Phosphatase and tensin homologue deleted on chromosome ten (PTEN) is a negative regulator of phosphoinositide-3 kinase (PI(3)K) signalling and a tumour suppressor. Parsons and colleagues (Science http://doi.org/m7z; 2013) have identified a translational variant of PTEN (PTEN-Long) that similarly antagonizes the PI(3)K pathway and suppresses tumour growth, but is secreted and can enter other cells.

The authors found an in-frame alternative translation initiation codon upstream of the canonical AUG in the PTEN transcript, and subsequently detected the 75-kDa PTEN-Long protein in mouse embryonic stem cells and human cancer cell lines. This extended variant reduced PI(3)K signalling in a phosphatase-dependent manner. Computer modelling revealed the presence of a secretion signal sequence within the additional 173 amino acids of PTEN-Long, and the authors accordingly detected endogenous PTEN-Long in human plasma and serum. Although PTEN interacts with heparan-sulphate-modified cell-surface receptors, Parsons and colleagues demonstrated that a poly-arginine stretch present within PTEN-Long facilitated cell penetration, and subsequently showed that purified PTEN-Long inhibited PI(3)K signalling, an effect that was abrogated by mutating the poly-arginine sequence. Like PTEN, PTEN-Long induced cell death, and treatment with PTEN-Long induced tumour regression in various mouse models. Notably, some cancers were found to contain a mutated form of PTEN-Long with reduced signalling capacity, which might be preferentially selected during tumour development. Whether PTEN-Long has therapeutic potential remains to be investigated.