Aiming drug discovery at lysophosphatidic acid targets

Abstract

Lysophosphatidic acid (LPA, 1-radyl-2-hydroxy-sn-glycero-3-phosphate) is the prototype member of a family of lipid mediators and second messengers. LPA and its naturally occurring analogues interact with G protein-coupled receptors on the cell surface and a nuclear hormone receptor within the cell. In addition, there are several enzymes that utilize LPA as a substrate or generate it as a product and are under its regulatory control. LPA is present in biological fluids, and attempts have been made to link changes in its concentration and molecular composition to specific disease conditions. Through their many targets, members of the LPA family regulate cell survival, apoptosis, motility, shape, differentiation, gene transcription, malignant transformation and more. The present review depicts arbitrary aspects of the physiological and pathophysiological actions of LPA and attempts to link them with select targets. Many of us are now convinced that therapies targeting LPA biosynthesis and signalling are feasible for the treatment of devastating human diseases such as cancer, fibrosis and degenerative conditions. However, successful targeting of the pathways associated with this pleiotropic lipid will depend on the future development of as yet undeveloped pharmacons.

Figure 1

Naturally occurring ligands of LPA targets. LPA 18:1, oleoyl-lysophosphatidic acid; AGP 18:1, 1-O-octadecyl glycerophosphate; CPA 18:1, oleoyl-cyclic phosphatidic acid; ALKENYL-GP, alkenyl glycerophosphate; NAG, N-arachidonoyl glycine; FMP, farnesyl monophosphate.

Figure 2

Phylogenetic tree of established and putative LPA GPCR generated by the NGBW program (http://www.ngbw.org). GPCR, G protein-coupled receptor.

Figure 3

Synthetic ligands of LPA GPCR (see Table 1 for details). GPCR, G protein-coupled receptor; LPA, lysophosphatidic acid.

Figure 4

Activation of Ca²⁺ transients in P2Y10-transfected (filled symbols) and empty vector-transfected Gα16-expressing CHO cells (open symbols) by LPA, AGP, CPA, S1P and LPS. Note that P2Y10-transfected cells dose-dependently respond to low micromolar CPA, S1P and LPS. These ligands either elicit no response (S1P and LPS) or greatly diminished response (CPA) in the vector transfected Gα16-expressing CHO cells. All ligands display lower EC₅₀ and higher E_max values in P2Y10-transfected cells compared with controls. The dose–response curves were generated using Fura2 in a FLEXStation.

Figure 5

Intracellular sources, targets and actions of LPA. LPA can be generated by iPLA2β in response to MCP1 or insulin stimulation at the leading-edge of migrating macrophages and regulate actin-binding/severing proteins. LPA is also generated by GPAT from fatty acids and can interact with PPARγ, which in turn up-regulates genes involved in adipogenesis and lipid storage. LPA can potentially excreted from cells and stimulate cell surface LPA GPCR setting up an inside-out signalling paradigm. LPA GPCR can synergize with the activation of intracellular targets as it may happen in the case of regulation of the actin cytoskeleton via Rho and Rac.

Figure 6

Macromolecular complex-mediated anti-apoptotic signalling by the LPA₂ receptor. The C-terminal tail of LPA₂ contains docking sites for PDZ-binding proteins (NHERF2) and LIM family proteins (Siva-1 and TRIP6). LPA₂ activation captures the pro-apoptotic Siva-1 and targets it to proteasomal degradation. LPA₂ receptor activation recruits a ternary complex formed with NHERF2 and TRIP6, which augments anti-apoptotic signals mediated via ERK1/2 and Akt kinase pathways.