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

John Silke; Perry Bartlett; Baoli Yang; Sharad Kumar; Lloyd C. Trotman; Seong-Seng Tan; Jason Howitt; Jenny Lackovic; Ley-Hian Low; Choo-Peng Goh; Jennifer K. Callaway; Adam Naguib; Alison Macintyre; Vicki Hammond; Tim Thomas; Ulrich Putz; Matthew Dixon

doi:10.1083/jcb.201105009

Back

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

Journal article

Open access

Peer reviewed

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

John Silke, Perry Bartlett, Baoli Yang, Sharad Kumar, Lloyd C. Trotman, Seong-Seng Tan, Jason Howitt, Jenny Lackovic, Ley-Hian Low, Choo-Peng Goh, …

Journal of Cell Biology, Vol.196(1), pp.29-36

01/09/2012

DOI: 10.1083/jcb.201105009

PMCID: PMC3255971

PMID: 22213801

Files and links (1)

url

https://doi.org/10.1083/jcb.201105009View

Published (Version of record) Open Access

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.

Obstetrics and Gynecology

Details

Title: Subtitle: Ndfip1 regulates nuclear Pten import in vivo to promote neuronal survival following cerebral ischemia
Creators: John Silke
Perry Bartlett
Baoli Yang - University of Iowa
Sharad Kumar
Lloyd C. Trotman
Seong-Seng Tan
Jason Howitt
Jenny Lackovic
Ley-Hian Low
Choo-Peng Goh
Jennifer K. Callaway
Adam Naguib
Alison Macintyre
Vicki Hammond
Tim Thomas
Ulrich Putz
Matthew Dixon
Resource Type: Journal article
Publication Details: Journal of Cell Biology, Vol.196(1), pp.29-36
DOI: 10.1083/jcb.201105009
PMID: 22213801
PMCID: PMC3255971
NLM abbreviation: J Cell Biol
ISSN: 0021-9525
Copyright: © 2012 Howitt et al.This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the pub-lication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/)
Language: English
Date published: 01/09/2012
Academic Unit: BioVentures Center; Obstetrics and Gynecology
Record Identifier: 9983557428002771

Metrics

18 Record Views

89 Times Cited - Web of Science