FLCN
entrez
201163
canonical
uniprot
Q8NFG4
canonical
ensembl
ENSG00000154803
resolver
ensp
ENSP00000285071
resolver
ensp
ENSP00000373821
resolver
ensp
ENSP00000558101
resolver
ensp
ENSP00000558102
resolver
ensp
ENSP00000558104
resolver
ensp
ENSP00000632786
resolver
ensp
ENSP00000632787
resolver
ensp
ENSP00000632790
resolver
ensp
ENSP00000632792
resolver
ensp
ENSP00000632795
resolver
ensp
ENSP00000632796
resolver
ensp
ENSP00000725833
resolver
genesymbol
FLCN
resolver
genesymbol_syn
BHD
resolver
hgnc
HGNC:27310
resolver
uniprot
A0A0S2Z5Y7
resolver
uniprot
A6NJJ8
resolver
uniprot
Q6ZRX1
resolver
uniprot
Q96BD2
resolver
uniprot
Q96BE4
resolver
uniprot_entry
A0A0S2Z5Y7_HUMAN
resolver
uniprot_entry
FLCN_HUMAN
resolver
uniprot_sec
A6NJJ8
resolver
uniprot_sec
Q6ZRX1
resolver
uniprot_sec
Q96BD2
resolver
uniprot_sec
Q96BE4
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 (PubMed:31672913). Disassembly of the LFC complex upon amino acid restimulation liberates the GTPase-activating activity (PubMed:31672913). {ECO:0000269|PubMed:31672913}.
uniprot
proteins
amino_acid_sequence
MNAIVALCHFCELHGPRTLFCTEVLHAPLPQGDGNEDSPGQGEQAEEEEGGIQMNSRMRAHSPAEGASVESSSPGPKKSDMCEGCRSLAAGHPGYISHDKETSIKYVSHQHPSHPQLFSIVRQACVRSLSCEVCPGREGPIFFGDEQHGFVFSHTFFIKDSLARGFQRWYSIITIMMDRIYLINSWPFLLGKVRGIIDELQGKALKVFEAEQFGCPQRAQRMNTAFTPFLHQRNGNAARSLTSLTSDDNLWACLHTSFAWLLKACGSRLTEKLLEGAPTEDTLVQMEKLADLEEESESWDNSEAEEEEKAPVLPESTEGRELTQGPAESSSLSGCGSWQPRKLPVFKSLRHMRQVLGAPSFRMLAWHVLMGNQVIWKSRDVDLVQSAFEVLRTMLPVGCVRIIPYSSQYEEAYRCNFLGLSPHVQIPPHVLSSEFAVIVEVHAAARSTLHPVGCEDDQSLSKYEFVVTSGSPVAADRVGPTILNKIEAALTNQNLSVDVVDQCLVCLKEEWMNKVKVLFKFTKVDSRPKEDTQKLLSILGASEEDNVKLLKFWMTGLSKTYKSHLMSTVRSPTASESRN
uniprot
proteins
disease_involvement
DISEASE: Birt-Hogg-Dube syndrome 1 (BHD1) [MIM:135150]: A form of Birt-Hogg-Dube syndrome, a rare genodermatosis usually manifesting in adulthood and characterized by multiple fibrofolliculomas, trichodiscomas, and acrochordons. Patients with this syndrome have an increased susceptibility to develop renal cell carcinoma, lung cysts, and spontaneous pneumothorax. Inheritance is autosomal dominant. {ECO:0000269|PubMed:12204536, ECO:0000269|PubMed:15852235, ECO:0000269|PubMed:18234728, ECO:0000269|PubMed:19785621, ECO:0000269|PubMed:23784378, ECO:0000269|PubMed:31615547}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Primary spontaneous pneumothorax (PSP) [MIM:173600]: Condition in which air is present in the pleural space in the absence of a precipitating event, such as trauma or lung disease. This results in secondary collapse of the lung, either partially or completely, and some degree of hypoxia. PSP is relatively common, with an incidence between 7.4-18/100'000 for men and 1.2-6/100'000 for women and a dose-dependent, increased risk among smokers. Most cases are sporadic, typically occurring in tall, thin men aged 10-30 years and generally while at rest. Familial PSP is rarer and usually is inherited as an autosomal dominant condition with reduced penetrance, although X-linked recessive and autosomal recessive inheritance have also been suggested. {ECO:0000269|PubMed:15657874, ECO:0000269|PubMed:15805188, ECO:0000269|PubMed:17496196, ECO:0000269|PubMed:18505456, ECO:0000269|PubMed:18579543, ECO:0000269|PubMed:19483054, ECO:0000269|PubMed:25827758, ECO:0000269|PubMed:27486260, ECO:0000269|PubMed:31625278}. Note=The disease is caused by variants affecting the gene represented in this entry.; DISEASE: Renal cell carcinoma (RCC) [MIM:144700]: Renal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma. Clear cell renal cell carcinoma is the most common subtype. {ECO:0000269|PubMed:18794106, ECO:0000269|PubMed:23922894}. Note=The gene represented in this entry may be involved in disease pathogenesis.
