Finding partners for PI3Kgamma: when 84 is better than 101

Phosphatidylinositol 3-kinase (PI3K) enzymes phosphorylate phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P(2), also known as PIP(2)], a minor but critically important phospholipid of the inner leaflet of the plasma membrane. The resulting PtdIns(3,4,5)P(3) (PIP(3)) acts as a membrane-bound attractant that recruits and activates a set of proteins to execute specific downstream signaling events to achieve the desired biological outcomes. Several genes that encode different PI3Ks exist in mammalian cells, and in the case of each PI3K, a partner protein that is tightly associated with the kinase ensures that the enzyme is localized to and activated at the correct membrane compartment. Excess PtdIns(3,4,5)P(3) is a major contributor to many forms of cancer, and dysregulation of PI3Ks leads to severe immunological and metabolic abnormalities. Given the multitude of proteins that are regulated by PtdIns(3,4,5)P(3), it is puzzling that not all of these targets are activated as soon as the lipid is produced in the plasma membrane. Reports have begun to shed light on the mechanism by which cells can discriminate between PtdIns(3,4,5)P(3) depending on the distinct PI3K protein that produced it. A study shows that PtdIns(3,4,5)P(3) regulates the degranulation of mast cells, but only if it is made by a PI3K that is associated with a specific adaptor protein. This remarkable specificity challenges our views of how phosphoinositides regulate their downstream effectors.