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J Biol Chem. 2016 May 27;291(22):11689-97. doi: 10.1074/jbc.M116.719997. Epub 2016 Apr 12.

Tumor Suppressor Folliculin Regulates mTORC1 through Primary Cilia.

Author information

1
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.
2
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 and.
3
Department of Physiology, Nanjing Medical University, Nanjing 211166, China.
4
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.
5
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261 and yuj5@pitt.edu.

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.

KEYWORDS:

AMP-activated kinase (AMPK); FLCN; LKB1; folliculin; mTOR complex (mTORC); mammalian target of rapamycin (mTOR); primary cilium; tumor suppressor gene

PMID:
27072130
PMCID:
PMC4882437
DOI:
10.1074/jbc.M116.719997
[Indexed for MEDLINE]
Free PMC Article

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