Ndfip1 regulates nuclear Pten import in vivo to promote neuronal survival following cerebral ischemia

Howitt, Jason, Lackovic, Jenny, Low, Ley-Hian, Naguib, Adam, Macintyre, Alison, Goh, Choo-Peng, Callaway, Jennifer K., Hammond, Vicki, Thomas, Tim, Dixon, Matthew, Putz, Ulrich, Silke, John, Bartlett, Perry, Yang, Baoli, Kumar, Sharad, Trotman, Lloyd C. and Tan, Seong-Seng (2012) Ndfip1 regulates nuclear Pten import in vivo to promote neuronal survival following cerebral ischemia. Journal of Cell Biology, 196 1: 29-36. doi:10.1083/jcb.201105009

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Author Howitt, Jason
Lackovic, Jenny
Low, Ley-Hian
Naguib, Adam
Macintyre, Alison
Goh, Choo-Peng
Callaway, Jennifer K.
Hammond, Vicki
Thomas, Tim
Dixon, Matthew
Putz, Ulrich
Silke, John
Bartlett, Perry
Yang, Baoli
Kumar, Sharad
Trotman, Lloyd C.
Tan, Seong-Seng
Title Ndfip1 regulates nuclear Pten import in vivo to promote neuronal survival following cerebral ischemia
Journal name Journal of Cell Biology   Check publisher's open access policy
ISSN 0021-9525
Publication date 2012-01
Sub-type Article (original research)
DOI 10.1083/jcb.201105009
Open Access Status File (Publisher version)
Volume 196
Issue 1
Start page 29
End page 36
Total pages 8
Place of publication New York, NY, United States
Publisher Rockefeller University Press
Collection year 2013
Language eng
Formatted abstract
PTEN (phosphatase and tensin homologue deleted on chromosome TEN) is the major negative regulator of phosphatidylinositol 3-kinase signaling and has cell-specific functions including tumor suppression. Nuclear localization of PTEN is vital for tumor suppression; however, outside of cancer, the molecular and physiological events driving PTEN nuclear entry are unknown. In this paper, we demonstrate that cytoplasmic Pten was translocated into the nuclei of neurons after cerebral ischemia in mice. Critically, this transport event was dependent on a surge in the Nedd4 family-interacting protein 1 (Ndfip1), as neurons in Ndfip1-deficient mice failed to import Pten. Ndfip1 binds to Pten, resulting in enhanced ubiquitination by Nedd4 E3 ubiquitin ligases. In vitro, Ndfip1 overexpression increased the rate of Pten nuclear import detected by photobleaching experiments, whereas Ndfip1 -/ - fibroblasts showed negligible transport rates. In vivo, Ndfip1 mutant mice suffered larger infarct sizes associated with suppressed phosphorylated Akt activation. Our findings provide the first physiological example of when and why transient shuttling of nuclear Pten occurs and how this process is critical for neuron survival.
Keyword Lhermitte-Duclos-Disease
Tumor-Suppressor Pten
Ubiquitin Ligase
Soma Size
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Copyright © 2012 by The Rockefeller University Press.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2013 Collection
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Citation counts: TR Web of Science Citation Count  Cited 44 times in Thomson Reuters Web of Science Article | Citations
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