FLCN_BOVIN
ID FLCN_BOVIN Reviewed; 579 AA.
AC Q3B7L5;
DT 21-FEB-2006, integrated into UniProtKB/Swiss-Prot.
DT 22-NOV-2005, sequence version 1.
DT 03-AUG-2022, entry version 107.
DE RecName: Full=Folliculin {ECO:0000250|UniProtKB:Q8NFG4};
GN Name=FLCN {ECO:0000250|UniProtKB:Q8NFG4};
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Hereford; TISSUE=Uterus;
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (OCT-2005) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Multi-functional protein, involved in both the cellular
CC response to amino acid availability and in the regulation of glycolysis
CC (By similarity). GTPase-activating protein that plays a key role in the
CC cellular response to amino acid availability through regulation of the
CC mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3
CC (By similarity). Regulates glycolysis by binding to lactate
CC dehydrogenase LDHA, acting as an uncompetitive inhibitor (By
CC similarity). Activates mTORC1 by acting as a GTPase-activating protein:
CC specifically stimulates GTP hydrolysis by RRAGC/RagC or RRAGD/RagD,
CC promoting the conversion to the GDP-bound state of RRAGC/RagC or
CC RRAGD/RagD, and thereby activating the kinase activity of mTORC1 (By
CC similarity). The GTPase-activating activity is inhibited during
CC starvation and activated in presence of nutrients (By similarity). Acts
CC as a key component for mTORC1-dependent control of the MiT/TFE factors
CC TFEB and TFE3, while it is not involved in mTORC1-dependent
CC phosphorylation of canonical RPS6KB1/S6K1 and EIF4EBP1/4E-BP1 (By
CC similarity). In low-amino acid conditions, the lysosomal folliculin
CC complex (LFC) is formed on the membrane of lysosomes, which inhibits
CC the GTPase-activating activity of FLCN, inactivates mTORC1 and
CC maximizes nuclear translocation of TFEB and TFE3 (By similarity). Upon
CC amino acid restimulation, RRAGA/RagA (or RRAGB/RagB) nucleotide
CC exchange promotes disassembly of the LFC complex and liberates the
CC GTPase-activating activity of FLCN, leading to activation of mTORC1 and
CC subsequent cytoplasmic retention of TFEB and TFE3 (By similarity).
CC Indirectly acts as a positive regulator of Wnt signaling by promoting
CC mTOR-dependent cytoplasmic retention of MiT/TFE factor TFE3 (By
CC similarity). Required for the exit of hematopoietic stem cell from
CC pluripotency by promoting mTOR-dependent cytoplasmic retention of TFE3,
CC thereby increasing Wnt signaling (By similarity). Involved in the
CC control of embryonic stem cells differentiation; together with LAMTOR1
CC it is necessary to recruit and activate RRAGC/RagC and RRAGD/RagD at
CC the lysosomes, and to induce exit of embryonic stem cells from
CC pluripotency via non-canonical, mTOR-independent TFE3 inactivation (By
CC similarity). Acts as an inhibitor of browning of adipose tissue by
CC regulating mTOR-dependent cytoplasmic retention of TFE3 (By
CC 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 (By similarity).
CC Together with FNIP1 and/or FNIP2, regulates autophagy: following
CC phosphorylation by ULK1, interacts with GABARAP and promotes autophagy
CC (By similarity). Required for starvation-induced perinuclear clustering
CC of lysosomes by promoting association of RILP with its effector RAB34
CC (By similarity). {ECO:0000250|UniProtKB:Q8NFG4,
CC ECO:0000250|UniProtKB:Q8QZS3}.
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. Disassembly of the LFC
CC complex upon amino acid restimulation liberates the GTPase-activating
CC activity. {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), RRAGA/RagA or RRAGB/RagB GDP-bound,
CC RRAGC/RagC or RRAGD/RagD 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). Interacts with RILP; the
CC interaction is direct and promotes association between RILP and RAB34
CC (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 -!- 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 -!- PTM: Phosphorylation by ULK1 modulates the interaction with GABARAP and
CC is required to regulate autophagy. {ECO:0000250|UniProtKB:Q8NFG4}.
CC -!- SIMILARITY: Belongs to the folliculin family. {ECO:0000305}.
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DR EMBL; BC107555; AAI07556.1; -; mRNA.
DR RefSeq; NP_001030440.1; NM_001035363.1.
DR RefSeq; XP_015314213.1; XM_015458727.1.
