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.

Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch- dependent ubiquitination / DI MARCOTULLIO, Lucia; Ferretti, Elisabetta; Greco, Azzura; DE SMAELE, Enrico; Po, Agnese; Maria Anna, Sico; Alimandi, Maurizio; Giannini, Giuseppe; Maroder, Marella; Screpanti, Isabella; Gulino, Alberto. - In: NATURE CELL BIOLOGY. - ISSN 1465-7392. - STAMPA. - 8:12(2006), pp. 1415-U68. [10.1038/ncb1510]

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

DI MARCOTULLIO, LUCIA;FERRETTI, ELISABETTA;GRECO, Azzura;DE SMAELE, Enrico;PO, AGNESE;ALIMANDI, MAURIZIO;GIANNINI, Giuseppe;MARODER, Marella;SCREPANTI, Isabella;GULINO, Alberto
2006

Abstract

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.
2006
01 Pubblicazione su rivista::01a Articolo in rivista
Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch- dependent ubiquitination / DI MARCOTULLIO, Lucia; Ferretti, Elisabetta; Greco, Azzura; DE SMAELE, Enrico; Po, Agnese; Maria Anna, Sico; Alimandi, Maurizio; Giannini, Giuseppe; Maroder, Marella; Screpanti, Isabella; Gulino, Alberto. - In: NATURE CELL BIOLOGY. - ISSN 1465-7392. - STAMPA. - 8:12(2006), pp. 1415-U68. [10.1038/ncb1510]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/364857
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