, ECO:0000312|MGI:MGI:2442184}; GN Synonyms=Bhd {ECO:0000303|PubMed:19850877}; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=C57BL/6J; TISSUE=Adipose tissue, Egg, Hypothalamus, and Thymus; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=C57BL/6J; RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112; RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S., RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., RA Eichler E.E., Ponting C.P.; RT "Lineage-specific biology revealed by a finished genome assembly of the RT mouse."; RL PLoS Biol. 7:E1000112-E1000112(2009). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC STRAIN=FVB/N; TISSUE=Liver; 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 [4] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-62 AND SER-73, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19144319; DOI=10.1016/j.immuni.2008.11.006; RA Trost M., English L., Lemieux S., Courcelles M., Desjardins M., RA Thibault P.; RT "The phagosomal proteome in interferon-gamma-activated macrophages."; RL Immunity 30:143-154(2009). RN [5] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-62 AND SER-73, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brain, Kidney, Liver, Pancreas, Spleen, and Testis; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [6] RP DISRUPTION PHENOTYPE. RX PubMed=18182616; DOI=10.1093/jnci/djm288; RA Baba M., Furihata M., Hong S.B., Tessarollo L., Haines D.C., Southon E., RA Patel V., Igarashi P., Alvord W.G., Leighty R., Yao M., Bernardo M., RA Ileva L., Choyke P., Warren M.B., Zbar B., Linehan W.M., Schmidt L.S.; RT "Kidney-targeted Birt-Hogg-Dube gene inactivation in a mouse model: Erk1/2 RT and Akt-mTOR activation, cell hyperproliferation, and polycystic kidneys."; RL J. Natl. Cancer Inst. 100:140-154(2008). RN [7] RP DISRUPTION PHENOTYPE. RX PubMed=18974783; DOI=10.1371/journal.pone.0003581; RA Chen J., Futami K., Petillo D., Peng J., Wang P., Knol J., Li Y., RA Khoo S.K., Huang D., Qian C.N., Zhao P., Dykema K., Dykyma K., Zhang R., RA Cao B., Yang X.J., Furge K., Williams B.O., Teh B.T.; RT "Deficiency of FLCN in mouse kidney led to development of polycystic RT kidneys and renal neoplasia."; RL PLoS ONE 3:E3581-E3581(2008). RN [8] RP DISRUPTION PHENOTYPE, TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE. RX PubMed=19850877; DOI=10.1073/pnas.0908853106; RA Hasumi Y., Baba M., Ajima R., Hasumi H., Valera V.A., Klein M.E., RA Haines D.C., Merino M.J., Hong S.B., Yamaguchi T.P., Schmidt L.S., RA Linehan W.M.; RT "Homozygous loss of BHD causes early embryonic lethality and kidney tumor RT development with activation of mTORC1 and mTORC2."; RL Proc. Natl. Acad. Sci. U.S.A. 106:18722-18727(2009). RN [9] RP FUNCTION. RX PubMed=23582324; DOI=10.1016/j.cell.2013.03.012; RA Betschinger J., Nichols J., Dietmann S., Corrin P.D., Paddison P.J., RA Smith A.; RT "Exit from pluripotency is gated by intracellular redistribution of the RT bHLH transcription factor Tfe3."; RL Cell 153:335-347(2013). RN [10] RP DISRUPTION PHENOTYPE. RX PubMed=24908670; DOI=10.1093/hmg/ddu286; RA Hasumi Y., Baba M., Hasumi H., Huang Y., Lang M., Reindorf R., Oh H.B., RA Sciarretta S., Nagashima K., Haines D.C., Schneider M.D., Adelstein R.S., RA Schmidt L.S., Sadoshima J., Marston Linehan W.; RT "Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through RT mTORC1 deregulation."; RL Hum. Mol. Genet. 