uniprot
proteins
function
FUNCTION: Multi-functional protein, involved in both the cellular response to amino acid availability and in the regulation of glycolysis (PubMed:17028174, PubMed:18663353, PubMed:21209915, PubMed:24081491, PubMed:24095279, PubMed:31672913, PubMed:31704029, PubMed:32612235, PubMed:34381247, PubMed:36103527, PubMed:37079666). 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:17028174, PubMed:18663353, PubMed:21209915, PubMed:24081491, PubMed:24095279, PubMed:24448649, PubMed:31672913, PubMed:31704029, PubMed:32612235, PubMed:36103527, PubMed:37079666). 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 (PubMed:24095279, PubMed:31672913, PubMed:31704029, PubMed:32612235, PubMed:37079666). The GTPase-activating activity is inhibited during starvation and activated in presence of nutrients (PubMed:31672913, PubMed:32612235). 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:21209915, PubMed:24081491, PubMed:31672913, 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 (PubMed:31672913). 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 (PubMed:31672913). 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 (PubMed:30733432). Acts as an inhibitor of browning of adipose tissue by regulating mTOR-dependent cytoplasmic retention of TFE3 (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 (By similarity). 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 (PubMed:27072130). Together with FNIP1 and/or FNIP2, regulates autophagy: following phosphorylation by ULK1, interacts with GABARAP and promotes autophagy (PubMed:25126726). 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 (PubMed:34597140, PubMed:39423796). Required for starvation-induced perinuclear clustering of lysosomes by promoting association of RILP with its effector RAB34 (PubMed:27113757). Regulates glycolysis by binding to lactate dehydrogenase LDHA, acting as an uncompetitive inhibitor (PubMed:34381247). {ECO:0000250|UniProtKB:Q8QZS3, ECO:0000269|PubMed:17028174, ECO:0000269|PubMed:18663353, ECO:0000269|PubMed:21209915, ECO:0000269|PubMed:24081491, ECO:0000269|PubMed:24095279, ECO:0000269|PubMed:24448649, ECO:0000269|PubMed:25126726, ECO:0000269|PubMed:27072130, ECO:0000269|PubMed:27113757, ECO:0000269|PubMed:30733432, ECO:0000269|PubMed:31272105, ECO:0000269|PubMed:31672913, ECO:0000269|PubMed:31704029, ECO:0000269|PubMed:32612235, ECO:0000269|PubMed:34381247, ECO:0000269|PubMed:34597140, ECO:0000269|PubMed:36103527, ECO:0000269|PubMed:37079666, ECO:0000269|PubMed:39423796}.
uniprot
proteins
mass_dalton
64473
uniprot
proteins
mutagenesis
MUTAGEN 10; /note="F->D: Abolished GTPase activation (GAP) activity."; /evidence="ECO:0000269|PubMed:36103527"; MUTAGEN 118; /note="F->D: Does not assemble into a stable folliculin complex (LFC), preventing localization to the lysosomal membrane upon amino acid starvation."; /evidence="ECO:0000269|PubMed:31672913"; MUTAGEN 164; /note="R->A: Abolished GTPase activation (GAP) activity."; /evidence="ECO:0000269|PubMed:31672913, ECO:0000269|PubMed:31704029"; MUTAGEN 406; /note="S->A: Impaired ability to regulate autophagy; when associated with A-537 and A-542."; /evidence="ECO:0000269|PubMed:25126726"; MUTAGEN 537; /note="S->A: Impaired ability to regulate autophagy; when associated with A-406 and A-542."; /evidence="ECO:0000269|PubMed:25126726"; MUTAGEN 542; /note="S->A: Impaired ability to regulate autophagy; when associated with A-406 and A-537."; /evidence="ECO:0000269|PubMed:25126726
uniprot
proteins
post_translational_modification
PTM: Phosphorylation by ULK1 modulates the interaction with GABARAP and is required to regulate autophagy. {ECO:0000269|PubMed:25126726}.
