title: Nutrient-induced FNIP degradation by SCFβ-TRCP regulates FLCN complex localization and promotes renal cancer progression.
abstract: Folliculin-interacting protein 1 and 2 (FNIP1 and FNIP2) play critical roles in preventing renal malignancy through their association with the tumor suppressor FLCN. Mutations in FLCN are associated with Birt-Hogg-Dubé (BHD) syndrome, a rare disorder with increased risk of renal cancer. Recent studies indicated that FNIP1/FNIP2 double knockout mice display enlarged polycystic kidneys and renal carcinoma, which phenocopies FLCN knockout mice, suggesting that these two proteins function together to suppress renal cancer. However, the molecular mechanism functionally linking FNIP1/FNIP2 and FLCN remains largely elusive. Here, we demonstrated that FNIP2 protein is unstable and subjected to proteasome-dependent degradation via β-TRCP and Casein Kinase 1 (CK1)-directed ubiquitination in a nutrition-dependent manner. Degradation of FNIP2 leads to lysosomal dissociation of FLCN and subsequent lysosomal association of mTOR, which in turn promotes the proliferation of renal cancer cells. These results indicate that SCFβ-TRCP negatively regulates the FLCN complex by promoting FNIP degradation and provide molecular insight into the pathogenesis of BHD-associated renal cancer.
authors.affiliation: Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.|Department of Physiological Sciences and Molecular Biology, Fukuoka Dental College, Fukuoka 814-0193, Japan.|Department of Oral and Maxillofacial Surgery, Fukuoka Dental College, Fukuoka 814-0193, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Nagashima
authors.affiliation: Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Fukushima
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Yamada
authors.affiliation: Department of Physiological Sciences and Molecular Biology, Fukuoka Dental College, Fukuoka 814-0193, Japan.
authors.forename: Masumi
authors.initials: M
authors.lastname: Hidaka
authors.affiliation: Department of Urology and Molecular Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hasumi
authors.affiliation: Department of Oral and Maxillofacial Surgery, Fukuoka Dental College, Fukuoka 814-0193, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ikebe
authors.affiliation: Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.|Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukumoto
authors.affiliation: Department of Physiological Sciences and Molecular Biology, Fukuoka Dental College, Fukuoka 814-0193, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Okabe
authors.affiliation: Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.|Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inuzuka
mesh_terms: D000818:Animals; D058249:Birt-Hogg-Dube Syndrome / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D047389:Casein Kinase I / Q000378:metabolism; D049109:Cell Proliferation; D004734:Energy Metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism; D008819:Mice, Nude; D009752:Nutritional Status; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; C476078:FLCN protein, human; C529782:FNIP2 protein, human; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D044843:SKP Cullin F-Box Protein Ligases; C546842:MTOR protein, human; D047389:Casein Kinase I; D058570:TOR Serine-Threonine Kinases; D046988:Proteasome Endopeptidase Complex
keywords: FLCN; FNIP; renal cancer; tumor suppressor; β-TRCP