The KiSS-1/GPR54 system: Essential roles in physiological homeostasis and cancer biology

Abstract

KiSS-1, first identified as an anti-metastasis gene in melanoma, encodes C-terminally amidated peptide products, including kisspeptin-145, kisspeptin-54, kisspeptin-14, kisspeptin-13 and kisspeptin-10. These products are endogenous ligands coupled to G protein-coupled receptor 54 (GPR54)/hOT7T175/AXOR12. To date, the regulatory activities of the KiSS-1/GPR54 system, such as puberty initiation, antitumor metastasis, fertility in adulthood, hypothalamic-pituitary-gonadal axis (HPG axis) feedback, and trophoblast invasion, have been investigated intensively. Accumulating evidence has demonstrated that KiSS-1 played a key role in reproduction and served as a promising biomarker relative to the diagnosis, identification of therapeutic targets and prognosis in various carcinomas, while few studies have systematically summarized its subjective factors and concluded the functions of KiSS-1/GPR54 signaling in physiology homeostasis and cancer biology. In this review, we retrospectively summarized the regulators of the KiSS-1/GPR54 system in different animal models and reviewed its functions according to physiological homeostasis regulations and above all, cancer biology, which provided us with a profound understanding of applying the KiSS-1/GPR54 system into medical applications.

Keywords: KiSS-1/GPR54; Kisspeptin; Physiological homeostasis; Regulators in vivo and in vitro; Tumor metastasis.

Figure 1

The various structure and sequence of kisspeptin in species. (A) Structure and sequence of full length kisspeptin in human, rat and mouse. Sequence of amino acids are gained from NCBI. (B) Human kisspeptin size, signal peptide and cleavage points are showed. Precursor kisspepin-145 is easily truncated into kisspeptin-54 (metastin) (5.9 kDa), kisspeptin-14 (1.7 kDa), kisspeptin-13 (1.6 kDa) and kisspeptin-10 (1.3 kDa). (C) Evolution history of KiSS-1/GPR54 system researching development.

Figure 2

Confirmed schematic mechanism of the KiSS-1/GPR54 system. The KiSS-1/GPR54 system coupled to Gαq/11 activates PLC hydrolysis. IP3 and DAG act as two different potentials ‘second messengers’. IP3 contributes to upregulate intracellular Ca²⁺, and DAG activates PKC, leads to activation of MAPK2. Activated GPR54 could also recruit arrestin-1 and arrestin-2, arrestin-1 suppresses but arrestin-2 upregulates phosphorylation of ERK1/2. Additionally, NF-κB pathway and MMP-9 is downregulated. Dotted arrows are associated with cell metastasis, cell apoptosis and hormone-releasing.