uniprot
proteins
protein_family
Folliculin family
uniprot
proteins
pubmed
12204536
uniprot
proteins
pubmed
12843323
uniprot
proteins
pubmed
14627671
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15657874
uniprot
proteins
pubmed
15805188
uniprot
proteins
pubmed
15852235
uniprot
proteins
pubmed
16625196
uniprot
proteins
pubmed
17028174
uniprot
proteins
pubmed
17496196
uniprot
proteins
pubmed
18234728
uniprot
proteins
pubmed
18403135
uniprot
proteins
pubmed
18505456
uniprot
proteins
pubmed
18579543
uniprot
proteins
pubmed
18663353
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
18794106
uniprot
proteins
pubmed
19413330
uniprot
proteins
pubmed
19483054
uniprot
proteins
pubmed
19785621
uniprot
proteins
pubmed
21209915
uniprot
proteins
pubmed
21406692
uniprot
proteins
pubmed
21538689
uniprot
proteins
pubmed
22977732
uniprot
proteins
pubmed
23186163
uniprot
proteins
pubmed
23784378
uniprot
proteins
pubmed
23922894
uniprot
proteins
pubmed
24081491
uniprot
proteins
pubmed
24095279
uniprot
proteins
pubmed
24448649
uniprot
proteins
pubmed
25126726
uniprot
proteins
pubmed
25827758
uniprot
proteins
pubmed
27072130
uniprot
proteins
pubmed
27113757
uniprot
proteins
pubmed
27353360
uniprot
proteins
pubmed
27486260
uniprot
proteins
pubmed
29848618
uniprot
proteins
pubmed
30733432
uniprot
proteins
pubmed
31272105
uniprot
proteins
pubmed
31615547
uniprot
proteins
pubmed
31625278
uniprot
proteins
pubmed
31672913
uniprot
proteins
pubmed
31704029
uniprot
proteins
pubmed
32612235
uniprot
proteins
pubmed
34381247
uniprot
proteins
pubmed
34597140
uniprot
proteins
pubmed
36103527
uniprot
proteins
pubmed
37079666
uniprot
proteins
pubmed
39423796
uniprot
proteins
sequence_length
579
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Lysosome membrane {ECO:0000269|PubMed:24081491, ECO:0000269|PubMed:24095279, ECO:0000269|PubMed:27113757, ECO:0000269|PubMed:29848618, ECO:0000269|PubMed:31672913}. Cytoplasm, cytosol {ECO:0000269|PubMed:17028174, ECO:0000269|PubMed:18663353, ECO:0000269|PubMed:24081491, ECO:0000269|PubMed:24095279, ECO:0000269|PubMed:29848618, ECO:0000269|PubMed:31672913}. Cell projection, cilium {ECO:0000269|PubMed:23784378, ECO:0000269|PubMed:27072130}. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000269|PubMed:23784378}. Cytoplasm, cytoskeleton, spindle {ECO:0000269|PubMed:23784378}. Nucleus {ECO:0000269|PubMed:17028174, ECO:0000269|PubMed:18663353}. Note=Localizes to lysosome membrane in amino acid-depleted conditions and relocalizes to the cytosol upon refeeding (PubMed:24095279, PubMed:29848618, PubMed:31672913). Colocalizes with FNIP1 and FNIP2 in the cytoplasm (PubMed:17028174, PubMed:18663353). Also localizes to motile and non-motile cilia, centrosomes and the mitotic spindle (PubMed:23784378). {ECO:0000269|PubMed:17028174, ECO:0000269|PubMed:18663353, ECO:0000269|PubMed:23784378, ECO:0000269|PubMed:24095279, ECO:0000269|PubMed:29848618, ECO:0000269|PubMed:31672913}.
uniprot
proteins