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

Katsuyuki Nagashima, Hidefumi Fukushima, Kouhei Shimizu, Aya Yamada, Masumi Hidaka, Hisashi Hasumi, Tetsuro Ikebe, Satoshi Fukumoto, Koji Okabe, Hiroyuki Inuzuka

研究成果: ジャーナルへの寄稿記事

8 引用 (Scopus)

抜粋

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.

元の言語英語
ページ(範囲)9947-9960
ページ数14
ジャーナルOncotarget
8
発行部数6
DOI
出版物ステータス出版済み - 1 1 2017

    フィンガープリント

All Science Journal Classification (ASJC) codes

  • Oncology

これを引用

Nagashima, K., Fukushima, H., Shimizu, K., Yamada, A., Hidaka, M., Hasumi, H., ... Inuzuka, H. (2017). Nutrient-induced FNIP degradation by SCFβ-TRCP regulates FLCN complex localization and promotes renal cancer progression. Oncotarget, 8(6), 9947-9960. https://doi.org/10.18632/oncotarget.14221