The Metastasis Suppressor Gene KiSS-1 Encodes Kisspeptins, the Natural Ligands of the Orphan G Protein-coupled Receptor GPR54

Abstract

Natural peptides displaying agonist activity on the orphan G protein-coupled receptor GPR54 were isolated from human placenta. These 54-, 14,-and 13-amino acid peptides, with a common RF-amide C terminus, derive from the product of KiSS-1, a metastasis suppressor gene for melanoma cells, and were therefore designated kisspeptins. They bound with low nanomolar affinities to rat and human GPR54 expressed in Chinese hamster ovary K1 cells and stimulated PIP 2 hydrolysis, Ca 2؉ mobilization, arachidonic acid release, ERK1/2 and p38 MAP kinase phosphorylation, and stress fiber formation but inhibited cell proliferation. Human GPR54 was highly expressed in placenta, pituitary, pancreas, and spinal cord, suggesting a role in the regulation of endocrine function. Stimulation of oxytocin secretion after kisspeptin administration to rats confirmed this hypothesis.

Kisspeptin Prevention of Amyloid-β Peptide Neurotoxicityin Vitro

“…6 Shorter derivatives of KP peptide comprising the C-terminal 14 (KP 41−54), 13 (KP 42−54), and 10 (KP 45−54) amino acids have also been found in tissues and corresponding to residues 108− 121, 109−121, and 112−121 of KiSS-1. 6,7 Biological activity of KP peptides requires the KP 45−54 sequence and is mediated via a specific KP receptor (GPR-54). 6,7 Lack of KP signaling via the GPR-54 receptor is associated with reproductive system failure.…”

“…6,7 Biological activity of KP peptides requires the KP 45−54 sequence and is mediated via a specific KP receptor (GPR-54). 6,7 Lack of KP signaling via the GPR-54 receptor is associated with reproductive system failure. 8 Cleavage of the KP 45−54 peptide between residues 51 and 52 by matrix metalloproteinases abolishes the activation of GPR-54 by the KP 45−54 peptide.…”

Downregulation of KiSS‐1 expression is responsible for tumor invasion and worse prognosis in gastric carcinoma

“…4 More recently, it has been reported that kisspeptin or metastin, a product of the KiSS-1 gene, is thought to possess potent antimetastatic property and an orphan receptor for this protein has been detected. [7][8][9][10][11][12] Although the exact mechanism of the tumor suppressor activity of KiSS-1 is yet to be revealed, the KiSS-1 gene product has recently been shown to repress type IV collagenase (MMP-9) expression and a loss of KiSS-1 expression has been associated with loss of membrane E-cadherin expression. 4,10 Moreover, very recently it was shown that activation of a Gprotein-coupled receptor (also known as AXOR12, GPR54, or hOT7T175) by KiSS-1 peptide changed cell morphology and actin filament reorganization in NIH3T3 cells.…”

Current and future applications of GnRH, kisspeptin and neurokinin B analogues

“…An understanding of the structure of KP is a key point of departure in this endeavor. KP-54 and the smaller processed peptides of 14, 13 and 10 amino acids in length have been shown to bind to and activate the receptor with equal potency 77 . Therefore, the minimal 10 amino acid fragment of the carboxyl-terminus has been used to analyse the structure of KP and to design KP antagonists.…”

“…The human 54 amino acid peptide and rodent 52 amino acid peptide are further proteolytically processed to C-terminal peptides of 14, 13 and 10 amino acids, all of which are biologically active 75 . The 10 amino acid peptide (KP-10) has full intrinsic biological activity 76,77 . However the 54 or 52 amino acid peptides have longer half-lives and therefore increased LHreleasing activities than the shorter forms in vivo 78,79 .…”