PTEN Function Requires Its Protein Phosphatase Activity

The tumor suppressor activity of PTEN is thought to be largely attributable to its lipid phosphatase domain, which mediates dephosphorylation of phosphatidylinositol 3,4,5-trisphosphate (PIP₃) to antagonize phosphoinositide 3-kinase (PI3K) activity and prevent the activation of PIP₃ binding effector proteins such as AKT. PTEN also possesses protein phosphatase activity, although the contribution of PTEN-mediated protein dephosphorylation to tumor suppression is less clear. Tibarewal and colleagues used a protein phosphatase-defective PTEN mutant to determine the contribution of protein dephosphorylation to PTEN-mediated changes in gene expression and suppression of cell invasion in PTEN-null glioma cell lines. Despite its ability to decrease PIP₃ levels and thus inhibit AKT activation, the PTEN protein phosphatase mutant did not affect a large subset of PTEN-responsive genes. The PTEN protein phosphatase mutant also could not suppress cell invasion and could not be rescued by coexpression of a PTEN mutant lacking lipid phosphatase activity; this suggests that both domains must be present on the same protein and that PTEN protein phosphatase activity may be directed toward its own phosphorylation sites to regulate its lipid phosphatase domain. The authors found that levels of threonine-366 and serine-370 phosphorylation were increased in the PTEN phosphatase mutant, compared with wild-type PTEN, and that mutating either of these residues to alanine restored the ability of the PTEN phosphatase mutant to suppress invasion. Together, these findings suggest that a key role of the PTEN protein phosphastase domain is autodephosphorylation, which may contribute to aspects of PTEN-mediated tumor suppression that do require AKT inhibition. As the authors report that a metastatic small-cell lung cancer–derived cell line harbors a mutation that abolishes PTEN protein phosphatase activity without affecting AKT inhibition, these findings imply that therapies targeting the PI3K–AKT pathway may not be appropriate for every PTEN-mutant tumor.

Tibarewal P, Zilidis G, Spinelli L, Schurch N, Maccario H, Gray A, et al. PTEN protein phosphatase activity correlates with control of gene expression and invasion, a tumor-suppressing phenotype, but not with AKT activity. Sci Signal 2012;5:ra18.

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