Editors' ChoiceNeuroscience

Nuclear PTEN Promotes Neuronal Survival

Science Signaling  17 Jan 2012:
Vol. 5, Issue 207, pp. ec17
DOI: 10.1126/scisignal.2002856

PTEN is a lipid and protein phosphatase that is a well-known tumor suppressor through its ability to counter the activity of phosphoinositide 3-kinase (PI3K) and reduce phosphorylation and activation of the kinase Akt. PTEN ubiquitylation and nuclear transport have been reported to contribute to its tumor suppression activity, PTEN has been implicated in brain development, and reduction of PTEN activity has been associated with enhanced neuronal survival. Howitt et al. investigated PTEN trafficking in the brains of mice after ischemia. In the region near the infarct, PTEN exhibited a predominantly nuclear localization, whereas in distal regions or in uninfarcted areas, PTEN was predominantly cytoplasmic. Because the abundance of the Nedd4 ubiquitin ligase Ndfip1 increased in the surviving neurons, the authors investigated whether this protein may contribute to PTEN trafficking. Indeed, in mice engineered to lack Ndfip1 in neurons, PTEN remained cytoplasmic in the periinfarct area and the infracted area was larger than in wild-type mice. However, PTEN abundance did not appear different, suggesting that the differences are related to PTEN trafficking rather than ubiquitin-mediated degradation. Experiments in transfected cells or with brain lysates confirmed an interaction between Ndfip1, PTEN, and Nedd4-2 and indicated that either Nedd4-1 or Nedd4-2 could mediate the ubiquitylation of PTEN in the presence of Ndfip1. Phosphorylation appeared to regulate the interaction of PTEN with Ndfip1, because a PTEN mutant with alanine substitutions in the C-terminal phosphorylation sites enhanced the interaction and a phosphomimetic mutant reduced the interaction. In a photobleaching assay, Ndfip1 overexpression enhanced PTEN nuclear import, and in Ndfip1-knockout mouse embryo fibroblasts PTEN nuclear transport was undetectable. Whether the enhanced survival after ischemia associated with the nuclear trafficking of PTEN is due to its regulation of nuclear lipid signaling or through an enhancement of PI3K signaling in the cytoplasm or a combination of both remains to be established.

J. Howitt, J. Lackovic, L.-H. Low, A. Naguib, A. Macintyre, C.-P. Goh, J. K. Callaway, V. Hammond, T. Thomas, M. Dixon, U. Putz, J. Silke, P. Bartlett, B. Yang, S. Kumar, L. C. Trotman, S.-S. Tan, Ndfip1 regulates nuclear Pten import in vivo to promote neuronal survival following cerebral ischemia. J. Cell Biol. 196, 29–36 (2012). [Abstract] [Full Text]