PTEN: Bridging Endocytosis and Signaling

The transduction of signals in the PTEN/PI3-kinase (PI3K) pathway is built around a phosphoinositide (PIP) lipid messenger, phosphatidylinositol trisphosphate, PI(3,4,5)P₃ or PIP₃ Another, more ancient role of this family of messengers is the control of endocytosis, where a handful of separate PIPs act like postal codes. Prominent among them is PI(3)P, which helps to ensure that endocytic vesicles, their cargo, and membranes themselves reach their correct destinations. Traditionally, the cancer and the endocytic functions of the PI3K signaling pathway have been studied by cancer and membrane biologists, respectively, with some notable but overall minimal overlap. Modern microscopy has enabled monitoring of the PTEN/PI3K pathway in action. Here, we explore the flurry of groundbreaking concepts emerging from those efforts. The discovery that PTEN contains an autonomous PI(3)P reader domain, fused to the catalytic PIP₃ eraser domain has prompted us to explore the relationship between PI3K signaling and endocytosis. This revealed how PTEN can achieve signal termination in a precisely controlled fashion, because endocytosis can package the PIP₃ signal into discrete units that PTEN will erase. We explore how PTEN can bridge the worlds of endocytosis and PI3K signaling and discuss progress on how PI3K/AKT signaling can be acting from internal membranes. We discuss how the PTEN/PI3K system for growth control may have emerged from principles of endocytosis, and how this development could have affected the evolution of multicellular organisms.