title: Tumor Suppressor Folliculin Regulates mTORC1 through Primary Cilia.
abstract: Folliculin (FLCN) is the tumor suppressor associated with Birt-Hogg-Dubé (BHD) syndrome that predisposes patients to incident of hamartomas and cysts in multiple organs. Its inactivation causes deregulation in the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. However, the underlying mechanism is poorly defined. In this study, we show that FLCN is a ciliary protein that functions through primary cilia to regulate mTORC1. In response to flow stress, FLCN associates with LKB1 and recruits the kinase to primary cilia for activation of AMPK resided at basal bodies, which causes mTORC1 down-regulation. In cells depleted of FLCN, LKB1 fails to accumulate in primary cilia and AMPK at the basal bodies remains inactive, thus nullifying the inhibitory effect of flow stress on mTORC1 activity. Our results demonstrate that FLCN is part of a flow sensory mechanism that regulates mTORC1 through primary cilia.
authors.affiliation: From the Guangdong Provincial Key Laboratory of Proteomics; Key laboratory of Transcriptomics and Proteomics of Ministry of Education of China, State Key Laboratory of Organ Failure Research, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 and.
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhong
authors.affiliation: From the Guangdong Provincial Key Laboratory of Proteomics; Key laboratory of Transcriptomics and Proteomics of Ministry of Education of China, State Key Laboratory of Organ Failure Research, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 and.
authors.forename: Xuwen
authors.initials: X
authors.lastname: Zhao
authors.affiliation: From the Guangdong Provincial Key Laboratory of Proteomics; Key laboratory of Transcriptomics and Proteomics of Ministry of Education of China, State Key Laboratory of Organ Failure Research, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 and.
authors.forename: Jinmei
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 and.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 and.
authors.forename: Gonghong
authors.initials: G
authors.lastname: Yan
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 and.
authors.forename: Mingming
authors.initials: M
authors.lastname: Tong
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 and.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Yichao
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: From the Guangdong Provincial Key Laboratory of Proteomics; Key laboratory of Transcriptomics and Proteomics of Ministry of Education of China, State Key Laboratory of Organ Failure Research, Department of Pathophysiology, Southern Medical University, Guangzhou 510515, China, jiang48321@163.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 211166, China.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 and yuj5@pitt.edu.
authors.forename: Yu
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D015153:Blotting, Western; D002478:Cells, Cultured; D002923:Cilia / Q000502:physiology*; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D006801:Humans; D047468:Immunoprecipitation; D016547:Kinesins / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C476078:FLCN protein, human; C509805:KIF2A protein, human; D046912:Multiprotein Complexes; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D058570:TOR Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D016547:Kinesins
keywords: AMP-activated kinase (AMPK); FLCN; LKB1; folliculin; mTOR complex (mTORC); mammalian target of rapamycin (mTOR); primary cilium; tumor suppressor gene