The phosphatase PTEN acts as a negative regulator of neuronal survival. Its dephosphorylation of phosphatidylinositol 3,4,5-triphosphate inhibits survival and proliferation signals that are triggered by phosphatidylinositol 3-kinase (PI3K) in the Akt pathway. PTEN's activity is strongly regulated by its cellular localization: in order to counteract PI3K's activity, PTEN has to be at the plasma membrane. Phosphorylation of the C terminus of PTEN results in its accumulation in the nucleus, where it has phosphatase-independent but still unknown functions. Association of the PTEN C-terminal tail with the PDZ domain of the MASK2 kinase increases PTEN phosphorylation. Interestingly, inactivation of MASK2 also triggers cell survival. The envelope glycoprotein G from rabies virus also interacts with MASK2-PDZ through its C-terminal tail, which results in survival of infected neurons. In an effort to gain more insight into the role of PTEN in dictating neuronal survival, Wolff, Lagon and colleagues determined the solution structures of MASK2-PDZ bound to the C-terminal tails of PTEN and rabies virus glycoprotein G, to reveal a similar network of MASK2-PDZ interactions with the two proteins. Competition binding assays confirmed that PTEN and glycoprotein G have overlapping binding sites on MASK2-PDZ. Additional biochemical data indicate that C-terminal tails of PTEN and glycoprotein G are both able to disrupt the MASK2-PDZ homodimer, providing further support for their similar binding mechanisms. Rabies virus–infected neuroblastoma cells showed a substantial decrease in nuclear-localized PTEN, an effect that required the presence of glycoprotein G's C-terminal tail. In all, the findings suggest that rabies virus excludes PTEN from the nucleus, in a MASK2-PDZ–dependent manner, to promote neuronal survival. Further work will be needed to understand how the nuclear activity of PTEN regulates cell survival, and the rabies virus glycoprotein G may be a useful tool in dissecting this mechanism. (Sci. Signal. 5, ra58, 2012)