Sharing of unrelated receptors and ligands by cognate partners: possible implications for ovarian and endometrial physiology

The majority of the recognized extracellular signalling molecules are known to participate in paracrine and autocrine functions. The classical model of signalling involves a ligand and its cognate receptor. A unique number of ligands activate two phylogenetically unrelated receptors; some receptors are activated by more than one unrelated polypeptide ligand, and some unrelated receptors share common co-receptors. Such a situation introduces a new dimension of complexity into the processes governed by these signalling mechanisms. These unique 'three-way partnerships' often involve signalling molecules that have key roles in the reproductive system. This review presents the known cases of three-way partnerships and examines their possible significance to the reproductive processes in the ovary and endometrium. Most notably present in the ovary are Wnt, Frizzled, Dickkopf (Dkk), low density lipoprotein receptor-related protein (LRP)5, RYK and Kremen system, and semaphorin, plexin, vascular endothelial growth factor and neuropilin system. In the endometrium one finds potential three-way partnerships in Wnt, Frizzled and RYK system, and ATP, P2X7, P2Y2 system. Three-way partnerships may explain previously enigmatic cases of biphasic effects of a ligand, or may reveal that a ligand thought to be pleiotrophic through the activation of one receptor is actually affecting two unrelated signalling receptors in the same tissue. The potential significance to new pharmacological developments is evident.