Engineering PTEN function: membrane association and activity.

Many tumors are associated with deficiency of the tumor suppressor, PTEN, a PIP3 phosphatase that turns off PIP3 signaling. The major site of PTEN action is the plasma membrane, where PIP3 is produced by PI3 kinases. However, the mechanism and functional importance of PTEN membrane recruitment are poorly defined. Using the heterologous expression system in which human PTEN is expressed in Dictyostelium discoideum, we defined the molecular mechanisms that regulate the membrane-binding site through inhibitory interactions with the phosphorylated C-terminal tail. In addition, we potentiated mechanisms that mediate PTEN membrane association and engineered an enhanced PTEN with increased tumor suppressor functions. Moreover, we identified a new class of cancer-associated PTEN mutations that are specifically defective in membrane association. In this review, we summarize recent advances in PTEN-membrane interactions and methods useful in addressing PTEN function.