Ubiquitin E3 ligase Nedd4-1 acts as a downstream target of PI3K/PTEN-mTORC1 signaling to promote neurite growth

2014 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​Ubiquitin E3 ligase Nedd4-1 acts as a downstream target of PI3K/PTEN-mTORC1 signaling to promote neurite growth​
Hsia, H.-E.; Kumar, R.; Luca, R.; Takeda, M.; Courchet, J.; Nakashima, J. & Wu, S. et al.​ (2014) 
Proceedings of the National Academy of Sciences111(36) pp. 13205​-13210​.​ DOI: https://doi.org/10.1073/pnas.1400737111 

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Authors
Hsia, Hung-En; Kumar, Rohit; Luca, Rossella; Takeda, Michiko; Courchet, Julien; Nakashima, Jonathan; Wu, Shumin; Goebbels, Sandra ; An, Wenlin; Eickholt, Britta J.; Polleux, Franck; Rotin, Daniela; Wu, Hong; Rossner, Moritz J. ; Bagni, Claudia; Rhee, Jeong-Seop ; Brose, Nils ; Kawabe, Hiroshi
Abstract
Protein ubiquitination is a core regulatory determinant of neural development. Previous studies have indicated that the Nedd4-family E3 ubiquitin ligases Nedd4-1 and Nedd4-2 may ubiquitinate phosphatase and tensin homolog (PTEN) and thereby regulate axonal growth in neurons. Using conditional knockout mice, we show here that Nedd4-1 and Nedd4-2 are indeed required for axonal growth in murine central nervous system neurons. However, in contrast to previously published data, we demonstrate that PTEN is not a substrate of Nedd4-1 and Nedd4-2, and that aberrant PTEN ubiquitination is not involved in the impaired axon growth upon deletion of Nedd4-1 and Nedd4-2. Rather, PTEN limits Nedd4-1 protein levels by modulating the activity of mTORC1, a protein complex that controls protein synthesis and cell growth. Our data demonstrate that Nedd4-family E3 ligases promote axonal growth and branching in the developing mammalian brain, where PTEN is not a relevant substrate. Instead, PTEN controls neurite growth by regulating Nedd4-1 expression.
Issue Date
2014
Journal
Proceedings of the National Academy of Sciences 
ISSN
0027-8424

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