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. Act...[+]

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. 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. The GTPase-activating activity is inhibited during starvation and activated in presence of nutrients. 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. 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. Required for the exit of hematopoietic stem cell from pluripotency by promoting mTOR-dependent cytoplasmic retention of tfe3, thereby increasing Wnt signaling. Acts as an inhibitor of browning of adipose tissue by regulating mTOR-dependent cytoplasmic retention of tfe3. In response to flow stress, regulates STK11/LKB1 accumulation and mTORC1 activation through primary cilia. Required for starvation-induced perinuclear clustering of lysosomes by promoting association of rilp with its effector rab34. [-]

             Birt-Hogg-Dube syndrome
             Potocki-Lupski syndrome
             colorectal cancer
             primary spontaneous pneumothorax

          RENAL CELL CARCINOMA, NONPAPILLARY; RCC
          BIRT-HOGG-DUBE SYNDROME; BHD
          PNEUMOTHORAX, PRIMARY SPONTANEOUS
          POTOCKI-LUPSKI SYNDROME; PTLS

ClinVar, ClinGen, MalaCards, KEGG Disease, DECIPHER, COSMIC, MARRVEL, GTR, DisGeNET, dbVAR, GHR, gnomAD