The puzzles of the prokineticin 2 pathway in human reproduction

Prokineticin, 1 (PROK1) and prokineticin 2 (PROK2), are two closely related proteins that were identified as the mammalian homologs of their two amphibian homologs, mamba intestinal toxin (MIT-1) and Bv8. MIT-1 was initially identified as a non-toxic constituent in the venom of the black mamba snake (Dendroaspis polylepis) ( Joubert and Strydom, 1980) while Bv8 was identified in the skin secretion of the toad, Bombina variegate ( Mollay et al., 1999). All three homologs stimulate gastrointestinal motility thus accounting for their family name “prokineticins” ( Schweitz et al., 1990 and Schweitz et al., 1999). However, since its initial description, both PROK1 and PROK2 have been found to regulate a dazzling array of biological functions throughout the body. In particular, PROK1 acts as a potent angiogenic mitogen on endocrine vascular epithelium, thus earning its other name, Endocrine gland–vascular endothelial factor (EG–VEGF) (LeCouter et al., 2002). In contrast, the PROK2 signaling pathway is a critical regulator of olfactory bulb morphogenesis and sexual maturation in mammals and this function is the focus of this review.