23:5706-5719(2014). RN [11] RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE. RX PubMed=27913603; DOI=10.1101/gad.287953.116; RA Wada S., Neinast M., Jang C., Ibrahim Y.H., Lee G., Babu A., Li J., RA Hoshino A., Rowe G.C., Rhee J., Martina J.A., Puertollano R., Blenis J., RA Morley M., Baur J.A., Seale P., Arany Z.; RT "The tumor suppressor FLCN mediates an alternate mTOR pathway to regulate RT browning of adipose tissue."; RL Genes Dev. 30:2551-2564(2016). RN [12] 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 [13] RP FUNCTION. RX PubMed=30595499; DOI=10.1016/j.stem.2018.11.021; RA Villegas F., Lehalle D., Mayer D., Rittirsch M., Stadler M.B., Zinner M., RA Olivieri D., Vabres P., Duplomb-Jego L., De Bont E.S.J.M., Duffourd Y., RA Duijkers F., Avila M., Genevieve D., Houcinat N., Jouan T., Kuentz P., RA Lichtenbelt K.D., Thauvin-Robinet C., St-Onge J., Thevenon J., RA van Gassen K.L.I., van Haelst M., van Koningsbruggen S., Hess D., RA Smallwood S.A., Riviere J.B., Faivre L., Betschinger J.; RT "Lysosomal signaling licenses embryonic stem cell differentiation via RT inactivation of Tfe3."; RL Cell Stem Cell 24:257-270(2019). RN [14] RP FUNCTION, AND DISRUPTION PHENOTYPE. RX PubMed=32612235; DOI=10.1038/s41586-020-2444-0; RA Napolitano G., Di Malta C., Esposito A., de Araujo M.E.G., Pece S., RA Bertalot G., Matarese M., Benedetti V., Zampelli A., Stasyk T., RA Siciliano D., Venuta A., Cesana M., Vilardo C., Nusco E., Monfregola J., RA Calcagni A., Di Fiore P.P., Huber L.A., Ballabio A.; RT "A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dube syndrome."; RL Nature 585:597-602(2020). CC -!- FUNCTION: Multi-functional protein, involved in both the cellular CC response to amino acid availability and in the regulation of glycolysis CC (PubMed:23582324, PubMed:27913603, PubMed:32612235). GTPase-activating CC protein that plays a key role in the cellular response to amino acid CC availability through regulation of the non-canonical mTORC1 signaling CC cascade controlling the MiT/TFE factors TFEB and TFE3 (PubMed:23582324, CC PubMed:27913603, PubMed:32612235). Activates mTORC1 by acting as a CC GTPase-activating protein: specifically stimulates GTP hydrolysis by CC RagC/RRAGC or RagD/RRAGD, promoting the conversion to the GDP-bound CC state of RagC/RRAGC or RagD/RRAGD, and thereby activating the kinase CC activity of mTORC1 (By similarity). The GTPase-activating activity is CC inhibited during starvation and activated in presence of nutrients (By CC similarity). Acts as a key component for non-canonical mTORC1-dependent CC control of the MiT/TFE factors TFEB and TFE3, while it is not involved CC in mTORC1-dependent phosphorylation of canonical RPS6KB1/S6K1 and CC EIF4EBP1/4E-BP1 (PubMed:27913603, PubMed:32612235). In low-amino acid CC conditions, the lysosomal folliculin complex (LFC) is formed on the CC membrane of lysosomes, which inhibits the GTPase-activating activity of CC FLCN, inactivates mTORC1 and maximizes nuclear translocation of TFEB CC and TFE3 (By similarity). Upon amino acid restimulation, RagA/RRAGA (or CC RagB/RRAGB) 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 (By similarity). 