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 Sciences, 111(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