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

doi:10.18632/oncotarget.14221

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

Oncotarget. 2017 Feb 7;8(6):9947-9960. doi: 10.18632/oncotarget.14221.

Authors

Katsuyuki Nagashima^{1

2

3}, Hidefumi Fukushima¹, Kouhei Shimizu⁴, Aya Yamada⁵, Masumi Hidaka², Hisashi Hasumi⁶, Tetsuro Ikebe³, Satoshi Fukumoto^{1

5}, Koji Okabe², Hiroyuki Inuzuka^{1

4}

Affiliations

¹ Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
² Department of Physiological Sciences and Molecular Biology, Fukuoka Dental College, Fukuoka 814-0193, Japan.
³ Department of Oral and Maxillofacial Surgery, Fukuoka Dental College, Fukuoka 814-0193, Japan.
⁴ Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
⁵ Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
⁶ Department of Urology and Molecular Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.

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.

Keywords: FLCN; FNIP; renal cancer; tumor suppressor; β-TRCP.

MeSH terms

Animals
Birt-Hogg-Dube Syndrome / enzymology*
Birt-Hogg-Dube Syndrome / genetics
Birt-Hogg-Dube Syndrome / pathology
Carcinoma, Renal Cell / enzymology*
Carcinoma, Renal Cell / genetics
Carcinoma, Renal Cell / pathology
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Casein Kinase I / metabolism
Cell Proliferation*
Energy Metabolism
HEK293 Cells
HeLa Cells
Humans
Kidney Neoplasms / enzymology*
Kidney Neoplasms / genetics
Kidney Neoplasms / pathology
Lysosomes / metabolism
Mice, Nude
Nutritional Status*
Phosphorylation
Proteasome Endopeptidase Complex / metabolism
Protein Stability
Proteolysis
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins / metabolism*
RNA Interference
SKP Cullin F-Box Protein Ligases / genetics
SKP Cullin F-Box Protein Ligases / metabolism*
Signal Transduction
TOR Serine-Threonine Kinases / metabolism
Time Factors
Transfection
Tumor Burden
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*
Ubiquitination

Substances

Carrier Proteins
FLCN protein, human
FNIP2 protein, human
Proto-Oncogene Proteins
Tumor Suppressor Proteins
SKP Cullin F-Box Protein Ligases
MTOR protein, human
Casein Kinase I
TOR Serine-Threonine Kinases
Proteasome Endopeptidase Complex

Grants and funding

K01 AG041218/AG/NIA NIH HHS/United States