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 (By similarity). CC Involved in the control of embryonic stem cells differentiation; CC together with LAMTOR1 it is necessary to recruit and activate CC RagC/RRAGC and RagD/RRAGD at the lysosomes, and to induce exit of CC embryonic stem cells from pluripotency via non-canonical, mTOR- CC independent TFE3 inactivation (PubMed:30595499). Acts as an inhibitor CC of browning of adipose tissue by regulating mTOR-dependent cytoplasmic CC retention of TFE3 (PubMed:27913603). In response to flow stress, CC regulates STK11/LKB1 accumulation and mTORC1 activation through primary CC cilia: may act by recruiting STK11/LKB1 to primary cilia for activation CC of AMPK resided at basal bodies, causing mTORC1 down-regulation (By CC similarity). Together with FNIP1 and/or FNIP2, regulates autophagy: CC following phosphorylation by ULK1, interacts with GABARAP and promotes CC autophagy (By similarity). Interaction with GABARAP also inhibits the CC non-canonical mTORC1 signaling cascade: GABARAP sequesters FLCN, CC thereby inactivating mTORC1 and promoting nuclear translocation of TFEB CC and TFE3 (By similarity). Required for starvation-induced perinuclear CC clustering of lysosomes by promoting association of RILP with its CC effector RAB34 (By similarity). Regulates glycolysis by binding to CC lactate dehydrogenase LDHA, acting as an uncompetitive inhibitor (By CC similarity). {ECO:0000250|UniProtKB:Q8NFG4, CC ECO:0000269|PubMed:23582324, ECO:0000269|PubMed:27913603, CC ECO:0000269|PubMed:30595499, ECO:0000269|PubMed:31272105, CC ECO:0000269|PubMed:32612235}. CC -!- ACTIVITY REGULATION: GTPase-activating activity is inhibited in the CC folliculin complex (LFC), which stabilizes the GDP-bound state of CC RagA/RRAGA (or RagB/RRAGB), because Arg-164 is located far from the CC RagC/RRAGC or RagD/RRAGD nucleotide pocket (By similarity). Disassembly CC of the LFC complex upon amino acid restimulation liberates the GTPase- CC activating activity (By similarity). {ECO:0000250|UniProtKB:Q8NFG4}. CC -!- SUBUNIT: Interacts (via C-terminus) with FNIP1 or FNIP2 (via C- CC terminus). Component of the lysosomal folliculin complex (LFC), CC composed of FLCN, FNIP1 (or FNIP2), RagA/RRAGA or RagB/RRAGB GDP-bound, CC RagC/RRAGC or RagD/RRAGD GTP-bound, and Ragulator. Interaction with CC FNIP1 or FNIP2 mediates indirect interaction with the PRKAA1, PRKAB1 CC and PRKAG1 subunits of 5'-AMP-activated protein kinase (AMPK). CC Interacts with HSP90AA1 in the presence of FNIP1. Interacts with HSP70, CC STUB1, CDC37, AHSA1, CCT2, STIP1, PTGES3 and PPP5C (By similarity). CC Interacts with GABARAP; interaction takes place in the presence of CC FNIP1 and/or FNIP2 (By similarity). Interaction with GABARAP sequesters CC FLCN, thereby inactivating mTORC1 (By similarity). Interacts with RILP; CC the interaction is direct and promotes association between RILP and CC RAB34 (By similarity). Interacts with KIF3A and KIF3B (By similarity). CC Interacts with lactate dehydrogenase LDHA, but not LDHB; the CC interaction is direct, may preferentially bind LDHA dimers rather than CC tetramers, and regulates LDHA activity, acting as an uncompetitive CC inhibitor. {ECO:0000250|UniProtKB:Q8NFG4}. CC -!- INTERACTION: CC Q8QZS3; Q68FD7: Fnip1; NbExp=3; IntAct=EBI-6911093, EBI-6911068; CC -!- SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000250|UniProtKB:Q8NFG4}. CC Cytoplasm, cytosol {ECO:0000250|UniProtKB:Q8NFG4}. Cell projection, CC cilium {ECO:0000250|UniProtKB:Q8NFG4}. Cytoplasm, cytoskeleton, CC microtubule organizing center, centrosome CC {ECO:0000250|UniProtKB:Q8NFG4}. Cytoplasm, cytoskeleton, spindle CC {ECO:0000250|UniProtKB:Q8NFG4}. Nucleus {ECO:0000250|UniProtKB:Q8NFG4}. CC Note=Localizes to lysosome membrane in amino acid-depleted conditions CC and relocalizes to the cytosol upon refeeding. Colocalizes with FNIP1 CC and FNIP2 in the cytoplasm. Also localizes to motile and non-motile CC cilia, centrosomes and the mitotic spindle. CC {ECO:0000250|UniProtKB:Q8NFG4}. CC -!