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J. Cell Biol. 196 (1): 29-36

Copyright © 2012 by the Rockefeller University Press.

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

Jason Howitt1, Jenny Lackovic1, Ley-Hian Low1, Adam Naguib4, Alison Macintyre1, Choo-Peng Goh1, Jennifer K. Callaway2, Vicki Hammond1, Tim Thomas3, Matthew Dixon3, Ulrich Putz1, John Silke3, Perry Bartlett5, Baoli Yang6, Sharad Kumar7, Lloyd C. Trotman4, , and Seong-Seng Tan1

1 Brain Development and Regeneration Laboratory, Florey Neuroscience Institutes, 2 Department of Pharmacology, and 3 Walter and Eliza Hall Institute of Medical Research, The University of Melbourne, Parkville, Victoria 3010, Australia
4 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
5 Queensland Brain Institute, University of Queensland, St. Lucia QLD 4072, Australia
6 Department of Obstetrics and Gynecology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242
7 Center for Cancer Biology, SA Pathology, Adelaide SA 5000, Australia

Correspondence to Lloyd C. Trotman: trotman{at}cshl.edu; or Seong-Seng Tan: stan{at}florey.edu.au

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.

Abbreviations: CCA, common carotid artery • HI, hypoxia-ischemia • KO, knockout • MEF, mouse embryonic fibroblast • pAkt, phosphorylated Akt • RCCAo, right carotid artery occlusion • WT, wild type

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