Kisspeptin

KiSS-1 metastasis-suppressor
Identifiers
Symbols	KISS1; KiSS-1; METASTIN; MGC39258
External IDs	OMIM: 603286 MGI: 2663985 HomoloGene: 1701 GeneCards: KISS1 Gene
Gene Ontology Molecular function • protein binding Cellular component • extracellular region • extracellular region Biological process • cytoskeleton organization Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3814	280287
Ensembl	ENSG00000170498	ENSMUSG00000091251
UniProt	Q15726	n/a
RefSeq (mRNA)	NM_002256.3	NM_178260.3
RefSeq (protein)	NP_002247.3	NP_839991.2
Location (UCSC)	Chr 1: 204.16 – 204.17 Mb	Chr 1: 135.22 – 135.23 Mb
PubMed search	[1]	[2]

Kisspeptin (formerly known as Metastin), the product of the gene Kiss1, is a G-protein coupled receptor ligand for GPR54.^[1] Kiss1 was originally identified as a human metastasis suppressor gene that has the ability to suppress melanoma and breast cancer metastasis. It recently became clear that kisspeptin-GPR54 signaling has an important role in initiating secretion of gonadotropin-releasing hormone (GnRH) at puberty, the extent of which is an area of ongoing research.^[2][3]

Genomics

Kisspeptins are a family of peptides encoded by the KiSS-1 gene. This gene is located on the long arm of chromosome 1 (1q32) and has four exons of which the 5' and 3' exons are only partly translated. The gene product is a 145 amino acid precursor peptide which is cleaved to 54 amino acids in length, which may be further truncated to 14, 13 or 10 amino acid carboxyl terminal fragments. These N-terminally truncated peptides are known as the kisspeptins and belong to a larger family of peptides known as RFamides which all share a common arginine-phenylalanine-NH2 motif at their C-terminus.

A polymorphism in the terminal exon of this mRNA results in two protein isoforms. An adenosine present at the polymorphic site represents the third position in a stop codon. When the adenosine is absent, a downstream stop codon is utilized and the encoded protein extends for an additional seven amino acid residues.^[4]

Function

In the brain this gene is transcribed within the hippocampal dentate gyrus. It is also transcribed in the vascular endothelium.^[5]

It is transcribed within the neocortex of the adrenal gland with higher levels in foetal compared to adult tissues. Kisspeptin-54 can stimulate secretion of aldosterone.

It is transcribed in the pancreas within the islet cells and where it can stimulate release of insulin.

Studies suggest a putative role in the regulation of events downstream of cell-matrix adhesion, perhaps involving cytoskeletal reorganization.

Pathological importance

The protein encoded by this gene is a metastasis suppressor of melanomas and breast cancers without affecting tumorigenicity. The encoded protein may function to inhibit chemotaxis and invasion, attenuating metastasis in malignant melanomas.

It is found in atherosclerotic plaques of the coronary arteries.

Discovery

The receptor for kisspeptin, GPR54, was first identified as an orphan GPCR in rat in 1999.^[6] Following in 2001, a natural ligand for GPR54 was discovered, which was the product of the Kiss1 gene, originally identified as a human metastasis suppressor gene.^[7] Subsequent mutant studies led to the discovery that LOF mutations in GPR54 causes failure to progress through puberty in man, due to hypogonadotropic hypogonadism. Thus, it was concluded that Kisspeptin-GPR54 signaling is essential to initiate gonadotropin (LH/FSH) secretion at puberty.

The original nomenclature of the KiSS-1 gene and its product, kisspeptin, may have been named with a bit of whimsy, to ensure everyone knew (or might guess) where it was discovered— in Hershey, Pennsylvania, the home of the chocolate "Hershey's Kisses".^[8]

Kisspeptin Neurons

Kisspeptin expressing neurons are located in:

• Anteroventral periventricular nucleus (AVPV)
• Periventricular nucleus (PVN)
• Anterodorsal preoptic nucleus (ADP)
• The arcuate nucleus (Arc)

Kisspeptin neurons reside in nuclei such as Arc and AVPV and send projections into the MPOA, where there is an abundance of GnRH cell bodies. This anatomical evidence suggests that Kisspeptin fibers appear in close anatomical relationship to GnRH (parvicellular) neurons. In fact, Kisspeptin appears to act directly on GnRH neurons (via GPR54) to stimulate the secretion of GnRH.

However, for kisspeptin to be involved in the regulation of GnRH release, it must also be sensitive to steroid levels within the circulation, as it has already been established that steroids produced by the gonads exert regulatory effects on FSH and LH levels through GnRH mediation. Therefore, there are (at least) two possible scenarios: That either kisspeptin neurons express steroid receptors (such as ERα, ERβ, and AR) themselves, or they receive input from another mechanism about circulating steroid levels.

