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

Hung-En Hsia, Rohit Kumar, Rossella Luca, Michiko Takeda, Julien Courchet, Jonathan Nakashima, Shumin Wu, Sandra Goebbels, Wenlin An, Britta J. Eickholt, Franck Polleux, Daniela Rotin, Hong Wu, Moritz J. Rossner, Claudia Bagni, Jeong-Seop Rhee, Nils Brose, Hiroshi Kawabe*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

67 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)13205-13210
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number36
DOIs
Publication statusPublished - 9 Sept 2014

Keywords

  • PTEN TUMOR-SUPPRESSOR
  • IN-VIVO
  • REGULATES PTEN
  • HIPPOCAMPAL-NEURONS
  • CELLS
  • DELETION
  • POLARITY
  • MICE
  • ESTABLISHMENT
  • NEUROGENESIS

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