The PTEN phosphatase has long been known to have tumour-suppressive activity through its ability to antagonize the phosphatidylinositol 3-kinase (PI3K)–AKT signalling pathway. Its loss in many cancers upregulates the pathway and leads to increased cell growth, proliferation and survival. Recently, PTEN has been implicated in another common function of cancer cells — cell migration — and Alan Hall and colleagues now show that the C2 domain of PTEN controls this process.

As glioma cells are invasive and lack expression of PTEN, the authors used them in wound-healing assays to investigate how PTEN regulates migration. Cells engineered to express wild-type PTEN did not migrate and were overtaken by control cells, indicating that PTEN inhibits motility. A PTEN mutant that lacked lipid-phosphatase activity could also inhibit migration, indicating that this effect is not regulated by the PI3K–AKT pathway. However, mutants lacking protein-phosphatase activity or the C2 domain of PTEN could not prevent cell movement and were therefore required for this property of PTEN. Expression of C2 domains derived from other proteins had no effect on migration, indicating that this inhibition requires the presence of the C2 domain of PTEN. As both the phosphatase catalytic domain and the C2 domain are required for PTEN to inhibit migration, might they somehow work together?

The authors mutated the phosphate sites in the carboxyl terminus that control PTEN phosphatase activity, and found that mutation of threonine 383 completely restored the ability of catalytically inactive PTEN to prevent migration. So, in the wild-type protein, Thr383 must be dephosphorylated for PTEN to inhibit migration, and this process is dependent on protein-phosphatase acitivity. Intramolecular interaction between the C2 and phosphatase domains of PTEN has been observed by X-ray crystallography, and Thr383 phosphorylation might prevent this interaction. Immunoprecipitation experiments showed that the carboxyl and amino termini of PTEN could, in fact, co-precipitate, but only if an intact C2 domain was present within the C terminus. This interaction was unaffected, however, by phosphorylation status.

Instead, Thr383 phosphorylation seems to be directly controlled by the phosphatase activity — catalytically inactive PTEN is phosphorylated at Thr383, whereas wild-type PTEN is not. These results indicate that the C2 domain of PTEN is inactive when it is phosphorylated and activation by dephosphorylation of Thr383 enables PTEN to interfere with migration. This ability to control cell migration might have important implications for tumour progression.