Coexpression imaging of Kiss-1 mRNA (using vector red) and steroid receptors determined that KiSS-1 neurons are direct target for the action of sex steroids in both the male and female mouse.

Role in Puberty

The following evidence has been cited to support a role for kisspeptin in puberty:

• Animals with LOF mutations and targeted deletions of GPR54 fail to progress through puberty as a result of hypogonadotropic * hypogonadism (HH).
• Activation of GnRH neurons is the key event that initiates the onset of puberty.
• Peripheral administration of kisspeptin to prepubertal, 25-day-old female rats stimulates LH secretion and induces ovulation in the rat.
• If kisspeptins trigger puberty onset, one would expect to see an increase in KiSS-1 mRNA and/or GPR54 mRNA expression during this time. RT-PCR essays and semiquantitative results support this hypothesis.
• The electrophysiologic response of GnRH neurons to kisspeptins appears to change dramatically over the course of puberty.

Mechanism of Action

Kisspeptin appears to directly activate GnRH neurons. Evidence for this involves the persistence of a neural response to kisspeptin levels even in the presence of TTX, a neurotoxin that blocks nerve signals.

• Gramicidin-perforated patch recordings: approx. 30% of GnRH neurons respond to kisspeptin administration in prepubertal males, whereas 60% of GnRH neurons in adult mice responded.
• Because only adult mice respond to low doses of kisspeptin, it appears that GnRH neurons become developmentally activated by kisspeptin over the course of puberty.
• Kisspeptin induces production of LH and FSH, which are required for female's menstruation. Athletes may not undergo menstruation due to low fat levels; fat produces the hormone "Leptin", which induces production of "Kisspeptin".

References

1. ^ Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D, Carlton MB, Colledge WH, Caraty A, Aparicio SA (2005). "Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54". Proc. Natl. Acad. Sci. U.S.A. 102 (5): 1761–6. doi:10.1073/pnas.0409330102. PMC 545088. PMID 15665093. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=545088. 
2. ^ Smith JT, Clifton DK, Steiner RA (2006). "Regulation of the neuroendocrine reproductive axis by kisspeptin-GPR54 signaling". Reproduction 131 (4): 623–30. doi:10.1530/rep.1.00368. PMID 16595713. 
3. ^ Dungan HM, Clifton DK, Steiner RA (2006). "Minireview: kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion". Endocrinology 147 (3): 1154–8. doi:10.1210/en.2005-1282. PMID 16373418. 
4. ^ "Entrez Gene: KISS1 KiSS-1 metastasis-suppressor". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3814. 
5. ^ Mead EJ, Maguire JJ, Kuc RE, Davenport AP (January 2007). "Kisspeptins are novel potent vasoconstrictors in humans, with a discrete localization of their receptor, G protein-coupled receptor 54, to atherosclerosis-prone vessels". Endocrinology 148 (1): 140–7. doi:10.1210/en.2006-0818. PMID 17023533. 
6. ^ Lee D, Nguyen T, O'Neill G, Cheng R, Liu Y, Howard A, Coulombe N, Tan C, Tang-Nguyen A, George S, O'Dowd B (1999). "Discovery of a receptor related to the galanin receptors". FEBS Lett 446 (1): 103–7. doi:10.1016/S0014-5793(99)00009-5. PMID 10100623. 
7. ^ Kotani M, Detheux M, Vandenbogaerde A, Communi D, Vanderwinden J, Le Poul E, Brézillon S, Tyldesley R, Suarez-Huerta N, Vandeput F, Blanpain C, Schiffmann S, 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): 34631–6. doi:10.1074/jbc.M104847200. PMID 11457843. 
8. ^ Gottsch ML, Clifton DK, Steiner RA (January 2009). "From KISS1 to kisspeptins: An historical perspective and suggested nomenclature". Peptides 30 (1): 4–9. doi:10.1016/j.peptides.2008.06.016. PMC 2683679. PMID 18644415. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2683679. 

