Phosphoinositide (Lipid) Signaling

Phosphatidylinositol (PtdIns) is a small lipid molecule composed of an inositol ring and two fatty acid chains connected through a glycerol backbone, a structure that allows PtdIns to anchor on the cytoplasmic face of cellular membranes. PtdIns is phosphorylated by a host of lipid kinases at the 3, 4, and/or 5 hydroxyl positions of the inositol ring, producing a variety of phosphatidylinositol monophosphates (PI3P, PI4P, and PI5P), diphosphates [PI(3,4)P2, PI(3,5)P2, PI(4,5)P2], and a triphosphate [PI(3,4,5)P3] that are collectively known as phosphoinositides. The phosphorylations are removed by site-specific lipid phosphatases, enabling dynamic flux between lipid phosphorylation states. In general, phosphatidylinositol monophosphates are localized to intracellular membranes (endocytic vesicles, golgi apparatus, nucleus), while di- and triphosphates are found at the plasma membrane. PtdIns (synthesized at the endoplasmic reticulum) and phosphoinositides shuttle among various subcellular compartments by intracellular vesicles that enable association with their corresponding modifying enzymes. Phosphoinositides are universal signaling entities that regulate cell activities through direct interaction with membrane proteins (e.g., ion channels, GPCRs) or through membrane recruitment of cytosolic proteins containing domains that directly bind phosphoinositides, such as pleckstrin homology (PH), FYVE, WD40 repeats, FERM, PTB, and PDZ domains, among others. By far the best studied phosphoinositide is PI(3,4,5)P3, which is synthesized from PI(4,5)P2 by PI3K Class I and dephosphorylated by PTEN. Both PI3K Class I and PTEN are central mediators of receptor tyrosine kinase-induced Akt signaling, and are often mutated in many forms of cancer. In addition to its effect on cell proliferation, survival, and metabolism associated with Akt signaling, phosphoinositide signaling also induces cytoskeletal changes and actin remodeling, and plays a role in clathrin-mediated endocytosis, vesicle trafficking, membrane dynamics, autophagy, cell division/cytokinesis, cell migration, and UV stress response.

Selected Reviews:

• Balla T (2013) Phosphoinositides: tiny lipids with giant impact on cell regulation. Physiol. Rev. 93(3), 1019–137.
• Hammond GR, Balla T (2015) Polyphosphoinositide binding domains: Key to inositol lipid biology. Biochim. Biophys. Acta 1851(6), 746–58.
• Lystad AH, Simonsen A (2016) Phosphoinositide-binding proteins in autophagy. FEBS Lett. 590(15), 2454–68.
• Marat AL, Haucke V (2016) Phosphatidylinositol 3-phosphates-at the interface between cell signalling and membrane traffic. EMBO J. 35(6), 561–79.
• Cauvin C, Echard A (2015) Phosphoinositides: Lipids with informative heads and mastermind functions in cell division. Biochim. Biophys. Acta 1851(6), 832–43.
• Wang W, Lv J, Wang L, Wang X, Ye L (2017) The impact of heterogeneity in phosphoinositide 3-kinase pathway in human cancer and possible therapeutic treatments. Semin. Cell Dev. Biol. 64, 116–124.