Figure 8. Schematic model for the regulation of PTEN activity by NDRG2.

In normal cells, PP2A is efficiently recruited to PTEN via its interaction with NDRG2, which may facilitate dephosphorylation of PTEN at Ser380/Thr382/Thr383, resulting in an active open conformation of PTEN and subsequently leading to the dephosphorylation of PIP₃ to PIP₂. In tumour cells, expression of NDRG2 is inhibited by DNA methylation of its promoter, causing sustained phosphorylation of PTEN, which keeps PTEN in an inactive closed conformation. Loss of PTEN activity leads to increased PIP₃ levels and AKT activation. The balance between the expression of NDRG2 and an unidentified kinase(s) may have an important role in regulating the phosphorylation status of PTEN.