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Nutrient-induced FNIP degradation by SCFβ-TRCP regulates FLCN complex localization and promotes renal cancer progression

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Oncotarget. 2017; 8:9947-9960. https://doi.org/10.18632/oncotarget.14221

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Katsuyuki Nagashima1,2,6, Hidefumi Fukushima1, Kouhei Shimizu3, Aya Yamada4, Masumi Hidaka2, Hisashi Hasumi5, Tetsuro Ikebe6, Satoshi Fukumoto1,4, Koji Okabe2, Hiroyuki Inuzuka1,3

1Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan

2Department of Physiological Sciences and Molecular Biology, Fukuoka Dental College, Fukuoka 814-0193, Japan

3Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA

4Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan

5Department of Urology and Molecular Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan

6Department of Oral and Maxillofacial Surgery, Fukuoka Dental College, Fukuoka 814-0193, Japan

Correspondence to:

Hiroyuki Inuzuka, email: hinuzuka@bidmc.harvard.edu

Hidefumi Fukushima, email: hidefumi.fukushima.b7@tohoku.ac.jp

Keywords: FNIP, FLCN, tumor suppressor, β-TRCP, renal cancer

Received: October 11, 2016     Accepted: November 22, 2016     Published: December 25, 2016

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.


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