FLCN

This gene is located within the Smith-Magenis syndrome region on chromosome 17. Mutations in this gene are associated with Birt-Hogg-Dube syndrome, which is characterized by fibrofolliculomas, renal tumors, lung cysts, and pneumothorax. Alternative splicing of this gene results in two transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

Folliculin

GTPase-activating protein that plays a key role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3 (PubMed:17028174, PubMed:18663353, PubMed:21209915, PubMed:24081491, PubMed:24095279, PubMed:31704029, PubMed:31672913).

Activates mTORC1 by acting as a GTPase-activating protein: specifically stimulates GTP hydrolysis by RRAGC/RagC or RRAGD/RagD, promoting the conversion to the GDP-bound state of RRAGC/RagC or RRAGD/RagD, and thereby activating the kinase activity of mTORC1 (PubMed:24095279, PubMed:31704029, PubMed:31672913).

The GTPase-activating activity is inhibited during starvation and activated in presence of nutrients (PubMed:31672913).

Acts as a key component for 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).

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, RRAGA/RagA (or RRAGB/RagB) 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).

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).

Required for starvation-induced perinuclear clustering of lysosomes by promoting association of RILP with its effector RAB34 (PubMed:27113757).

Cell-cell junction assembly Source: UniProtKB
Cellular response to amino acid starvation Source: UniProtKB
Cellular response to starvation Source: UniProtKB
Energy homeostasis Source: UniProtKB
Hemopoiesis Source: UniProtKB
In utero embryonic development Source: UniProtKB
Lysosome localization Source: UniProtKB
Negative regulation of ATP biosynthetic process Source: UniProtKB
Negative regulation of brown fat cell differentiation Source: UniProtKB
Negative regulation of cell growth Source: UniProtKB
Negative regulation of cell migration Source: UniProtKB
Negative regulation of cell proliferation involved in kidney development Source: UniProtKB
Negative regulation of cold-induced thermogenesis Source: YuBioLab
Negative regulation of ERK1 and ERK2 cascade Source: UniProtKB
Negative regulation of gene expression Source: UniProtKB
Negative regulation of mitochondrion organization Source: UniProtKB
Negative regulation of protein kinase B signaling Source: UniProtKB
Negative regulation of protein localization to nucleus Source: UniProtKB
Negative regulation of Rho protein signal transduction Source: UniProtKB
Negative regulation of TOR signaling Source: UniProtKB
Negative regulation of transcription by RNA polymerase II Source: UniProtKB
Positive regulation of apoptotic process Source: UniProtKB
Positive regulation of autophagy Source: UniProtKB
Positive regulation of cell adhesion Source: UniProtKB
Positive regulation of GTPase activity Source: GO_Central
Positive regulation of protein phosphorylation Source: UniProtKB
Positive regulation of TORC1 signaling Source: GO_Central
Positive regulation of TOR signaling Source: UniProtKB
Positive regulation of transcription by RNA polymerase II Source: UniProtKB
Positive regulation of transforming growth factor beta receptor signaling pathway Source: UniProtKB
Regulation of cytokinesis Source: UniProtKB
Regulation of histone acetylation Source: UniProtKB
Regulation of pro-B cell differentiation Source: UniProtKB
Regulation of protein phosphorylation Source: UniProtKB
Regulation of Ras protein signal transduction Source: UniProtKB
Regulation of TOR signaling Source: UniProtKB
TOR signaling Source: UniProtKB

Lysosome membrane; Cytosol; Nucleus; Centrosome; Spindle; Cilium. 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).

Birt-Hogg-Dube syndrome (BHD):
A rare autosomal dominant genodermatosis characterized by hair follicle hamartomas (fibrofolliculomas), kidney tumors, and spontaneous pneumothorax. Fibrofolliculomas are part of the triad of Birt-Hogg-Dube syndrome skin lesions that also includes trichodiscomas and acrochordons. Onset of this dermatologic condition is invariably in adulthood. Birt-Hogg-Dube syndrome is associated with a variety of histologic types of renal tumors, including chromophobe renal cell carcinoma (RCC), benign renal oncocytoma, clear-cell RCC and papillary type I RCC. Multiple lipomas, angiolipomas, and parathyroid adenomas are also seen in Birt-Hogg-Dube syndrome patients.
Primary spontaneous pneumothorax (PSP):
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.
Renal cell carcinoma (RCC):
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.

Phosphorylation by ULK1 modulates the interaction with GABARAP and is required to regulate autophagy.