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

Luca Lignitto, Antonietta Arcella, Maria Sepe, Laura Rinaldi, Rossella Delle Donne, Adriana Gallo, Eduard Stefan, Verena A. Bachmann, Maria A. Oliva, Clelia Tiziana Storlazzi, Alberto L'Abbate, Arturo Brunetti, Sara Gargiulo, Matteo Gramanzini, Luigi Insabato, Corrado Garbi, Max E. Gottesman and Antonio Feliciello ()
Additional contact information
Luca Lignitto: University Federico II and IEOS-CNR
Antonietta Arcella: I.R.C.C.S Neuromed Località Camerelle
Maria Sepe: University Federico II and IEOS-CNR
Laura Rinaldi: University Federico II and IEOS-CNR
Rossella Delle Donne: University Federico II and IEOS-CNR
Adriana Gallo: University Federico II and IEOS-CNR
Eduard Stefan: Institute of Biochemistry and Center for Molecular Biosciences Innsbruck (CMBI), Innrain 80/82
Verena A. Bachmann: Institute of Biochemistry and Center for Molecular Biosciences Innsbruck (CMBI), Innrain 80/82
Maria A. Oliva: I.R.C.C.S Neuromed Località Camerelle
Clelia Tiziana Storlazzi: University of Bari
Alberto L'Abbate: University of Bari
Arturo Brunetti: CEINGE Biotecnologie Avanzate Scarl, University Federico II
Sara Gargiulo: CEINGE Biotecnologie Avanzate Scarl, University Federico II
Matteo Gramanzini: CEINGE Biotecnologie Avanzate Scarl, University Federico II
Luigi Insabato: CEINGE Biotecnologie Avanzate Scarl, University Federico II
Corrado Garbi: University Federico II and IEOS-CNR
Max E. Gottesman: Institute of Cancer Research, Columbia University Medical Center
Antonio Feliciello: University Federico II and IEOS-CNR

Nature Communications, 2013, vol. 4, issue 1, 1-13

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/ncomms2791

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