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

6 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

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Kidney Neoplasms
Polycystic Kidney Diseases
Knockout Mice
Food
Casein Kinase I
Proteins
Estrone
Ubiquitination
Proteasome Endopeptidase Complex
Renal Cell Carcinoma
Neoplasms
Carcinoma
Kidney
Mutation

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

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

Nutrient-induced FNIP degradation by SCFβ-TRCP regulates FLCN complex localization and promotes renal cancer progression. / Nagashima, Katsuyuki; Fukushima, Hidefumi; Shimizu, Kouhei; Yamada, Aya; Hidaka, Masumi; Hasumi, Hisashi; Ikebe, Tetsuro; Fukumoto, Satoshi; Okabe, Koji; Inuzuka, Hiroyuki.

In: Oncotarget, Vol. 8, No. 6, 01.01.2017, p. 9947-9960.

Research output: Contribution to journalArticle

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, vol. 8, no. 6, pp. 9947-9960. https://doi.org/10.18632/oncotarget.14221
Nagashima, Katsuyuki ; Fukushima, Hidefumi ; Shimizu, Kouhei ; Yamada, Aya ; Hidaka, Masumi ; Hasumi, Hisashi ; Ikebe, Tetsuro ; Fukumoto, Satoshi ; Okabe, Koji ; Inuzuka, Hiroyuki. / Nutrient-induced FNIP degradation by SCFβ-TRCP regulates FLCN complex localization and promotes renal cancer progression. In: Oncotarget. 2017 ; Vol. 8, No. 6. pp. 9947-9960.
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