Fig. 3. Schematic overview of the versatile impact of ether lipids on signaling pathways.

(A) Plasmalogens are essential membrane constituents that modulate membrane properties. Their lack can disturb the dynamics of membrane-associated signaling processes, as demonstrated for the impaired membrane recruitment and functioning of AKT/PKB. Other pathways may be affected similarly. (B) Ether-linked diglycerides have been proposed to compete with diacylglycerol (DAG) for binding of PKC but exert a weaker (or no) activation, thus dampening downstream responses. (C) Secreted ether-linked species like alkyl-LPA, alkenyl-LPA and PAF bind G protein-coupled receptors on the cell surface; receptor binding triggers a cascade involving activation and dissociation of G proteins followed by induction of downstream pathways including, but not limited to, MAP kinase pathways. Note that LPA and PAF receptors are not necessarily expressed by the same cell type, as shown here for simplicity. (D) Ether lipids serve as ligands for nuclear receptors like PPARα or PPARγ. Upon ligand binding in the nucleus, or in the cytoplasm triggering nuclear translocation, the PPARs bind to response elements in the DNA. As heterodimers with the retinoid X receptor (RXR), PPARs associate with coactivators (not shown), thus inducing the expression of target genes. Several ether lipid ligands have been suggested, including chlorinated plasmalogens and noladin ether for PPARα as well as alkyl-LPA and plasmanyl phospholipids for PPARγ.

For image clarity, the signaling pathways are drawn highly simplified and several intermediate steps are omitted for easier understanding. MAPKK, MAP kinase kinase; MAPKKK, MAP kinase kinase kinase.