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.

PtdIns(4,5)P 2 signaling regulates ATG14 and autophagy

“…S6B), indicating that PIPKIγi5 levels must be tightly controlled for proper functioning in autophagy. This is generally the case for PIP kinases as they lose normal targeting when overexpressed (9). Of note, although LC3-II generation was blocked in PIPKIγi5-knockdown cells, the basal LC3-II levels without lysosomal inhibition were consistently higher than in control cells (Fig.…”

“…Increasing evidence supports the specific and essential functions of intracellular PtdIns(4,5)P 2 (10). However, PtdIns(4,5)P 2 is poorly detected on intracellular compartments likely because of the lack of free PtdIns(4,5)P 2 , as it is bound to effectors that associate with PIP kinases (9). More PtdIns(4,5)P 2 exists on the plasma membrane and high expression of PLCδ-PH could mask its intracellular targeting with only apparent localization to the plasma membrane.…”

“…ATG14 membrane targeting depends on its carboxylterminal BATS domain that binds both PtdIns(3)P and PtdIns(4,5)P 2 (8). PtdIns(4,5)P 2 binding proteins are often regulated by association with PIP kinases, which generates localized PtdIns(4,5)P 2 (9). To identify a PIP kinase that associates with ATG14, a coimmunoprecipitation (co-IP) assay was performed to examine ATG14 interaction with different PIPKIs.…”

“…PtdIns(4,5)P 2 plays multiple roles at the plasma membrane, such as in endocytosis, exocytosis, focal adhesion assembly, and so on (9). However, recently studies have argued for roles for PtdIns(4,5)P 2 at intracellular compartments (10).…”

Phosphatidylinositol Phosphate 5-Kinase Iγ and Phosphoinositide 3-Kinase/Akt Signaling Couple to Promote Oncogenic Growth

“…PIPKI enzymes often assemble into complexes, where the PIP 2 generated modulates an effector molecule (5,6,9). In this case, the proximity of PIPKI␥i2 and PI3K may facilitate the generation of the spatial pool of PIP 2 that is used by PI3K for generation of the PIP 3 that then activates Akt.…”