Nutrient-induced FNIP degradation by SCFβ-TRCP regulates FLCN complex localization and promotes renal cancer progression
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Nagashima, Katsuyuki
Fukushima, Hidefumi
Shimizu, Kouhei
Yamada, Aya
Hidaka, Masumi
Hasumi, Hisashi
Ikebe, Tetsuro
Fukumoto, Satoshi
Okabe, Koji
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https://doi.org/10.18632/oncotarget.14221Metadata
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Nagashima, Katsuyuki, Hidefumi Fukushima, Kouhei Shimizu, Aya Yamada, Masumi Hidaka, Hisashi Hasumi, Tetsuro Ikebe, Satoshi Fukumoto, Koji Okabe, and Hiroyuki Inuzuka. 2017. “Nutrient-induced FNIP degradation by SCFβ-TRCP regulates FLCN complex localization and promotes renal cancer progression.” Oncotarget 8 (6): 9947-9960. doi:10.18632/oncotarget.14221. http://dx.doi.org/10.18632/oncotarget.14221.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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354783/pdf/Terms of Use
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