FLCN
FLCN (folliculin, also known as BHD or DENND8B) is a multi-functional GTPase-activating protein that links amino acid availability to mTORC1 signalling and also regulates glycolysis. Mutations in the FLCN gene are associated with Birt-Hogg-Dube syndrome. Browse Assay Genie's current range of FLCN research reagents below, or read on for the biology behind the target.
FLCN acts in the cellular response to amino acid availability. As a GTPase-activating protein, it stimulates GTP hydrolysis by RagC/RRAGC or RagD/RRAGD, promoting their GDP-bound state and activating the kinase activity of mTORC1. This activity is inhibited during starvation and activated when nutrients are present. FLCN is a key component of non-canonical mTORC1 control of the MiT/TFE factors TFEB and TFE3, but it is not involved in mTORC1-dependent phosphorylation of canonical targets S6K1 and 4E-BP1. In low-amino acid conditions, the lysosomal folliculin complex forms on the lysosomal membrane, inhibits FLCN activity and favours nuclear translocation of TFEB and TFE3. Amino acid restimulation disassembles the complex and releases FLCN activity.
Beyond mTORC1, the folliculin protein has a range of roles. Together with FNIP1 and/or FNIP2, it regulates autophagy: after phosphorylation by ULK1 it interacts with GABARAP, which sequesters FLCN and promotes autophagy. It supports starvation-induced perinuclear clustering of lysosomes by promoting association of RILP with RAB34, and it regulates glycolysis by binding lactate dehydrogenase LDHA as an uncompetitive inhibitor. In response to flow stress, it regulates STK11/LKB1 accumulation and mTORC1 activation through primary cilia. Through mTOR-dependent cytoplasmic retention of TFE3, it indirectly promotes Wnt signalling, is required for haematopoietic stem cell exit from pluripotency and inhibits browning of adipose tissue. Together with LAMTOR1, it also contributes to embryonic stem cell differentiation. FLCN is found at the lysosome membrane, in the cytosol, cilium, centrosome, spindle and nucleus.
The FLCN gene lies within the Smith-Magenis syndrome region on chromosome 17, and alternative splicing yields two transcript variants encoding different isoforms. Mutations are associated with Birt-Hogg-Dube syndrome, characterised by fibrofolliculomas, renal tumours, lung cysts and pneumothorax. FLCN belongs to the folliculin family and is classed in the DENN domain containing gene group, with mouse and rat orthologs named Flcn.
FLCN activates mTORC1 by stimulating GTP hydrolysis by RagC and RagD in response to amino acid availability.
FLCN controls non-canonical mTORC1 signalling that determines nuclear translocation or cytoplasmic retention of the MiT/TFE factors TFEB and TFE3.
With FNIP1/FNIP2 and GABARAP, FLCN regulates autophagy and supports starvation-induced perinuclear clustering of lysosomes.
FLCN mutations are associated with Birt-Hogg-Dube syndrome, featuring fibrofolliculomas, renal tumours, lung cysts and pneumothorax.
FLCN is a GTPase-activating protein that stimulates GTP hydrolysis by RagC/RRAGC and RagD/RRAGD, activating mTORC1 when amino acids are available. It controls TFEB and TFE3 localisation, helps regulate autophagy and glycolysis, and binds LDHA as an uncompetitive inhibitor.
FLCN stands for folliculin. Aliases and previous symbols include BHD, MGC17998, MGC23445 and DENND8B. Alternative splicing of the FLCN gene produces two transcript variants that encode different isoforms, according to the NCBI Gene summary.
Mouse and rat both have an ortholog named Flcn. In humans, FLCN mutations are associated with Birt-Hogg-Dube syndrome, characterised by fibrofolliculomas, renal tumours, lung cysts and pneumothorax. Check the datasheet of any product for its validated reactivity.
Pathway partners in mTORC1 signalling, MiT/TFE regulation, autophagy and glycolysis that are linked to FLCN function.
Gene and protein annotations from HGNC, NCBI Gene and UniProt Q8NFG4; product specifications from Assay Genie datasheets.