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000132650 0247_ $$2doi$$a10.1038/s41467-018-03339-0
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000132650 1001_ $$aInfante, Paola$$b0
000132650 245__ $$aItch/β-arrestin2-dependent non-proteolytic ubiquitylation of SuFu controls Hedgehog signalling and medulloblastoma tumorigenesis.
000132650 260__ $$aLondon$$bNature Publishing Group$$c2018
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000132650 520__ $$aSuppressor of Fused (SuFu), a tumour suppressor mutated in medulloblastoma, is a central player of Hh signalling, a pathway crucial for development and deregulated in cancer. Although the control of Gli transcription factors by SuFu is critical in Hh signalling, our understanding of the mechanism regulating this key event remains limited. Here, we show that the Itch/β-arrestin2 complex binds SuFu and induces its Lys63-linked polyubiquitylation without affecting its stability. This process increases the association of SuFu with Gli3, promoting the conversion of Gli3 into a repressor, which keeps Hh signalling off. Activation of Hh signalling antagonises the Itch-dependent polyubiquitylation of SuFu. Notably, different SuFu mutations occurring in medulloblastoma patients are insensitive to Itch activity, thus leading to deregulated Hh signalling and enhancing medulloblastoma cell growth. Our findings uncover mechanisms controlling the tumour suppressive functions of SuFu and reveal that their alterations are implicated in medulloblastoma tumorigenesis.
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000132650 7001_ $$aFaedda, Roberta$$b1
000132650 7001_ $$aBernardi, Flavia$$b2
000132650 7001_ $$aBufalieri, Francesca$$b3
000132650 7001_ $$aLospinoso Severini, Ludovica$$b4
000132650 7001_ $$aAlfonsi, Romina$$b5
000132650 7001_ $$aMazzà, Daniela$$b6
000132650 7001_ $$aSiler, Mariangela$$b7
000132650 7001_ $$aConi, Sonia$$b8
000132650 7001_ $$aPo, Agnese$$b9
000132650 7001_ $$aPetroni, Marialaura$$b10
000132650 7001_ $$aFerretti, Elisabetta$$b11
000132650 7001_ $$00000-0003-2398-1254$$aMori, Mattia$$b12
000132650 7001_ $$aDe Smaele, Enrico$$b13
000132650 7001_ $$aCanettieri, Gianluca$$b14
000132650 7001_ $$aCapalbo, Carlo$$b15
000132650 7001_ $$aMaroder, Marella$$b16
000132650 7001_ $$aScrepanti, Isabella$$b17
000132650 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b18$$udkfz
000132650 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b19$$udkfz
000132650 7001_ $$00000-0002-4517-1765$$aGuardavaccaro, Daniele$$b20
000132650 7001_ $$aGulino, Alberto$$b21
000132650 7001_ $$aDi Marcotullio, Lucia$$b22
000132650 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-018-03339-0$$gVol. 9, no. 1, p. 976$$n1$$p976$$tNature Communications$$v9$$x2041-1723$$y2018
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