Flcn
entrez
216805
canonical
uniprot
Q8QZS3
canonical
ensembl
ENSMUSG00000032633
resolver
ensp
ENSMUSP00000091696
resolver
ensp
ENSMUSP00000099758
resolver
ensp
ENSMUSP00000226237
resolver
ensp
ENSMUSP00000226244
resolver
enst
ENSMUST00000091246
resolver
enst
ENSMUST00000102697
resolver
genesymbol
Flcn
resolver
genesymbol_syn
Bhd
resolver
uniprot
Q3U4U8
resolver
uniprot
Q3UFZ1
resolver
uniprot
Q5SWZ2
resolver
uniprot
Q5SX01
resolver
uniprot
Q5SX02
resolver
uniprot
Q8CAC0
resolver
uniprot_entry
FLCN_MOUSE
resolver
uniprot_sec
Q3U4U8
resolver
uniprot_sec
Q3UFZ1
resolver
uniprot_sec
Q5SWZ2
resolver
uniprot_sec
Q5SX01
resolver
uniprot_sec
Q5SX02
resolver
uniprot_sec
Q8CAC0
resolver
activity_regulation
ACTIVITY REGULATION: GTPase-activating activity is inhibited in the folliculin complex (LFC), which stabilizes the GDP-bound state of RagA/RRAGA (or RagB/RRAGB), because Arg-164 is located far from the RagC/RRAGC or RagD/RRAGD nucleotide pocket (By similarity). Disassembly of the LFC complex upon amino acid restimulation liberates the GTPase-activating activity (By similarity). {ECO:0000250|UniProtKB:Q8NFG4}.
uniprot
proteins
amino_acid_sequence
MNAIVALCHFCELHGPRTLFCTEVLHAPLPQGAGSGDSPDQVEQAEEEEGGIQMSSRVRAHSPAEGASSESSSPGPKKSDMCEGCRSLAVGHPGYISHDKETSIKYVSHQHPNHPQLFSIVRQACVRSLSCEVCPGREGPIFFGDEQHGFVFSHTFFIKDSLARGFQRWYSIIAIMMDRIYLINSWPFLLGRIRGIISELQAKAFKVFEAEQFGCPQRAQRMNTAFTPFLHQRNGNAARSLTSLTSDDNLWACLHTSFAWLLKACGSRLTEKLLEGAPTEDTLVQMEKLADLEEESESWDNSEAEEEEKAPVTPEGAEGRELTSCPTESSFLSACGSWQPPKLTGFKSLRHMRQVLGAPSFRMLAWHVLMGNQVIWKSRDVNLVHSAFEVLRTMLPVGCVRIIPYSSQYEEAYRCNFLGLSPPVPIPAHVLASEFVVVVEVHTATRSNLHPAGCEDDQSLSKYEFVVTSGSPVAADRVGPTILNKIEAALTNQNLSVDVVDQCLICLKEEWMNKVKVLFKFTKVDSRPKEDTQKLLSVLGASEEDNVKLLKFWMTGLSKTYKSHLMSTVRSPTATESRS
uniprot
proteins
function
FUNCTION: Multi-functional protein, involved in both the cellular response to amino acid availability and in the regulation of glycolysis (PubMed:23582324, PubMed:27913603, PubMed:32612235). GTPase-activating protein that plays a key role in the cellular response to amino acid availability through regulation of the non-canonical mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3 (PubMed:23582324, PubMed:27913603, PubMed:32612235). Activates mTORC1 by acting as a GTPase-activating protein: specifically stimulates GTP hydrolysis by RagC/RRAGC or RagD/RRAGD, promoting the conversion to the GDP-bound state of RagC/RRAGC or RagD/RRAGD, and thereby activating the kinase activity of mTORC1 (By similarity). The GTPase-activating activity is inhibited during starvation and activated in presence of nutrients (By similarity). Acts as a key component for non-canonical mTORC1-dependent control of the MiT/TFE factors TFEB and TFE3, while it is not involved in mTORC1-dependent phosphorylation of canonical RPS6KB1/S6K1 and EIF4EBP1/4E-BP1 (PubMed:27913603, PubMed:32612235). In low-amino acid conditions, the lysosomal folliculin complex (LFC) is formed on the membrane of lysosomes, which inhibits the GTPase-activating activity of FLCN, inactivates mTORC1 and maximizes nuclear translocation of TFEB and TFE3 (By similarity). Upon amino acid restimulation, RagA/RRAGA (or RagB/RRAGB) nucleotide exchange promotes disassembly of the LFC complex and liberates the GTPase-activating activity of FLCN, leading to activation of mTORC1 and