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; Antonio Feliciello

doi:10.1038/ncomms2791

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, Antonio Feliciello

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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.

Original language	English
Article number	1822
Journal	Nature Communications
Volume	4
DOIs	https://doi.org/10.1038/ncomms2791
Publication status	Published - 2013

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Chemistry(all)
Physics and Astronomy(all)

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Lignitto, L., Arcella, A., Sepe, M., Rinaldi, L., Delle Donne, R., Gallo, A., Stefan, E., Bachmann, V. A., Oliva, M. A., Tiziana Storlazzi, C., L'Abbate, A., Brunetti, A., Gargiulo, S., Gramanzini, M., Insabato, L., Garbi, C., Gottesman, M. E., & Feliciello, A. (2013). Proteolysis of MOB1 by the ubiquitin ligase praja2 attenuates Hippo signalling and supports glioblastoma growth. Nature Communications, 4, [1822]. https://doi.org/10.1038/ncomms2791

Lignitto, L, Arcella, A, Sepe, M, Rinaldi, L, Delle Donne, R, Gallo, A, Stefan, E, Bachmann, VA, Oliva, MA, Tiziana Storlazzi, C, L'Abbate, A, Brunetti, A, Gargiulo, S, Gramanzini, M, Insabato, L, Garbi, C, Gottesman, ME & Feliciello, A 2013, 'Proteolysis of MOB1 by the ubiquitin ligase praja2 attenuates Hippo signalling and supports glioblastoma growth', Nature Communications, vol. 4, 1822. https://doi.org/10.1038/ncomms2791

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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.",

author = "Luca Lignitto and Antonietta Arcella and Maria Sepe and Laura Rinaldi and {Delle Donne}, Rossella and Adriana Gallo and Eduard Stefan and Bachmann, {Verena A.} and Oliva, {Maria A.} and {Tiziana Storlazzi}, Clelia and Alberto L'Abbate and Arturo Brunetti and Sara Gargiulo and Matteo Gramanzini and Luigi Insabato and Corrado Garbi and Gottesman, {Max E.} and Antonio Feliciello",

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AU - Lignitto, Luca

AU - Arcella, Antonietta

AU - Sepe, Maria

AU - Rinaldi, Laura

AU - Delle Donne, Rossella

AU - Gallo, Adriana

AU - Stefan, Eduard

AU - Bachmann, Verena A.

AU - Oliva, Maria A.

AU - Tiziana Storlazzi, Clelia

AU - L'Abbate, Alberto

AU - Brunetti, Arturo

AU - Gargiulo, Sara

AU - Gramanzini, Matteo

AU - Insabato, Luigi

AU - Garbi, Corrado

AU - Gottesman, Max E.

AU - Feliciello, Antonio

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

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

Abstract

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