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


Howitt, J; Lackovic, J; Low, LH; Naguib, A; Macintyre, A; Goh, CP; Callaway, JK; Hammond, V; Thomas, T; Dixon, M; Putz, U; Silke, J; Bartlett, P; Yang, BL; Kumar, S; Trotman, LC; Tan, SS
2012-01-09
JOURNAL OF CELL BIOLOGY
Journal Article
196
1
29-36
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.
ROCKEFELLER UNIV PRESS
LHERMITTE-DUCLOS-DISEASE; TUMOR-SUPPRESSOR PTEN; UBIQUITIN LIGASE; SOMA SIZE; BRAIN; PHOSPHATASE; STROKE; PHOSPHORYLATION; MOUSE; INHIBITION
Cell Signalling and Cell Death; Development and Cancer
10.1083/jcb.201105009
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 publication 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/).

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Creation Date 2012-01-09 12:00:00