DR AlphaFoldDB; Q3B7L5; -.
DR SMR; Q3B7L5; -.
DR STRING; 9913.ENSBTAP00000010532; -.
DR PaxDb; Q3B7L5; -.
DR PRIDE; Q3B7L5; -.
DR Ensembl; ENSBTAT00000010532; ENSBTAP00000010532; ENSBTAG00000008010.
DR GeneID; 526652; -.
DR KEGG; bta:526652; -.
DR CTD; 201163; -.
DR VEuPathDB; HostDB:ENSBTAG00000008010; -.
DR VGNC; VGNC:101448; FLCN.
DR eggNOG; KOG3715; Eukaryota.
DR GeneTree; ENSGT00390000009864; -.
DR HOGENOM; CLU_035854_2_0_1; -.
DR InParanoid; Q3B7L5; -.
DR OMA; WKNKVTC; -.
DR OrthoDB; 998434at2759; -.
DR TreeFam; TF315084; -.
DR Reactome; R-BTA-9639288; Amino acids regulate mTORC1.
DR Proteomes; UP000009136; Chromosome 19.
DR Bgee; ENSBTAG00000008010; Expressed in retina and 103 other tissues.
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: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; IEA:Ensembl.
DR GO; GO:0004857; F:enzyme inhibitor activity; IEA:Ensembl.
DR GO; GO:0005096; F:GTPase activator activity; ISS:UniProtKB.
DR GO; GO:0044877; F:protein-containing complex binding; ISS: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; ISS:UniProtKB.
DR GO; GO:0009267; P:cellular response to starvation; ISS: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; ISS: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; ISS:UniProtKB.
DR GO; GO:0030336; P:negative regulation of cell migration; ISS: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; IEA:Ensembl.
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; IEA:Ensembl.
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; ISS:UniProtKB.
DR GO; GO:0035024; P:negative regulation of Rho protein signal transduction; ISS: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; ISS:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0010508; P:positive regulation of autophagy; ISS:UniProtKB.
DR GO; GO:0045785; P:positive regulation of cell adhesion; ISS: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; ISS: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; ISS:UniProtKB.
DR GO; GO:0030511; P:positive regulation of transforming growth factor beta receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0043491; P:protein kinase B signaling; IEA:Ensembl.
DR GO; GO:0032465; P:regulation of cytokinesis; ISS: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; ISS:UniProtKB.
DR GO; GO:0046578; P:regulation of Ras protein signal transduction; ISS:UniProtKB.
DR GO; GO:0032006; P:regulation of TOR signaling; ISS:UniProtKB.
DR GO; GO:0031929; P:TOR signaling; ISS: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 2: Evidence at transcript 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_0000223939"
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 32..82
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 294..321
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COILED 285..309
FT /evidence="ECO:0000255"
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:0000250|UniProtKB:Q8NFG4"
FT MOD_RES 73
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8NFG4"
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"
SQ SEQUENCE 579 AA; 64204 MW; 2629737C147DC497 CRC64;
MNAIVALCHF CELHGPRTLF CTEVLHAPLP QGAGSGDGAG RGEPADEEEG GIQMSSRIRA
HSPAEGASAE SSSPGPKKSD MCEGCRSLAA GHPGYISHDK ETSIKYVSHQ HPNHPQLFSI
VRQACVRSLS CEVCPGREGP IFFGDEQHGF VFSHTFFIKD SLARGFQRWY SIIAIMMDRI
YLINSWPFLL GKIRGIIDEL QGKALKVFEA EQFGCPQRAQ RMNTAFTPFL HQRNGNAARS
LTSLTNDDSL WACLHTSFAW LLKACGSRLT EKLLEGAPTE DTLVQMEQLA ELEEESESWD
NSEAEEEEKG PALPEGAEGR ELTKCPAESS LLSDCGAWQP RKLSVFKSLR HMRQVLGAPS
FRTLAWHVLM GNQVIWKSRD SDLVHSAFEV LRTMLPVGCV RVIPYSSQYE EAYRCNFLGL
SPHVQIPPHV LASEFAVVVE VHTATRSSLH AVGCESEQPL SKYEFVVTSG SPVAADRVGP
TILNKMEAAL TNQNLSVDVV DQCLVCLKEE WMNKVKVLFK FTKVDSRPKE DTQKLLSILG
ASEEDNVKLL KFWMTGLSKT YKSHLMSTVR SPTALEPRN
