Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch-dependent ubiquitination.
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.
Di Marcotullio
Lucia
L
Department of Experimental Medicine and Pathology, University La Sapienza, Roma, 324 Viale Regina Elena, 00161 Roma, Italy.
Ferretti
Elisabetta
E
Greco
Azzura
A
De Smaele
Enrico
E
Po
Agnese
A
Sico
Maria Anna
MA
Alimandi
Maurizio
M
Giannini
Giuseppe
G
Maroder
Marella
M
Screpanti
Isabella
I
Gulino
Alberto
A
D000818:Animals; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000473:pathology; D002531:Cerebellum / Q000166:cytology / Q000473:pathology; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008527:Medulloblastoma / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
C400551:GLI1 protein, human; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; C106293:Numb protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins; D014157:Transcription Factors; D014452:Ubiquitins; D000071676:Zinc Finger Protein GLI1; C432966:ITCH protein, human; D044767:Ubiquitin-Protein Ligases