subsequent cytoplasmic retention of TFEB and TFE3 (By similarity). Indirectly acts as a positive regulator of Wnt signaling by promoting mTOR-dependent cytoplasmic retention of MiT/TFE factor TFE3 (PubMed:31272105). Required for the exit of hematopoietic stem cell from pluripotency by promoting mTOR-dependent cytoplasmic retention of TFE3, thereby increasing Wnt signaling (By similarity). Involved in the control of embryonic stem cells differentiation; together with LAMTOR1 it is necessary to recruit and activate RagC/RRAGC and RagD/RRAGD at the lysosomes, and to induce exit of embryonic stem cells from pluripotency via non-canonical, mTOR-independent TFE3 inactivation (PubMed:30595499). Acts as an inhibitor of browning of adipose tissue by regulating mTOR-dependent cytoplasmic retention of TFE3 (PubMed:27913603). In response to flow stress, regulates STK11/LKB1 accumulation and mTORC1 activation through primary cilia: may act by recruiting STK11/LKB1 to primary cilia for activation of AMPK resided at basal bodies, causing mTORC1 down-regulation (By similarity). Together with FNIP1 and/or FNIP2, regulates autophagy: following phosphorylation by ULK1, interacts with GABARAP and promotes autophagy (By similarity). Interaction with GABARAP also inhibits the non-canonical mTORC1 signaling cascade: GABARAP sequesters FLCN, thereby inactivating mTORC1 and promoting nuclear translocation of TFEB and TFE3 (By similarity). Required for starvation-induced perinuclear clustering of lysosomes by promoting association of RILP with its effector RAB34 (By similarity). Regulates glycolysis by binding to lactate dehydrogenase LDHA, acting as an uncompetitive inhibitor (By similarity). {ECO:0000250|UniProtKB:Q8NFG4, ECO:0000269|PubMed:23582324, ECO:0000269|PubMed:27913603, ECO:0000269|PubMed:30595499, ECO:0000269|PubMed:31272105, ECO:0000269|PubMed:32612235}.
uniprot
proteins
mass_dalton
64327
uniprot
proteins
post_translational_modification
PTM: Phosphorylation by ULK1 modulates the interaction with GABARAP and is required to regulate autophagy. {ECO:0000250|UniProtKB:Q8NFG4}.
uniprot
proteins
protein_family
Folliculin family
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16141072
uniprot
proteins
pubmed
18182616
uniprot
proteins
pubmed
18974783
uniprot
proteins
pubmed
19144319
uniprot
proteins
pubmed
19468303
uniprot
proteins
pubmed
19850877
uniprot
proteins
pubmed
21183079
uniprot
proteins
pubmed
23582324
uniprot
proteins
pubmed
24908670
uniprot
proteins
pubmed
27913603
uniprot
proteins
pubmed
30595499
uniprot
proteins
pubmed
31272105
uniprot
proteins
pubmed
32612235
uniprot
proteins
sequence_length
579
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000250|UniProtKB:Q8NFG4}. Cytoplasm, cytosol {ECO:0000250|UniProtKB:Q8NFG4}. Cell projection, cilium {ECO:0000250|UniProtKB:Q8NFG4}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000250|UniProtKB:Q8NFG4}. Cytoplasm, cytoskeleton, spindle {ECO:0000250|UniProtKB:Q8NFG4}. Nucleus {ECO:0000250|UniProtKB:Q8NFG4}. Note=Localizes to lysosome membrane in amino acid-depleted conditions and relocalizes to the cytosol upon refeeding. Colocalizes with FNIP1 and FNIP2 in the cytoplasm. Also localizes to motile and non-motile cilia, centrosomes and the mitotic spindle. {ECO:0000250|UniProtKB:Q8NFG4}.
uniprot
proteins