Kisspeptin Peptides

Definition
The KISS1 receptor (previously designated GPR54) has been paired with biologically active cleavage peptides of the KiSS-1 gene product, the kisspeptins (KP).

Discovery
KP was originally identified in 1996 from a metastasis suppressor gene, KiSS-1, in malignant melanomas. Initially, the largest cleavage product, KP-54, was identified for its ability to suppress metastatic potential in human melanoma cells. Its expression also resulted in suppression of melanoma metastasis in athymic nude mice and it was therefore termed metastin1. In 2001, one of the orphans KISS1 (previously designated GPR54, AXOR12, hOT7T175) was paired with three biologically active cleavage peptides of the kisspeptin gene (KiSS-1) gene product isolated from human placenta, the KP’s (KP)-54, KP-13 and KP-10 2, 3. The KP, as a collective group, where individual KP is referred to, their amino acid sequence length e.g., KP-54, KP-13 and KP-10.

Structural Characteristics
The full-length KP protein (KP-145) has a PEST sequence (proline, glutamic acid, serine, threonine and aspartic acid residue-rich sequence). This motif predisposes proteins for ubiquitination and proteosome degradation and suggests that cytosolic KP-145 would have a short half-life 4. In rat and mouse, the longest KP cleavage fragment is composed of 52 amino acids. Although overall homology of human KiSS-1 gene products to rat and mouse is relatively low (B52%), KP-10 is highly conserved between human, mouse and rat, with only one amino acid difference in the sequence between species 1.

Mode of Action
Activation of KISS1 (GPR54) results in intracellular calcium mobilization that is not affected by pertussis toxin and does not result in changes in cAMP accumulation, suggesting that it is a Gq-coupled receptor. KP activation of KISS1 (GPR54) has been shown to simultaneously result in release of arachidonic acid and stimulation of the mitogen-activated protein kinase (MAPKs) extracellular signal-regulated kinase (ERK) 1 and ERK2. This has been attributed to increased phosphorylation of MAPK 5.

Functions
KP and matrix metalloproteinases- Downregulation of one or both of the gelatinase matrix metalloproteinases (MMPs), MMP-2 and MMP-9, by KP has been shown. KP has been described as regulator of MMPs at both the transcriptional and protein level. Transcriptional changes have been shown not to function through the MAPK signalling pathways. Instead, nuclear factor-kB binding to the MMP-9 promoter region, necessary for expression of MMP-9 6.

KP and cancer metastasis- Direct interaction of KiSS-1 has been identified with two transcription factors, activator protein-2a and specificity protein-1, both of which have been shown to be important regulators of genes involved in tumourigenesis, metastasis and development 7.

KP and placentation- Microarray analysis confirmed the higher KISS1 (GPR54) expression in first trimester invasive trophoblasts, when compared to non/low-invasive term cells.

KISS1 (GPR54) – an unexpected molecular switch for puberty- In 2003, three different groups identified KISS1 (GPR54) as an unexpected molecular switch for puberty 8.

KP and GnRH release-The signalling pathway showed that injection of KP-10 and KP-54 directly into the lateral cerebral ventricle of the mouse brain potently stimulated LH and follicle-stimulating hormone (FSH) secretion, an effect that could be blocked by pretreatment with the GnRH antagonist acyline 8.

KP neurones in the brain- Approximately 75% of GnRH neurones co-express KISS1 (GPR54), a finding that has been confirmed in sheep, where intra cerebral injection of KP resulted in direct release of GnRH into the cerebrospinal fluid 8.

Direct effects of KP on the testes-Continuous chronic administration of KP in male rats resulted in decreased testicular weight and degeneration of the seminiferous tubules, leading to the hypothesis that KP may alter testicular blood flow 8.

References
1.Lee JH, Miele ME, Hicks DJ, Phillips KK, Trent JM, Weissman BE, Welch DR. (1996). KiSS-1, a novel human malignant melanoma metastasissuppressor gene. J Natl Cancer Inst., 88: 1731-1737.
2.Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden JM, Le Poul E, Brézillon S, Tyldesley R, Suarez-Huerta N, Vandeput F, Blanpain C, Schiffmann SN, Vassart G, Parmentier M. (2001). The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem., 276(37):34631-34636.
3.Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, Terao Y, Kumano S, Takatsu Y, Masuda Y, Ishibashi Y, Watanabe T, Asada M, Yamada T, Suenaga M, Kitada C, Usuki S, Kurokawa T, Onda H, Nishimura O, Fujino M. (2001). Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature., 411 (6837): 613–617.
4.Harms JF, Welch DR, Miele ME (2003). KISS1 metastasis suppression and emergent pathways. Clin Exp Metastasis., 20(1):11-18.
5.Becker JA, Mirjolet JF, Bernard J, Burgeon E, Simons MJ, Vassart G, Parmentier M, Libert F. (2005). Activation of GPR54 promotes cell cycle arrest and apoptosis of human tumor cells through a specific transcriptional program not shared by other Gq-coupled receptors. Biochem Biophys Res Commun., 326(3):677-686.
6.Qiao C, Wang CH, Shang T, Lin QD (2005). Clinical significance of KiSS-1 and matrix metalloproteinase-9 expression in trophoblasts of women with preeclampsia and their relation to perinatal outcome of neonates. Zhonghua Fu Chan Ke Za Zhi., 40(9): 585–590.
7.Mitchell DC, Abdelrahim M, Weng J, Stafford LJ, Safe S, Bar-Eli M, Liu M.(2006). Regulation of KiSS-1 metastasis suppressor gene expression in breast cancer cells by direct interaction of transcription factors activator protein-2alpha and specificity protein-1. J Biol Chem., 281: 51–58.
8.Mead EJ, Maguire JJ, Kuc RE,Davenport AP (2007). Kisspeptins: a multifunctional peptide system with a role in reproduction, cancer and the cardiovascular system. Br J Pharmacol., 151 (8):1143-1153.

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