FLCN_XENTR
ID FLCN_XENTR Reviewed; 579 AA.
AC Q5M7Q1;
DT 21-FEB-2006, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-2005, sequence version 1.
DT 03-AUG-2022, entry version 81.
DE RecName: Full=Folliculin {ECO:0000250|UniProtKB:Q8NFG4};
GN Name=flcn {ECO:0000250|UniProtKB:Q8NFG4};
OS Xenopus tropicalis (Western clawed frog) (Silurana tropicalis).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Amphibia;
OC Batrachia; Anura; Pipoidea; Pipidae; Xenopodinae; Xenopus; Silurana.
OX NCBI_TaxID=8364;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Embryo;
RG NIH - Xenopus Gene Collection (XGC) project;
RL Submitted (DEC-2004) 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 Regulates glycolysis by binding to lactate dehydrogenase ldha, acting
CC as an uncompetitive inhibitor (By similarity). Activates mTORC1 by
CC acting as a GTPase-activating protein: specifically stimulates GTP
CC hydrolysis by rragc/RagC or rragd/RagD, promoting the conversion to the
CC GDP-bound state of rragc/RagC or rragd/RagD, and thereby activating the
CC kinase activity of mTORC1. The GTPase-activating activity is inhibited
CC during starvation and activated in presence of nutrients. In low-amino
CC acid conditions, the lysosomal folliculin complex (LFC) is formed on
CC the membrane of lysosomes, which inhibits the GTPase-activating
CC activity of flcn, inactivates mTORC1 and maximizes nuclear
CC translocation of tfeb and tfe3. Upon amino acid restimulation,
CC rraga/RagA (or rragb/RagB) nucleotide exchange promotes disassembly of
CC the LFC complex and liberates the GTPase-activating activity of flcn,
CC leading to activation of mTORC1 and subsequent cytoplasmic retention of
CC tfeb and tfe3. 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). Acts as an inhibitor
CC of browning of adipose tissue by regulating mTOR-dependent cytoplasmic
CC retention of tfe3 (By similarity). In response to flow stress,
CC regulates STK11/LKB1 accumulation and mTORC1 activation through primary
CC cilia. Required for starvation-induced perinuclear clustering of
CC lysosomes by promoting association of rilp with its effector rab34 (By
CC similarity). Involved in the control of embryonic stem cells
CC differentiation; together with lamtor1 it is necessary to recruit and
CC activate rragc/RagC and rragd/RagD at the lysosomes, and to induce exit
CC of embryonic stem cells from pluripotency via non-canonical, mTOR-
CC independent tfe3 inactivation (By similarity).
CC {ECO:0000250|UniProtKB:Q8NFG4, 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: Component of the lysosomal folliculin complex (LFC).
CC {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. Also localizes to motile
CC and non-motile cilia, centrosomes and the mitotic spindle.
CC {ECO:0000250|UniProtKB:Q8NFG4}.
CC -!- SIMILARITY: Belongs to the folliculin family. {ECO:0000305}.
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DR EMBL; BC088516; AAH88516.1; -; mRNA.
DR RefSeq; NP_001011353.1; NM_001011353.1.
DR AlphaFoldDB; Q5M7Q1; -.
DR SMR; Q5M7Q1; -.
DR STRING; 8364.ENSXETP00000012652; -.
DR PaxDb; Q5M7Q1; -.
DR DNASU; 496819; -.
DR GeneID; 496819; -.
DR KEGG; xtr:496819; -.
DR CTD; 201163; -.
DR Xenbase; XB-GENE-1003590; flcn.
DR eggNOG; KOG3715; Eukaryota.
DR HOGENOM; CLU_035854_2_0_1; -.
DR InParanoid; Q5M7Q1; -.
DR OMA; WKNKVTC; -.
DR OrthoDB; 998434at2759; -.
DR PhylomeDB; Q5M7Q1; -.
DR TreeFam; TF315084; -.
DR Reactome; R-XTR-9639288; Amino acids regulate mTORC1.
DR Proteomes; UP000008143; Chromosome 9.
DR Proteomes; UP000790000; Unplaced.
DR Bgee; ENSXETG00000005745; Expressed in skeletal muscle tissue and 13 other tissues.
DR ExpressionAtlas; Q5M7Q1; baseline and differential.
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: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:0005096; F:GTPase activator activity; ISS:UniProtKB.
DR GO; GO:0044877; F:protein-containing complex binding; ISS:UniProtKB.
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:0030097; P:hemopoiesis; ISS:UniProtKB.
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: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:0010823; P:negative regulation of mitochondrion organization; ISS:UniProtKB.
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: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: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 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; Cytoplasm; Cytoskeleton; GTPase activation; Lysosome;
KW Membrane; Nucleus; Reference proteome.
FT CHAIN 1..579
FT /note="Folliculin"
FT /id="PRO_0000223943"
FT DOMAIN 86..242
FT /note="uDENN FLCN/SMCR8-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01178"
FT DOMAIN 337..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..52
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 164
FT /note="Essential for GTPase activation (GAP) activity"
FT /evidence="ECO:0000250|UniProtKB:Q8NFG4"
SQ SEQUENCE 579 AA; 65018 MW; BA2B446785A030C9 CRC64;
MNAIVALCHF CELHGPRTLF CTEALHSPHP QGASCGDSIG QGEQAEDEEM GIQMSSRIRC
HSPAEGASAD SNSPRPKKSD MCEGCRSLAA GHPGYISHDK ETSIKYVSHQ HPNHPQLFSI
VRQACVRSLS CEVCPGREGP IFFGDEQHGF VFSHTFFIKD SLARGFQRWY SIIVIMMDRI
YLINSWPFLL AKIRGVIDEL QGKALKVFEA EQFGCPQRPL RINTAFTPFL HQRNGNAARS
LTSLTSDDNL WACLHTSFAW LLKACGCRLT EKLLEGAPTE DTLVQMEKQA DLEEECAARE
VADGEEGRPR LQPELMEGRE LSKCPTESSV LSDCSWNMVQ RRMGVFRSLR HMRQVLGASA
FRMLAWHVLM GNQVIWKGQD QELIQSAFDV LQAMLPVGCV RVIPYSEKYE DAYRCNFLGL
SPQAEIPLHV QSSEFSVMVD VRHANRSNLY PALFVDDEPL SKYEFVVASG SPVTIDKVGL
TILNKIEAAL SNENLSMDVV DQCLICLKEE WMNKVKVLFK FTKVDSRPKE DTQKLLGILG
ASEEDNIKLL KFWMTGLSKT YKSHLMSSVR SPTASECRN
