PTEN can behave as a phosphatase in most situations, controlling the phosphorylation status of lipids and proteins and hence their activities. The structure of PTEN's N-terminal domain determines its dephosphorylation activity. However, it is regulated by its C2 and C-tail domains, which are boosted when homodimers develop. Although it is not directly connected with the PTEN dimer interface, the C2 domain is required to produce PTEN dimers . PTEN may flip between open and closed conformations in solution, and phosphorylation of the C tail promotes the closed conformation . PTEN's C2 domain is structurally identical to the C2 domains of phospholipase C1, phospholipase A2, and protein kinase C (PKC). It is capable of binding to phospholipid vesicles and regulating PTEN's subcellular distribution . The C2 domain of PTEN interacts with the phosphatase domain and modulates the activity of the phosphatase domain . PTEN has a broader spectrum of actions due to its interaction with proteins via the C-2 and PDZ-BD domains . The eight residues "HTQITKVT" in the C-terminal tail of PTEN is required for specific recognition of the PDZ domain. Phosphorylation of the proximal C-terminal tail residues of PTEN (Ser380/Thr382/Thr383) can decrease binding to the PDZ domain. It preserves the closed conformation of PTEN's C-terminus . PTEN-L is a secreted translational variation(51), a PTEN phosphatase that enters cells to change signaling and survival. It contains an additional 173 amino acids at the PTEN N-terminus. PTEN's membrane recruitment requires and is facilitated by the phosphatase and C2 domains. Phosphorylation of the C-terminal tail decreases its membrane affinity . PTEN must shuttle dynamically between the cell membrane and the cytoplasm to exhibit PI(3,4,5)P3 phosphatase activity . The positively charged C2 domain has been shown to limit excessive PTEN jumping and stabilize the membrane binding of PTEN . Phosphatidylinositol 3-phosphate (PI(3)P), an endosomal marker lipid, is associated with vesicles . PTEN is a protein that specifically targets the endosomal membrane. PTEN's non-catalytic C2 domain binds to PI(3)P(54), mainly via the CBR3 loop. The phosphorylation/dephosphorylation of the C-terminal region acts as an electrostatic switch that regulates protein-membrane translocation . Phosphorylation affects PTEN's plasma membrane targeting by inhibiting the PDZ domain's binding site and interfering with PTEN's electrostatic membrane binding.