Nature Cell Biology
- 8, 1415 - 1423 (2006)
Published online: 19 November 2006; | doi:10.1038/ncb1510
Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch-dependent ubiquitinationLucia Di Marcotullio1, 4, Elisabetta Ferretti1, 4, Azzura Greco1, Enrico De Smaele1, Agnese Po1, Maria Anna Sico1, Maurizio Alimandi1, Giuseppe Giannini1, Marella Maroder1, Isabella Screpanti1, 2 & Alberto Gulino1, 2, 31
Department of Experimental Medicine and Pathology, University La Sapienza, Roma, 324 Viale Regina Elena, 00161 Roma, Italy. 2
Pasteur Institute, Cenci Bolognetti Foundation, University La Sapienza, Roma, 324 Viale Regina Elena, 00161 Roma, Italy. 3
Neuromed Institute, 86077 Pozzilli, Italy. 4
These authors contributed equally to this work.
Correspondence should be addressed to Alberto Gulino alberto.gulino@uniroma1.it 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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