Further reading

• Harms JF, Welch DR, Miele ME (2003). "KISS1 metastasis suppression and emergent pathways.". Clin. Exp. Metastasis 20 (1): 11–8. doi:10.1023/A:1022530100931. PMID 12650602. 
• Kaiser UB, Kuohung W (2006). "KiSS-1 and GPR54 as new players in gonadotropin regulation and puberty.". Endocrine 26 (3): 277–84. doi:10.1385/ENDO:26:3:277. PMID 16034182. 
• Nash KT, Welch DR (2006). "The KISS1 metastasis suppressor: mechanistic insights and clinical utility.". Front. Biosci. 11: 647–59. doi:10.2741/1824. PMC 1343480. PMID 16146758. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1343480. 
• Tena-Sempere M (2006). "GPR54 and kisspeptin in reproduction.". Hum. Reprod. Update 12 (5): 631–9. doi:10.1093/humupd/dml023. PMID 16731583. 
• Dhillo WS, Murphy KG, Bloom SR (2007). "The neuroendocrine physiology of kisspeptin in the human.". Reviews in endocrine & metabolic disorders 8 (1): 41–6. doi:10.1007/s11154-007-9029-1. PMID 17323132. 
• Smith JT, Clarke IJ (2007). "Kisspeptin expression in the brain: catalyst for the initiation of puberty.". Reviews in endocrine & metabolic disorders 8 (1): 1–9. doi:10.1007/s11154-007-9026-4. PMID 17334929. 
• Lee JH, Miele ME, Hicks DJ, et al. (1996). "KiSS-1, a novel human malignant melanoma metastasis-suppressor gene.". J. Natl. Cancer Inst. 88 (23): 1731–7. doi:10.1093/jnci/88.23.1731. PMID 8944003. 
• Lee JH, Welch DR (1997). "Identification of highly expressed genes in metastasis-suppressed chromosome 6/human malignant melanoma hybrid cells using subtractive hybridization and differential display.". Int. J. Cancer 71 (6): 1035–44. doi:10.1002/(SICI)1097-0215(19970611)71:6<1035::AID-IJC20>3.0.CO;2-B. PMID 9185708. 
• Lee JH, Welch DR (1997). "Suppression of metastasis in human breast carcinoma MDA-MB-435 cells after transfection with the metastasis suppressor gene, KiSS-1.". Cancer Res. 57 (12): 2384–7. PMID 9192814. 
• West A, Vojta PJ, Welch DR, Weissman BE (1999). "Chromosome localization and genomic structure of the KiSS-1 metastasis suppressor gene (KISS1).". Genomics 54 (1): 145–8. doi:10.1006/geno.1998.5566. PMID 9806840. 
• Yan C, Wang H, Boyd DD (2001). "KiSS-1 represses 92-kDa type IV collagenase expression by down-regulating NF-kappa B binding to the promoter as a consequence of Ikappa Balpha -induced block of p65/p50 nuclear translocation.". J. Biol. Chem. 276 (2): 1164–72. doi:10.1074/jbc.M008681200. PMID 11060311. 
• Ohtaki T, Shintani Y, Honda S, et al. (2001). "Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor.". Nature 411 (6837): 613–7. doi:10.1038/35079135. PMID 11385580. 
• Muir AI, Chamberlain L, Elshourbagy NA, et al. (2001). "AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1.". J. Biol. Chem. 276 (31): 28969–75. doi:10.1074/jbc.M102743200. PMID 11387329. 
• Kotani M, Detheux M, Vandenbogaerde A, et al. (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): 34631–6. doi:10.1074/jbc.M104847200. PMID 11457843. 
• Hori A, Honda S, Asada M, et al. (2001). "Metastin suppresses the motility and growth of CHO cells transfected with its receptor.". Biochem. Biophys. Res. Commun. 286 (5): 958–63. doi:10.1006/bbrc.2001.5470. PMID 11527393. 
• Shirasaki F, Takata M, Hatta N, Takehara K (2001). "Loss of expression of the metastasis suppressor gene KiSS1 during melanoma progression and its association with LOH of chromosome 6q16.3-q23.". Cancer Res. 61 (20): 7422–5. PMID 11606374. 
• Ringel MD, Hardy E, Bernet VJ, et al. (2002). "Metastin receptor is overexpressed in papillary thyroid cancer and activates MAP kinase in thyroid cancer cells.". J. Clin. Endocrinol. Metab. 87 (5): 2399. doi:10.1210/jc.87.5.2399. PMID 11994395. 
• Janneau JL, Maldonado-Estrada J, Tachdjian G, et al. (2002). "Transcriptional expression of genes involved in cell invasion and migration by normal and tumoral trophoblast cells.". J. Clin. Endocrinol. Metab. 87 (11): 5336–9. doi:10.1210/jc.2002-021093. PMID 12414911. 
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241. 
• Kisspeptin.org is a dedicated web portal for Kisspeptin researchers. link title. http://www.kisspeptin.org. 

External links

• MeSH KISS1+protein,+human