The PI-3 Kinase Pathway Is Negatively Regulated by PTEN Phosphatase

Like virtually all intracellular signaling events, phosphorylation by PI-3 kinase is reversible. The relevant phosphatase, termed PTEN, has an unusually broad specificity. Although PTEN can remove phosphate groups attached to serine, threonine, and tyrosine residues in proteins, its ability to remove the 3-phosphate from PI(3,4,5)P3 is thought to be its major function in cells. Overexpression of PTEN in cultured mammalian cells promotes apoptosis by reducing the level of PI(3,4,5)P3, and hence the activation and anti-apoptotic effect of PKB.

The PTEN gene is deleted in multiple types of advanced human cancers. The resulting loss of the PTEN protein contributes to the uncontrolled growth of cells. Indeed, cells lacking PTEN have elevated levels PI(3,4,5)P3 and PKB activity. Because PKB exerts an anti-apoptotic effect, loss of PTEN reduces the programmed cell death that is the normal fate of many cells. In certain cells, such as neuronal stem cells, absence of PTEN not only prevents apoptosis, but also leads to stimulation of cell cycle progression and an enhanced rate of cell proliferation. Knockout mice lacking PTEN have big brains with an excess numbers of neurons, attesting to PTEN’s importance in the control of normal development.