title: Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling.
abstract: Birt-Hogg-Dubé syndrome, a hamartoma disorder characterized by benign tumors of the hair follicle, lung cysts, and renal neoplasia, is caused by germ-line mutations in the BHD(FLCN) gene, which encodes a tumor-suppressor protein, folliculin (FLCN), with unknown function. The tumor-suppressor proteins encoded by genes responsible for several other hamartoma syndromes, LKB1, TSC1/2, and PTEN, have been shown to be involved in the mammalian target of rapamycin (mTOR) signaling pathway. Here, we report the identification of the FLCN-interacting protein, FNIP1, and demonstrate its interaction with 5' AMP-activated protein kinase (AMPK), a key molecule for energy sensing that negatively regulates mTOR activity. FNIP1 was phosphorylated by AMPK, and its phosphorylation was reduced by AMPK inhibitors, which resulted in reduced FNIP1 expression. AMPK inhibitors also reduced FLCN phosphorylation. Moreover, FLCN phosphorylation was diminished by rapamycin and amino acid starvation and facilitated by FNIP1 overexpression, suggesting that FLCN may be regulated by mTOR and AMPK signaling. Our data suggest that FLCN, mutated in Birt-Hogg-Dubé syndrome, and its interacting partner FNIP1 may be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways.
authors.affiliation: Laboratories of Immunobiology, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702, USA.
authors.forename: Masaya
authors.initials: M
authors.lastname: Baba
authors.forename: Seung-Beom
authors.initials: SB
authors.lastname: Hong
authors.forename: Nirmala
authors.initials: N
authors.lastname: Sharma
authors.forename: Michelle B
authors.initials: MB
authors.lastname: Warren
authors.forename: Michael L
authors.initials: ML
authors.lastname: Nickerson
authors.forename: Akihiro
authors.initials: A
authors.lastname: Iwamatsu
authors.forename: Dominic
authors.initials: D
authors.lastname: Esposito
authors.forename: William K
authors.initials: WK
authors.lastname: Gillette
authors.forename: Ralph F
authors.initials: RF
authors.lastname: Hopkins
authors.forename: James L
authors.initials: JL
authors.lastname: Hartley
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Furihata
authors.forename: Shinya
authors.initials: S
authors.lastname: Oishi
authors.forename: Wei
authors.initials: W
authors.lastname: Zhen
authors.forename: Terrence R
authors.initials: TR
authors.lastname: Burke
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
authors.forename: Laura S
authors.initials: LS
authors.lastname: Schmidt
authors.forename: Berton
authors.initials: B
authors.lastname: Zbar
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003001:Cloning, Molecular; D004789:Enzyme Activation; D006801:Humans; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism*; D046912:Multiprotein Complexes; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013577:Syndrome; D058570:TOR Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C476078:FLCN protein, human; C516440:FNIP1 protein, human; D009097:Multienzyme Complexes; D046912:Multiprotein Complexes; D011506:Proteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases