Mitogen-activated kinase kinase kinase 1 inhibits hedgehog signaling and medulloblastoma growth through GLI1 phosphorylation

Antonucci,Laura; Di Magno,Laura; D'Amico,Davide; Manni,Simona; Serrao,Silvia Maria; Di Pastena,Fiorella; Bordone,Rosa; Yurtsever,Zuleyha Nihan; Caimano,Miriam; Petroni,Marialaura; Giorgi,Alessandra; Schininà,Maria Eugenia; Yates III,John R.; Di Marcotullio,Lucia; De Smaele,Enrico; Checquolo,Saula; Capalbo,Carlo; Agostinelli,Enzo; Maroder,Marella; Coni,Sonia; Canettieri,Gianluca

doi:10.3892/ijo.2018.4638

Mitogen-activated kinase kinase kinase 1 inhibits hedgehog signaling and medulloblastoma growth through GLI1 phosphorylation

Authors:
- Laura Antonucci
- Laura Di Magno
- Davide D'Amico
- Simona Manni
- Silvia Maria Serrao
- Fiorella Di Pastena
- Rosa Bordone
- Zuleyha Nihan Yurtsever
- Miriam Caimano
- Marialaura Petroni
- Alessandra Giorgi
- Maria Eugenia Schininà
- John R. Yates III
- Lucia Di Marcotullio
- Enrico De Smaele
- Saula Checquolo
- Carlo Capalbo
- Enzo Agostinelli
- Marella Maroder
- Sonia Coni
- Gianluca Canettieri
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Affiliations: Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy, Center for Life Nano Science at Sapienza, Italian Institute of Technology, 00161 Rome, Italy, Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100 Latina, Italy, Department of Biochemical Sciences 'A. Rossi Fanelli', Sapienza University of Rome, 00161 Rome, Italy, Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037, USA, Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
Published online on: November 19, 2018 https://doi.org/10.3892/ijo.2018.4638
Pages: 505-514
Copyright: © Antonucci et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aberrant activation of hedgehog (HH) signaling is a leading cause of the development of medulloblastoma, a pediatric tumor of the cerebellum. The FDA‑approved HH inhibitor, Vismodegib, which targets the transmembrane transducer SMO, has shown limited efficacy in patients with medulloblastoma, due to compensatory mechanisms that maintain an active HH‑GLI signaling status. Thus, the identification of novel actionable mechanisms, directly affecting the activity of the HH‑regulated GLI transcription factors is an important goal for these malignancies. In this study, using gene expression and reporter assays, combined with biochemical and cellular analyses, we demonstrate that mitogen‑activated kinase kinase kinase 1 (MEKK1), the most upstream kinase of the mitogen‑activated protein kinase (MAPK) phosphorylation modules, suppresses HH signaling by associating and phosphorylating GLI1, the most potent HH‑regulated transcription factor. Phosphorylation occurred at multiple residues in the C‑terminal region of GLI1 and was followed by an increased association with the cytoplasmic proteins 14‑3‑3. Of note, the enforced expression of MEKK1 or the exposure of medulloblastoma cells to the MEKK1 activator, Nocodazole, resulted in a marked inhibitory effect on GLI1 activity and tumor cell proliferation and viability. Taken together, the results of this study shed light on a novel regulatory mechanism of HH signaling, with potentially relevant implications in cancer therapy.

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