- TISSUE SPECIFICITY: Highly expressed in adult heart, pancreas, and CC prostate with moderate expression in adult brain, kidney, liver, CC adipose tissue and lung. {ECO:0000269|PubMed:19850877, CC ECO:0000269|PubMed:27913603}. CC -!- DEVELOPMENTAL STAGE: Expressed throughout embryogenesis CC (PubMed:19850877). At 5.5 dpc, expression is restricted to CC extraembryonic tissues; by 6.5 dpc, expressed in both embryonic and CC extraembryonic tissues (PubMed:19850877). Strong expression is observed CC in certain tissues including neural ectoderm, headfold and limb buds, CC while it is weakly expressed in the surrounding endoderm and heart CC (PubMed:19850877). {ECO:0000269|PubMed:19850877}. CC -!- PTM: Phosphorylation by ULK1 modulates the interaction with GABARAP and CC is required to regulate autophagy. {ECO:0000250|UniProtKB:Q8NFG4}. CC -!- DISRUPTION PHENOTYPE: Embryonic lethality at 5.5-6.5 dpc, showing CC defects in the visceral endoderm (PubMed:18974783, PubMed:19850877). CC Heterozygous knockout mice appear normal at birth but develop kidney CC cysts and solid tumors as they age, probably caused by activation of CC the mTOR pathway (PubMed:19850877). Conditional deletion in kidney CC leads to development of polycystic kidneys and renal neoplasia, caused CC by activation of the mTOR pathway (PubMed:18182616, PubMed:18974783, CC PubMed:32612235). Mice lacking Tfeb and Flcn in the kidney do not show CC any abnormality in the kidney, suggesting that the kidney phenotype CC observed in Flcn knockout mice is due to constitutive activation of CC Tfeb (PubMed:32612235). Conditional deletion in heart causes cardiac CC hypertrophy with deregulated energy homeostasis leading to dilated CC cardiomyopathy: defects are caused by mTORC1 up-regulation CC (PubMed:24908670). Conditional deletion in adipose tissue leads to CC browning of white adipose tissue (WAT) caused by deregulation of mTORC1 CC that relieves cytoplasmic retention of Tfe3, leading to direct CC induction of the Ppargc1b/PGC-1 transcriptional coactivators, drivers CC of mitochondrial biogenesis and the browning program (PubMed:27913603). CC {ECO:0000269|PubMed:18182616, ECO:0000269|PubMed:18974783, CC ECO:0000269|PubMed:19850877, ECO:0000269|PubMed:24908670, CC ECO:0000269|PubMed:27913603, ECO:0000269|PubMed:32612235}. CC -!- SIMILARITY: Belongs to the folliculin family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=BAC30240.1; Type=Frameshift; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AK039106; BAC30240.1; ALT_FRAME; mRNA. DR EMBL; AK080933; BAC38084.1; -; mRNA. DR EMBL; AK136071; BAE22806.1; -; mRNA. DR EMBL; AK148216; BAE28418.1; -; mRNA. DR EMBL; AK154040; BAE32332.1; -; mRNA. DR EMBL; AL596204; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC025820; AAH25820.1; -; mRNA. DR CCDS; CCDS24777.1; -. DR RefSeq; NP_001258285.1; NM_001271356.1. DR RefSeq; NP_001258286.1; NM_001271357.1. DR RefSeq; NP_666130.1; NM_146018.2. DR RefSeq; XP_011247207.1; XM_011248905.4. DR RefSeq; XP_036012443.1; XM_036156550.1. DR AlphaFoldDB; Q8QZS3; -. DR SMR; Q8QZS3; -. DR FunCoup; Q8QZS3; 2888. DR IntAct; Q8QZS3; 1. DR STRING; 10090.ENSMUSP00000099758; -. DR iPTMnet; Q8QZS3; -. DR PhosphoSitePlus; Q8QZS3; -. DR SwissPalm; Q8QZS3; -. DR jPOST; Q8QZS3; -. DR PaxDb; 10090-ENSMUSP00000099758; -. DR PeptideAtlas; Q8QZS3; -. DR ProteomicsDB; 267593; -. DR Pumba; Q8QZS3; -. DR