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

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

Research output: Contribution to journalArticlepeer-review


The developmental protein Numb is a major determinant of binary cell fates. It is also required for the differentiation of cerebellar granule cell progenitors (GCPs) at a stage of development responsive to the morphogenic glycoprotein Hedehog. Hedgehog signalling is crucial for the physiological maintenance and self-renewal of neural stem cells and its deregulation is responsible for their progression towards tumorigenesis. 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.

Original languageEnglish
Pages (from-to)1415-1423
Number of pages9
JournalNature Cell Biology
Issue number12
Publication statusPublished - Dec 2006

ASJC Scopus subject areas

  • Cell Biology


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