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

Abstract 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.