DNASU; 216805; -. DR Ensembl; ENSMUST00000091246.11; ENSMUSP00000091696.4; ENSMUSG00000032633.13. DR Ensembl; ENSMUST00000102697.10; ENSMUSP00000099758.4; ENSMUSG00000032633.13. DR GeneID; 216805; -. DR KEGG; mmu:216805; -. DR UCSC; uc007jew.2; mouse. DR AGR; MGI:2442184; -. DR CTD; 201163; -. DR MGI; MGI:2442184; Flcn. DR VEuPathDB; HostDB:ENSMUSG00000032633; -. DR eggNOG; KOG3715; Eukaryota. DR GeneTree; ENSGT00390000009864; -. DR HOGENOM; CLU_035854_2_0_1; -. DR InParanoid; Q8QZS3; -. DR OMA; LWASLHC; -. DR OrthoDB; 5599713at2759; -. DR PhylomeDB; Q8QZS3; -. DR Reactome; R-MMU-9639288; Amino acids regulate mTORC1. DR BioGRID-ORCS; 216805; 25 hits in 80 CRISPR screens. DR PRO; PR:Q8QZS3; -. DR Proteomes; UP000000589; Chromosome 11. DR RNAct; Q8QZS3; protein. DR Bgee; ENSMUSG00000032633; Expressed in submandibular gland and 259 other cell types or tissues. DR ExpressionAtlas; Q8QZS3; baseline and differential. DR GO; GO:0044291; C:cell-cell contact zone; IEA:Ensembl. DR GO; GO:0005813; C:centrosome; ISS:UniProtKB. DR GO; GO:0005929; C:cilium; ISS:UniProtKB. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; ISS:UniProtKB. DR GO; GO:1990877; C:FNIP-folliculin RagC/D GAP; ISS:UniProtKB. DR GO; GO:0005765; C:lysosomal membrane; ISS:UniProtKB. DR GO; GO:0030496; C:midbody; IEA:Ensembl. DR GO; GO:0072686; C:mitotic spindle; ISS:UniProtKB. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB. DR GO; GO:0019899; F:enzyme binding; ISO:GO_Central. DR GO; GO:0004857; F:enzyme inhibitor activity; ISO:GO_Central. DR GO; GO:0005096; F:GTPase activator activity; ISS:UniProtKB. DR GO; GO:0044877; F:protein-containing complex binding; ISO:GO_Central. DR GO; GO:0007043; P:cell-cell junction assembly; IMP:UniProtKB. DR GO; GO:0034198; P:cellular response to amino acid starvation; ISS:UniProtKB. DR GO; GO:0031669; P:cellular response to nutrient levels; ISO:GO_Central. DR GO; GO:0009267; P:cellular response to starvation; ISS:UniProtKB. DR GO; GO:0097009; P:energy homeostasis; IMP:UniProtKB. DR GO; GO:0030097; P:hemopoiesis; IMP:MGI. DR GO; GO:0001701; P:in utero embryonic development; IMP:MGI. DR GO; GO:0035556; P:intracellular signal transduction; ISS:UniProtKB. DR GO; GO:0032418; P:lysosome localization; ISS:UniProtKB. DR GO; GO:0007040; P:lysosome organization; ISO:GO_Central. DR GO; GO:1903444; P:negative regulation of brown fat cell differentiation; IMP:UniProtKB. DR GO; GO:0008285; P:negative regulation of cell population proliferation; IGI:MGI. DR GO; GO:1901723; P:negative regulation of cell proliferation involved in kidney development; IMP:MGI. DR GO; GO:0120163; P:negative regulation of cold-induced thermogenesis; IMP:YuBioLab. DR GO; GO:0045892; P:negative regulation of DNA-templated transcription; IMP:UniProtKB. DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; IMP:MGI. DR GO; GO:0045820; P:negative regulation of glycolytic process; ISO:GO_Central. DR GO; GO:1905672; P:negative regulation of lysosome organization; ISO:GO_Central. DR GO; GO:0051898; P:negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; IMP:MGI. DR GO; GO:1901874; P:negative regulation of post-translational protein modification; IMP:UniProtKB. DR GO; GO:1900181; P:negative regulation of protein localization to nucleus; ISO:GO_Central. DR GO; GO:0035024; P:negative regulation of Rho protein signal transduction; ISS:UniProtKB. DR GO; GO:0032007; P:negative regulation of TOR signaling; IMP:MGI. