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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)9947-9960
Number of pages14
JournalOncotarget
Volume8
Issue number6
DOIs
Publication statusPublished - Jan 1 2017

All Science Journal Classification (ASJC) codes

  • Oncology

Fingerprint Dive into the research topics of 'Nutrient-induced FNIP degradation by SCF<sup>β-TRCP</sup> regulates FLCN complex localization and promotes renal cancer progression'. Together they form a unique fingerprint.

  • Cite this

    Nagashima, K., Fukushima, H., Shimizu, K., Yamada, A., Hidaka, M., Hasumi, H., Ikebe, T., Fukumoto, S., Okabe, K., & 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