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

Howitt, J., Lackovic, J., Low, L. H., Naguib, A., Macintyre, A., Goh, C. P., Callaway, J. K., Hammond, V., Thomas, T., Dixon, M., Putz, U., Silke, J., Bartlett, P., Yang, B. L., Kumar, S., Trotman, L. C., Tan, S. S. (January 2012) Ndfip1 regulates nuclear Pten import in vivo to promote neuronal survival following cerebral ischemia. Journal of Cell Biology, 196 (1). pp. 29-36. ISSN 0021-9525

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URL: http://www.ncbi.nlm.nih.gov/pubmed/22213801
DOI: 10.1083/jcb.201105009

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.

Item Type: Paper
Uncontrolled Keywords: lhermitte-duclos-disease Lhermitte Duclos disease tumor suppressor PTEN ubiquitin ligase soma size brain phosphatase stroke phosphorylation mouse inhibition
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > PTEN
CSHL Authors:
Communities: CSHL Post Doctoral Fellows
CSHL labs > Trotman lab
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > DNA Sequencing Service
CSHL Cancer Center Shared Resources > Gene Targeting Service
CSHL Cancer Center Shared Resources > Microscopy Service
Depositing User: Brian Soldo
Date: January 2012
Date Deposited: 23 Mar 2012 16:07
Last Modified: 26 Dec 2014 19:05
PMCID: PMC3255971
Related URLs:
URI: http://repository.cshl.edu/id/eprint/25519

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