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

doi:10.1073/pnas.1400737111

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

Developmental Neurobiology

Research output: Contribution to journal › Article › peer-review

74 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 language	English
Pages (from-to)	13205-13210
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	111
Issue number	36
DOIs	https://doi.org/10.1073/pnas.1400737111
Publication status	Published - 9 Sept 2014

Keywords

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

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Hsia, H.-E., Kumar, R., Luca, R., Takeda, M., Courchet, J., Nakashima, J., Wu, S., Goebbels, S., An, W., Eickholt, B. J., Polleux, F., Rotin, D., Wu, H., Rossner, M. J., Bagni, C., Rhee, J.-S., Brose, N., & Kawabe, H. (2014). Ubiquitin E3 ligase Nedd4-1 acts as a downstream target of PI3K/PTEN-mTORC1 signaling to promote neurite growth. Proceedings of the National Academy of Sciences of the United States of America, 111(36), 13205-13210. https://doi.org/10.1073/pnas.1400737111

@article{a8f7b2557a984dc1b788c9adec6b564c,

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.",

keywords = "PTEN TUMOR-SUPPRESSOR, IN-VIVO, REGULATES PTEN, HIPPOCAMPAL-NEURONS, CELLS, DELETION, POLARITY, MICE, ESTABLISHMENT, NEUROGENESIS",

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

year = "2014",

month = sep,

day = "9",

doi = "10.1073/pnas.1400737111",

language = "English",

volume = "111",

pages = "13205--13210",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Acad Sciences",

number = "36",

}

Hsia, H-E, Kumar, R, Luca, R, Takeda, M, Courchet, J, Nakashima, J, Wu, S, Goebbels, S, An, W, Eickholt, BJ, Polleux, F, Rotin, D, Wu, H, Rossner, MJ, Bagni, C, Rhee, J-S, Brose, N & Kawabe, H 2014, 'Ubiquitin E3 ligase Nedd4-1 acts as a downstream target of PI3K/PTEN-mTORC1 signaling to promote neurite growth', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 36, pp. 13205-13210. https://doi.org/10.1073/pnas.1400737111

TY - JOUR

T1 - Ubiquitin E3 ligase Nedd4-1 acts as a downstream target of PI3K/PTEN-mTORC1 signaling to promote neurite growth

AU - Hsia, Hung-En

AU - Kumar, Rohit

AU - Luca, Rossella

AU - Takeda, Michiko

AU - Courchet, Julien

AU - Nakashima, Jonathan

AU - Wu, Shumin

AU - Goebbels, Sandra

AU - An, Wenlin

AU - Eickholt, Britta J.

AU - Polleux, Franck

AU - Rotin, Daniela

AU - Wu, Hong

AU - Rossner, Moritz J.

AU - Bagni, Claudia

AU - Rhee, Jeong-Seop

AU - Brose, Nils

AU - Kawabe, Hiroshi

PY - 2014/9/9

Y1 - 2014/9/9

N2 - 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.

AB - 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.

KW - PTEN TUMOR-SUPPRESSOR

KW - IN-VIVO

KW - REGULATES PTEN

KW - HIPPOCAMPAL-NEURONS

KW - CELLS

KW - DELETION

KW - POLARITY

KW - MICE

KW - ESTABLISHMENT

KW - NEUROGENESIS

U2 - 10.1073/pnas.1400737111

DO - 10.1073/pnas.1400737111

M3 - Article

SN - 0027-8424

VL - 111

SP - 13205

EP - 13210

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 36

ER -

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

Abstract

Keywords

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