The puzzles of the prokineticin 2 pathway in human reproduction

Abstract

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, 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.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Figures

Fig 1. PROK2 mutations in humans with isolated GnRH deficiency

Schematic of PROK2 gene with identified mutations in humans with isolated GnRH deficiency. Residues from 75–95 is alternatively spliced and is shown in yellow. The “AVITGA” sequence is shown in blue. (Reprinted with permission from Martin C et al, Endo Reviews, 2011).

Fig 2. PROKR2 mutations in humans with isolated GnRH deficiency

Schematic of PROKR2 receptor with mutations identified in humans with KS and nIHH. Mutations labeled in red are identified in Kallmann patients, yellow label represent mutations in normosmic GnRH deficient (nIHH) probands, and hatch red and yellow label shows the mutations identified in patients either with nIHH or Kallmann syndrome. Homozygous mutations are marked with (*). (Reprinted with permission from Martin C et al, Endo Reviews, 2011).

Fig 3. Puzzles of Prokineticin pathway mutations in humans with isolated GnRH Deficiency

Human GnRH deficient subjects harboring PROK2 pathway mutations pose several puzzling observations (shown in jigsaws’) compared to the murine prok2/prokr2 pathway mutations. See text for details.