PMID- 29515120 OWN - NLM STAT- MEDLINE DCOM- 20180515 LR - 20190307 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 9 IP - 1 DP - 2018 Mar 7 TI - Itch/beta-arrestin2-dependent non-proteolytic ubiquitylation of SuFu controls Hedgehog signalling and medulloblastoma tumorigenesis. PG - 976 LID - 10.1038/s41467-018-03339-0 [doi] LID - 976 AB - Suppressor 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/beta-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. FAU - Infante, Paola AU - Infante P AD - Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, 00161, Rome, Italy. FAU - Faedda, Roberta AU - Faedda R AD - Department of Molecular Medicine, University La Sapienza, 00161, Rome, Italy. FAU - Bernardi, Flavia AU - Bernardi F AD - Department of Molecular Medicine, University La Sapienza, 00161, Rome, Italy. FAU - Bufalieri, Francesca AU - Bufalieri F AD - Department of Molecular Medicine, University La Sapienza, 00161, Rome, Italy. FAU - Lospinoso Severini, Ludovica AU - Lospinoso Severini L AD - Department of Molecular Medicine, University La Sapienza, 00161, Rome, Italy. FAU - Alfonsi, Romina AU - Alfonsi R AD - Department of Molecular Medicine, University La Sapienza, 00161, Rome, Italy. FAU - Mazza, Daniela AU - Mazza D AD - Department of Molecular Medicine, University La Sapienza, 00161, Rome, Italy. FAU - Siler, Mariangela AU - Siler M AD - Department of Molecular Medicine, University La Sapienza, 00161, Rome, Italy. FAU - Coni, Sonia AU - Coni S AD - Department of Molecular Medicine, University La Sapienza, 00161, Rome, Italy. FAU - Po, Agnese AU - Po A AD - Department of Molecular Medicine, University La Sapienza, 00161, Rome, Italy. FAU - Petroni, Marialaura AU - Petroni M AD - Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, 00161, Rome, Italy. FAU - Ferretti, Elisabetta AU - Ferretti E AD - Department of Experimental Medicine, University La Sapienza, 00161, Rome, Italy. FAU - Mori, Mattia AU - Mori M AUID- ORCID: 0000-0003-2398-1254 AD - Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, 00161, Rome, Italy. FAU - De Smaele, Enrico AU - De Smaele E AD - Department of Experimental Medicine, University La Sapienza, 00161, Rome, Italy. FAU - Canettieri, Gianluca AU - Canettieri G AD - Department of Molecular Medicine, University La Sapienza, 00161, Rome, Italy. AD - Istituto Pasteur-Fondazione Cenci Bolognetti, University La Sapienza, 00161, Rome, Italy. FAU - Capalbo, Carlo AU - Capalbo C AD - Department of Molecular Medicine, University La Sapienza, 00161, Rome, Italy. FAU - Maroder, Marella AU - Maroder M AD - Department of Medico-Surgical Sciences and Biotechnologies, University La Sapienza, 00161, Rome, Italy. FAU - Screpanti, Isabella AU - Screpanti I AD - Department of Molecular Medicine, University La Sapienza, 00161, Rome, Italy. FAU - Kool, Marcel AU - Kool M AD - Hopp Children's Cancer Center at the NCT (KiTZ), 69120 Heidelberg, Germany. AD - Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120, Heidelberg, Germany. FAU - Pfister, Stefan M AU - Pfister SM AD - Hopp Children's Cancer Center at the NCT (KiTZ), 69120 Heidelberg, Germany. AD - Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120, Heidelberg, Germany. AD - Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, 69120, Heidelberg, Germany. FAU - Guardavaccaro, Daniele AU - Guardavaccaro D AUID- ORCID: 0000-0002-4517-1765 AD - Hubrecht Institute-KNAW and University Medical Center Utrecht, 3584CT, Utrecht, The Netherlands. FAU - Gulino, Alberto AU - Gulino A AD - Department of Molecular Medicine, University La Sapienza, 00161, Rome, Italy. FAU - Di Marcotullio, Lucia AU - Di Marcotullio L AD - Department of Molecular Medicine, University La Sapienza, 00161, Rome, Italy. lucia.dimarcotullio@uniroma1.it. AD - Istituto Pasteur-Fondazione Cenci Bolognetti, University La Sapienza, 00161, Rome, Italy. lucia.dimarcotullio@uniroma1.it. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180307 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 0 (Hedgehog Proteins) RN - 0 (Repressor Proteins) RN - 0 (SUFU protein, human) RN - 0 (Sufu protein, mouse) RN - 0 (beta-Arrestin 2) RN - EC 2.3.2.26 (ITCH protein, human) RN - EC 2.3.2.26 (Itch protein, mouse) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) SB - IM MH - Amino Acid Motifs MH - Animals MH - Carcinogenesis MH - Female MH - Hedgehog Proteins/genetics/*metabolism MH - Humans MH - Medulloblastoma/enzymology/genetics/*metabolism/pathology MH - Mice MH - Mice, Inbred BALB C MH - Mice, Inbred NOD MH - Mice, Knockout MH - Mice, SCID MH - Repressor Proteins/chemistry/genetics/*metabolism MH - Signal Transduction MH - Ubiquitin-Protein Ligases/genetics/*metabolism MH - Ubiquitination MH - beta-Arrestin 2/genetics/*metabolism PMC - PMC5841288 COIS- The authors declare no competing interests. EDAT- 2018/03/09 06:00 MHDA- 2018/05/16 06:00 PMCR- 2018/03/07 CRDT- 2018/03/09 06:00 PHST- 2016/05/19 00:00 [received] PHST- 2018/02/06 00:00 [accepted] PHST- 2018/03/09 06:00 [entrez] PHST- 2018/03/09 06:00 [pubmed] PHST- 2018/05/16 06:00 [medline] PHST- 2018/03/07 00:00 [pmc-release] AID - 10.1038/s41467-018-03339-0 [pii] AID - 3339 [pii] AID - 10.1038/s41467-018-03339-0 [doi] PST - epublish SO - Nat Commun. 2018 Mar 7;9(1):976. doi: 10.1038/s41467-018-03339-0.