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:UniProtKB. DR GO; GO:0010508; P:positive regulation of autophagy; ISS:UniProtKB. DR GO; GO:2001244; P:positive regulation of intrinsic apoptotic signaling pathway; IMP:MGI. DR GO; GO:0032008; P:positive regulation of TOR signaling; IMP:MGI. DR GO; GO:1904263; P:positive regulation of TORC1 signaling; ISS:UniProtKB. DR GO; GO:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; IMP:MGI. DR GO; GO:0031648; P:protein destabilization; ISO:GO_Central. DR GO; GO:2000973; P:regulation of pro-B cell differentiation; IMP:MGI. DR GO; GO:0046578; P:regulation of Ras protein signal transduction; ISS:UniProtKB. DR GO; GO:0032006; P:regulation of TOR signaling; IMP:MGI. DR GO; GO:0031146; P:SCF-dependent proteasomal ubiquitin-dependent protein catabolic process; ISO:GO_Central. DR GO; GO:0038202; P:TORC1 signaling; ISO:GO_Central. DR FunFam; 1.10.10.1730:FF:000001; Folliculin; 1. DR FunFam; 3.40.50.12430:FF:000001; Folliculin; 1. DR Gene3D; 3.40.50.12430; -; 1. DR Gene3D; 1.10.10.1730; Folliculin; 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:SF2; FOLLICULIN; 1. DR PANTHER; PTHR31441; FOLLICULIN FAMILY MEMBER; 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 Cell projection; Coiled coil; Cytoplasm; Cytoskeleton; GTPase activation; KW Lysosome; Membrane; Nucleus; Phosphoprotein; Reference proteome; KW Tumor suppressor. FT CHAIN 1..579 FT /note="Folliculin" FT /id="PRO_0000223941" 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 31..82 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 294..323 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COILED 287..310 FT /evidence="ECO:0000255" FT COMPBIAS 63..76 FT /note="Low complexity" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 294..308 FT /note="Acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 164 FT /note="Essential for GTPase activation (GAP) activity" FT /evidence="ECO:0000250|UniProtKB:Q8NFG4" FT MOD_RES 62 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19144319, FT ECO:0007744|PubMed:21183079" FT MOD_RES 73 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19144319, FT ECO:0007744|PubMed:21183079" FT MOD_RES 302 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8NFG4" FT MOD_RES 406 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8NFG4" FT MOD_RES 537 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8NFG4" FT MOD_RES 542 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8NFG4" FT MOD_RES 571 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8NFG4" FT CONFLICT 29 FT /note="L -> M (in Ref. 1; BAE28418)" FT /evidence="ECO:0000305" FT CONFLICT 240 FT /note="S -> Y (in Ref. 1; BAE28418)" FT /evidence="ECO:0000305" FT CONFLICT 328 FT /note="E -> G (in Ref. 1; BAE32332)" FT /evidence="ECO:0000305" FT CONFLICT 377 FT /note="K -> R (in Ref. 1; BAC30240)" FT /evidence="ECO:0000305" SQ SEQUENCE 579 AA; 64327 MW; DD20DB9F7AFAC81C CRC64; MNAIVALCHF CELHGPRTLF CTEVLHAPLP QGAGSGDSPD QVEQAEEEEG GIQMSSRVRA HSPAEGASSE SSSPGPKKSD MCEGCRSLAV GHPGYISHDK ETSIKYVSHQ HPNHPQLFSI VRQACVRSLS CEVCPGREGP IFFGDEQHGF VFSHTFFIKD SLARGFQRWY SIIAIMMDRI YLINSWPFLL GRIRGIISEL QAKAFKVFEA EQFGCPQRAQ RMNTAFTPFL HQRNGNAARS LTSLTSDDNL WACLHTSFAW LLKACGSRLT EKLLEGAPTE DTLVQMEKLA DLEEESESWD NSEAEEEEKA PVTPEGAEGR ELTSCPTESS FLSACGSWQP PKLTGFKSLR HMRQVLGAPS FRMLAWHVLM GNQVIWKSRD VNLVHSAFEV LRTMLPVGCV RIIPYSSQYE EAYRCNFLGL SPPVPIPAHV LASEFVVVVE VHTATRSNLH PAGCEDDQSL SKYEFVVTSG SPVAADRVGP TILNKIEAAL TNQNLSVDVV DQCLICLKEE WMNKVKVLFK FTKVDSRPKE DTQKLLSVLG ASEEDNVKLL KFWMTGLSKT YKSHLMSTVR SPTATESRS //