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Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a phosphatase that suppresses many tumor types (1, 2). It plays a major role in the development of the nervous system and has been implicated in diseases such as autism (3). Despite its importance, we are only beginning to understand how this important protein is regulated. In 2000 and 2001, Vazquez et al. (4, 5) with great insight proposed that phosphorylation of the C terminus induces PTEN to assume a closed conformation with an inactive phosphatase domain. Upon dephosphorylation, PTEN assumes an open conformation, activating the phosphatase domain and enhancing degradation of PTEN protein. In this view, the phosphorylated closed form acts like a proenzyme, which is stable in the cytoplasm but ready for rapid activation, use, and degradation. Although not fully proven, this model (Fig. 1) has greatly influenced the PTEN field. The study in a recent issue of PNAS by Rahdar et al. (6) provides convincing proof for this model and new exciting insights into the interactions of PTEN with biological membranes. PTEN open/closed model explains how phosphorylation regulates membrane association. Dephosphorylation leads to the open conformation that allows PTEN to associate with the membrane. The initial association of PTEN with the negatively charged membrane likely occurs through nonspecific electrostatic interactions, as observed for other interfacial proteins (10). The association step is followed by binding of the C2 domain to phosphatidylserine (PS) (9) and the PBM to PI(4,5)P2 (17, 18), which leads to a conformational change (12) and activation of the phosphatase domain (PD) (11, 16). The trigger for PTEN dissociation is unknown, but Radhar et al. (6) suggest that it is not phosphorylation of the C-terminal tail. The PTEN protein is a phosphatidylinositol phosphate (PIP) phosphatase specific …

Phosphorylation keeps PTEN phosphatase closed for business