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Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch-dependent ubiquitination

Nature Cell Biology volume 8, pages 1415–1423 (2006)Cite this article

Abstract

The developmental protein Numb is a major determinant of binary cell fates1,2,3. It is also required for the differentiation of cerebellar granule cell progenitors (GCPs)4 at a stage of development responsive to the morphogenic glycoprotein Hedehog5,6. Hedgehog signalling is crucial for the physiological maintenance and self-renewal of neural stem cells and its deregulation is responsible for their progression towards tumorigenesis5,7,8,9,10,11. The mechanisms that inhibit this pathway during the differentiation stage are poorly understood. Here, we identify Numb as a Hedgehog-pathway inhibitor that is downregulated in early GCPs and GCP-derived cancer cells. We demonstrate that the Hedgehog transcription factor Gli1 is targeted by Numb for Itch-dependent ubiquitination, which suppresses Hedgehog signals, thus arresting growth and promoting cell differentiation. This novel Numb-dependent regulatory loop may limit the extent and duration of Hedgehog signalling during neural-progenitor differentiation, and its subversion may be a relevant event in brain tumorigenesis.

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Figure 1: Numb is downregulated in cerebellar GCPs and medulloblastomas.
Figure 2: Numb promotes Gli1 ubiquitination and degradation.
Figure 3: Itch targets Gli1 for Numb-induced ubiquitination.
Figure 4: Numb antagonizes Hedgehog signalling.
Figure 5: Numb antagonizes Hedgehog effects on medulloblastoma and cerebellar GCP cells.

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Acknowledgements

This work was supported by the Associazione Italiana per la Ricerca sul Cancro, Telethon Grant GGP04168, the Ministry of University & Research and National Research Council, the Ministry of Health, the Center of Excellence for Biology and Molecular Medicine and the Rome Oncogenomic Center. E.D.S. is supported by an Fondazione Italiana per la Ricerca sul Cancro (FIRC) fellowship. We thank all mentioned colleagues and R. De Maria for reagents, G. Canettieri and R. Paolini for sharing data and advice, M. Levrero for critical discussion and C. Fragomeli, T. Natale and S. Espinola for experimental assistance.

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Author notes

  1. Lucia Di Marcotullio and Elisabetta Ferretti: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Experimental Medicine and Pathology, University La Sapienza, Roma, 324 Viale Regina Elena, Roma, 00161, Italy

    Lucia Di Marcotullio, Elisabetta Ferretti, Azzura Greco, Enrico De Smaele, Agnese Po, Maria Anna Sico, Maurizio Alimandi, Giuseppe Giannini, Marella Maroder, Isabella Screpanti & Alberto Gulino

  2. Pasteur Institute, Cenci Bolognetti Foundation, University La Sapienza, Roma, 324 Viale Regina Elena, Roma, 00161, Italy

    Isabella Screpanti & Alberto Gulino

  3. Neuromed Institute, Pozzilli, 86077, Italy

    Alberto Gulino

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Correspondence to Alberto Gulino.

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Marcotullio, L., Ferretti, E., Greco, A. et al. Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch-dependent ubiquitination. Nat Cell Biol 8, 1415–1423 (2006). https://doi.org/10.1038/ncb1510

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