Primer Lipid signalling C. Peter Downes and Richard A. Currie If you believe the fluid mosaic model of membrane structure, all the important jobs of the cell membrane, such as nutrient uptake, ion transport and transduction of hormonal signals, are attributable to membrane proteins rather than to the lipid bilayer in which they sit. But if all the membrane lipids do is to form a permeability barrier, you might expect them to have quite uniform structures. In fact, they are highly diverse, suggesting they have additional, more subtle roles in membrane function. One of the most important and best understood roles of membrane lipids and/or their products is to function as intracellular second messengers, which convey the information encoded in extracellular messengers, such as hormones, neurotransmitters and growth factors, to produce an appropriate cellular response. More recently, lipids have been shown to regulate essential functions of membranes themselves, providing crucial, yet poorly understood, signals which control the flow of membrane traffic between the major organelles of eukaryotic cells. Specialised signalling roles The inositol-containing phospholipids are minor membrane constituents that have diverse chemical structures. They provide cells with an astonishing variety of signals whose functions we are only just beginning to understand in detail. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ) is one of the lynchpins of this network of putative signalling molecules. It is the major substrate for two groups of stimulus- dependent enzymes. Enzymes of the phospholipase C family (PLCs) cleave PI(4,5)P 2 to generate two independent second messengers: diacylglycerol (DAG), which activates several species of protein kinase C, and inositol 1,4,5-trisphosphate (I(1,4,5)P 3 ), which releases Ca 2+ from intracellular stores. The second group of enzymes, type I PI 3-kinases, phosphorylate PI(4,5)P 2 to generate phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P 3 ) whose functions will be discussed later (see Figure 1). PI 3-kinases and PLCs are found in all eukaryotic cells and their activities are regulated by a wide variety of hormones, neurotransmitters and growth factors. In addition to its role as a precursor of signals, PI(4,5)P 2 seems to function as a distinct signal in its own right. For example, it can regulate actin polymerisation via its interaction with proteins such as profilin, gelsolin and vinculin; it is a necessary co-factor for another signal-generating enzyme, phospholipase D (discussed later); and its synthesis on the cytosolic leaflets of secretory vesicles seems to be required to confer secretory competence on these structures. How can a single lipid have so many different roles? The answers are only just beginning to emerge but two important properties of PI(4,5)P 2 , and of the enzymes that regulate its level in cells, illustrate principles which are likely to be common themes of lipid signalling. Location One mechanism by which the functions of inositol phospholipids could remain distinct would be the spatial segregation of pools of different membrane lipids. The precursor phospholipid phosphatidylinositol (PI), can be targeted to distinct membrane compartments by a PI transfer protein. Because inositol phospholipids are likely to remain in the membrane in which they are synthesized, it should be possible for lipid kinases — which could be either cytosolic or specific to the Magazine R865 Figure 1 The many different roles of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ),which is a precursor of the signals PI(3,4,5)P 3 , DAG and I(1,4,5)P 3 , as well as functioning as a signal in its own right. The structure of PI(4,5)P 2 shows the typical inositol headgroup, which is linked by a phosphodiester phosphate group at the 1 position to the third carbon of the glycerol backbone. Stearic acid at the 1 position and arachidonic acid at the 2 position of glycerol provide the lipid components which anchor these inositol phospholipids within the cytosolic leaflets of cellular membranes. Phophate groups (P) are shown in green. PLCs OH DAG Plasma membrane Cytosol PLD P P P P P P P P PI 3-kinase Co-factor Actin polymerisation Priming of secretory vesicles C=O C=O O O OH OHHO O O–P=O CH 2 –CH–CH 2 O O– O 5 4 3 2 1 6 O=P–O– O O – O=P–O – Current Biology PI(4,5)P 2 PI(3,4,5)P 3 I(1,4,5)P 3