PIP kinases define PI4,5P2 signaling specificity by association with effectors

Phosphatidylinositol 4,5-bisphosphate (PI4,5P2) is an essential lipid messenger with roles in all eukaryotes and most aspects of human physiology. By controlling the targeting and activity of its effectors, PI4,5P2 modulates processes, such as cell migration, vesicular trafficking, cellular morphogenesis, signaling and gene expression. In cells, PI4,5P2 has a much higher concentration than other phosphoinositide species and its total content is largely unchanged in response to extracellular stimuli. The discovery of a vast array of PI4,5P2 binding proteins is consistent with data showing that the majority of cellular PI4,5P2 is sequestered. This supports a mechanism where PI4,5P2 functions as a localized and highly specific messenger. Further support of this mechanism comes from the de novo synthesis of PI4,5P2 which is often linked with PIP kinase interaction with PI4,5P2 effectors and is a mechanism to define specificity of PI4,5P2 signaling. The association of PI4,5P2-generating enzymes with PI4,5P2 effectors regulate effector function both temporally and spatially in cells. In this review, the PI4,5P2 effectors whose functions are tightly regulated by associations with PI4,5P2-generating enzymes will be discussed. This article is part of a Special Issue entitled Phosphoinositides.