title: Ubiquitin E3 ligase Nedd4-1 acts as a downstream target of PI3K/PTEN-mTORC1 signaling to promote neurite growth.
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.
authors.affiliation: Departments of Molecular Neurobiology and.
authors.forename: Hung-En
authors.initials: HE
authors.lastname: Hsia
authors.affiliation: Departments of Molecular Neurobiology and.
authors.forename: Rohit
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; Vlaams Instituut voor Biotechnologie Center for the Biology of Disease, 3000 Leuven, Belgium;
authors.forename: Rossella
authors.initials: R
authors.lastname: Luca
authors.affiliation: Departments of Molecular Neurobiology and.
authors.forename: Michiko
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Department of Cell Biology, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037; Department of Neuroscience, Columbia University, New York, NY 10032;
authors.forename: Julien
authors.initials: J
authors.lastname: Courchet
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
authors.forename: Jonathan
authors.initials: J
authors.lastname: Nakashima
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
authors.forename: Shumin
authors.initials: S
authors.lastname: Wu
authors.affiliation: Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany;
authors.forename: Sandra
authors.initials: S
authors.lastname: Goebbels
authors.affiliation: Medical Research Council Centre for Developmental Neurobiology, King's College London, London SE1 1UL, United Kingdom; Institute of Biochemistry, Charité-Universitätsmedizin Berlin, NeuroCure Cluster of Excellence, 10117 Berlin, Germany;
authors.forename: Wenlin
authors.initials: W
authors.lastname: An
authors.affiliation: Medical Research Council Centre for Developmental Neurobiology, King's College London, London SE1 1UL, United Kingdom; Institute of Biochemistry, Charité-Universitätsmedizin Berlin, NeuroCure Cluster of Excellence, 10117 Berlin, Germany;
authors.forename: Britta J
authors.initials: BJ
authors.lastname: Eickholt
authors.affiliation: Department of Cell Biology, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037; Department of Neuroscience, Columbia University, New York, NY 10032;
authors.forename: Franck
authors.initials: F
authors.lastname: Polleux
authors.affiliation: Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada, M5G 1X8; Biochemistry Department, University of Toronto, Toronto, ON, Canada M5S 1A8;
authors.forename: Daniela
authors.initials: D
authors.lastname: Rotin
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
authors.forename: Hong
authors.initials: H
authors.lastname: Wu
authors.affiliation: Neurogenetics, Max Planck Institute of Experimental Medicine, 37075 Göttingen, Germany; Department of Psychiatry, Ludwig-Maximilians University, 80336 Munich, Germany; and.
authors.forename: Moritz J
authors.initials: MJ
authors.lastname: Rossner
authors.affiliation: Center for Human Genetics and Leuven Institute for Neurodegenerative Diseases, Katholieke Universiteit Leuven, 3000 Leuven, Belgium; Vlaams Instituut voor Biotechnologie Center for the Biology of Disease, 3000 Leuven, Belgium; Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Bagni
authors.affiliation: Departments of Molecular Neurobiology and.
authors.forename: Jeong-Seop
authors.initials: JS
authors.lastname: Rhee
authors.affiliation: Departments of Molecular Neurobiology and.
authors.forename: Nils
authors.initials: N
authors.lastname: Brose
authors.affiliation: Departments of Molecular Neurobiology and kawabe@em.mpg.de.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawabe
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D000076222:Mechanistic Target of Rapamycin Complex 1; D018345:Mice, Knockout; D008954:Models, Biological; D009024:Morphogenesis; D046912:Multiprotein Complexes / Q000378:metabolism*; D000075702:Nedd4 Ubiquitin Protein Ligases; D016501:Neurites / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D025821:Polyubiquitin / Q000378:metabolism; D014176:Protein Biosynthesis; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D000075702:Nedd4 Ubiquitin Protein Ligases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D025821:Polyubiquitin; D058570:TOR Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; C000618461:Nedd4l protein, mouse