Control of phosphatidylinositol‐3‐kinase signaling by nanoscale membrane compartmentalization

Abstract

Phosphatidylinositol‐3‐kinases (PI3Ks) are lipid kinases that produce 3‐phosphorylated derivatives of phosphatidylinositol upon activation by various cues. These 3‐phosphorylated lipids bind to various protein effectors to control many cellular functions. Lipid phosphatases such as phosphatase and tensin homolog (PTEN) terminate PI3K‐derived signals and are critical to ensure appropriate signaling outcomes. Many lines of evidence indicate that PI3Ks and PTEN, as well as some specific lipid effectors are highly compartmentalized, either in plasma membrane nanodomains or in endosomal compartments. We examine the evidence for specific recruitment of PI3Ks, PTEN, and other related enzymes to membrane nanodomains and endocytic compartments. We then examine the hypothesis that scaffolding of the sources (PI3Ks), terminators (PTEN), and effectors of these lipid signals with a common plasma membrane nanodomain may achieve highly localized lipid signaling and ensure selective activation of specific effectors. This highlights the importance of spatial regulation of PI3K signaling in various physiological and disease contexts.

Nanoscale organization of phosphoinositide signaling in the plasma membrane?

“…The hypothesis article in this issue by Cabral‐Diaz and Antonescu [ 1 ] addresses such questions with a focus on the phosphatidylinositol 3‐kinase signaling pathway. Consisting of multiple kinases and phosphatases modifying PI lipid headgroups, as well as PI lipid‐binding proteins, the PI3K pathway is a fascinating module of regulated protein–membrane interactions.…”