The PTEN/ PI 3-Kinase enzyme system translates extracellular growth cues into intracellular signals. To achieve this, PTEN turns cell membrane phospholipids into an off-state for recruitment and activation of growth promoting kinases. Receptor tyrosine kinase activation reverts this by activating PI 3 Kinase, leading to membrane recruitment and activation of the oncogenic AKT kinase.

In spite of its plasma-membrane function, PTEN has been consistently observed in cell nuclei, but mechanism and relevance of this localization have remained unclear. We have recently resolved this paradox by demonstrating that contrary to poly-ubiquitination, nuclear PTEN import depends on its mono-ubiquitination and that mutation of the main PTEN ubiquitination site abolishes import in vitro and in patients, gives rise to inheritable Cowden’s Disease because of low cytoplasmic PTEN stability. But most notably, this mutant retains catalytic activity, demonstrating that PTEN nuclear import is essential for tumor suppression. These findings exemplify an elemental insight into cancer biology by demonstrating how the collaboration of a genetic lesion (the inherited mutation) with a post-translational cellular response (enhanced degradation) cooperate in tumorigenesis. Through this analysis, we have furthermore unraveled a link between two critical means of PTEN regulation, namely stability and nucleo-cytoplasmic shuttling. We are currently investigating the mediators of both processes in vitro by using RNAi approaches that can be expanded to in vivo analysis.