2. Academic Validation
  3. SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

  • EMBO J. 2016 Jul 1;35(13):1400-16. doi: 10.15252/embj.201593374.
Madalina Raducu 1,  Ella Fung 1,  Sébastien Serres 1,  Paola Infante 2,  Alessandro Barberis 1,  Roman Fischer 3,  Claire Bristow 1,  Marie-Laëtitia Thézénas 3,  Csaba Finta 4,  John C Christianson 5,  Francesca M Buffa 1,  Benedikt M Kessler 3,  Nicola R Sibson 1,  Lucia Di Marcotullio 6,  Rune Toftgård 4,  Vincenzo D'Angiolella 7
Affiliations

Affiliations

  • 1 Cancer Research UK and Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK.
  • 2 Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
  • 3 Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • 4 Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Huddinge, Sweden.
  • 5 Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK.
  • 6 Department of Molecular Medicine, University "La Sapienza", Rome, Italy Pasteur Institute/Cenci Bolognetti Foundation Sapienza University, Rome, Italy.
  • 7 Cancer Research UK and Medical Research Council Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, UK [email protected].
PMID: 27234298 DOI: 10.15252/embj.201593374
Abstract

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.

Keywords

Fbxl17; F‐box protein; Hedgehog signaling; Sufu; medulloblastoma.

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