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

HE Hsia, R Kumar, R Luca, M Takeda… - Proceedings of the …, 2014 - National Acad Sciences
HE Hsia, R Kumar, R Luca, M Takeda, J Courchet, J Nakashima, S Wu, S Goebbels, W An…
Proceedings of the National Academy of Sciences, 2014National Acad Sciences
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 …
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.
National Acad Sciences