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SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development
Author(s) -
Raducu Madalina,
Fung Ella,
Serres Sébastien,
Infante Paola,
Barberis Alessandro,
Fischer Roman,
Bristow Claire,
Thézénas MarieLaëtitia,
Finta Csaba,
Christianson John C,
Buffa Francesca M,
Kessler Benedikt M,
Sibson Nicola R,
Di Marcotullio Lucia,
Toftgård Rune,
D'Angiolella Vincenzo
Publication year - 2016
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201593374
Subject(s) - radiation oncology , library science , medicine , oncology , political science , radiation therapy , computer science
Skp1‐Cul1‐F‐box protein (SCF) ubiquitin ligases direct cell survival decisions by controlling protein ubiquitylation and degradation. Sufu (Suppressor of fused) is a central regulator of Hh (Hedgehog) signaling and acts as a tumor suppressor by maintaining the Gli (Glioma‐associated oncogene homolog) transcription factors inactive. Although Sufu has a pivotal role in Hh signaling, the players involved in controlling Sufu levels and their role in tumor growth are unknown. Here, we show that Fbxl17 (F‐box and leucine‐rich repeat protein 17) targets Sufu for proteolysis in the nucleus. The ubiquitylation of Sufu, mediated by Fbxl17, allows the release of Gli1 from Sufu for proper Hh signal transduction. Depletion of Fbxl17 leads to defective Hh signaling associated with an impaired cancer cell proliferation and medulloblastoma tumor growth. Furthermore, we identify a mutation in Sufu, occurring in medulloblastoma of patients with Gorlin syndrome, which increases Sufu turnover through Fbxl17‐mediated polyubiquitylation and leads to a sustained Hh signaling activation. In summary, our findings reveal Fbxl17 as a novel regulator of Hh pathway and highlight the perturbation of the Fbxl17–Sufu axis in the pathogenesis of medulloblastoma.