Proteolysis of MOB1 by the ubiquitin ligase praja2 attenuates Hippo signalling and supports glioblastoma growth

• Published in: Nature communications 2013-05, Vol.4 (1), p.1822-1822, Article 1822
• Main Authors: Lignitto, Luca, Arcella, Antonietta, Sepe, Maria, Rinaldi, Laura, Delle Donne, Rossella, Gallo, Adriana, Stefan, Eduard, Bachmann, Verena A., Oliva, Maria A., Tiziana Storlazzi, Clelia, L'Abbate, Alberto, Brunetti, Arturo, Gargiulo, Sara, Gramanzini, Matteo, Insabato, Luigi, Garbi, Corrado, Gottesman, Max E., Feliciello, Antonio
• Format: Article
• Language: English
• Subjects: 631/67/1922; 631/80/474/582; 631/80/83/2360; Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - metabolism; Amino Acid Sequence; Animals; Brain cancer; Brain Neoplasms - enzymology; Brain Neoplasms - pathology; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation; Enzymes; Genes; Glioblastoma - enzymology; Glioblastoma - pathology; HEK293 Cells; Hippo Signaling Pathway; Humanities and Social Sciences; Humans; Kinases; Male; Mice; Mice, Nude; Models, Biological; Molecular Sequence Data; multidisciplinary; Protein Binding; Protein Serine-Threonine Kinases - metabolism; Proteins; Proteolysis; Science; Science (multidisciplinary); Signal Transduction; Tumors; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms2791

Human glioblastoma is the most frequent and aggressive form of brain tumour in the adult population. Proteolytic turnover of tumour suppressors by the ubiquitin–proteasome system is a mechanism that tumour cells can adopt to sustain their growth and invasiveness. However, the identity of ubiquitin–proteasome targets and regulators in glioblastoma are still unknown. Here we report that the RING ligase praja2 ubiquitylates and degrades Mob, a core component of NDR/LATS kinase and a positive regulator of the tumour-suppressor Hippo cascade. Degradation of Mob through the ubiquitin–proteasome system attenuates the Hippo cascade and sustains glioblastoma growth in vivo . Accordingly, accumulation of praja2 during the transition from low- to high-grade glioma is associated with significant downregulation of the Hippo pathway. These findings identify praja2 as a novel upstream regulator of the Hippo cascade, linking the ubiquitin proteasome system to deregulated glioblastoma growth. Tumour suppressors can be inactivated in cancer not only as a result of mutation, but also by proteolytic degradation. Here the authors show that, during glioma development, the accumulation of the ubiquitin ligase praja2 sustains tumour growth by degrading MOB1—a core component of the Hippo pathway.