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Updated: Sep 29, 2026
Mutagenesis and Analysis of Genetic Mutations in the GC-rich KISS1 Receptor Sequence Identified in Humans with Reproductive Disorders
Published on: September 4, 2011
Identification and characterization of mouse metastasis-suppressor KiSS1 and its G-protein-coupled receptor
Lewis Joe Stafford1, Chunzhi Xia, Wenbin Ma
1Center for Cancer Biology and Nutrition, Alkek Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas 77030, USA.
Abstract:
G-protein-coupled receptors receive many different signals to activate different functions such as cellgrowth, proliferation, and migration. KiSS1 is a metastasis suppressor gene that has been shown to inhibit metastasis of human melanomas and breast carcinomas. The human KiSS1 gene encodes a COOH-terminally amidated active peptide, and this peptide is the ligand of a novel G-protein-coupled receptor. However, the mechanism of the antimetastatic actions of KiSS1 and its G-protein-coupled receptor has not been elucidated. In this study, we identified the mouse homologues of the KiSS1 peptide and its G-protein-coupled receptor and characterized the signaling pathways mediated by the activation of the KiSS1 receptor. Although human and mouse KiSS1 proteins share relatively low overall homology (52%), the active peptides (10-amino-acid residues) are highly conserved between mouse and human KiSS1 proteins, varying by only one conserved amino acid [Tyr (Y) to Phe (F)]. Activation of the receptor by KiSS1 peptide leads to the activation of G-protein-activated phospholipase C (PLC-beta), which suggests direct coupling of the KiSS1 peptide to the Galphaq-mediate PLC-Ca2+ signaling pathway. Furthermore, activation of the KiSS1 receptor inhibits cell proliferation and cell migration, key characteristics of tumor metastasis.
Insights
The KiSS1 peptide and its receptor inhibit tumor metastasis by blocking cell growth and migration. This study identifies mouse versions and their signaling pathways, revealing a G-protein-coupled phospholipase C mechanism.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- G-protein-coupled receptors (GPCRs) regulate critical cellular functions including growth, proliferation, and migration.
- The KiSS1 gene acts as a metastasis suppressor, inhibiting the spread of human melanomas and breast carcinomas.
- The KiSS1 gene encodes a peptide ligand for a novel GPCR, but its antimetastatic mechanism remains unclear.
Purpose of the Study:
- To identify mouse homologues of the KiSS1 peptide and its cognate GPCR.
- To characterize the signaling pathways activated by the KiSS1 receptor.
- To elucidate the mechanism underlying KiSS1's antimetastatic actions.
Main Methods:
- Comparative sequence analysis of human and mouse KiSS1 proteins and peptides.
- Identification and characterization of mouse KiSS1 receptor homologues.
- Investigation of signaling pathways, including G-protein-activated phospholipase C (PLC-beta) and Ca2+ signaling, upon receptor activation.
Main Results:
- Mouse and human KiSS1 active peptides are highly conserved (10 amino acids), differing by only one residue.
- KiSS1 peptide activation of its receptor triggers the Galphaq-mediated PLC-beta signaling pathway.
- Activation of the KiSS1 receptor demonstrably inhibits cancer cell proliferation and migration.
Conclusions:
- The study elucidates the molecular mechanism of KiSS1's antimetastatic function through GPCR signaling.
- The conserved KiSS1-GPCR pathway offers potential therapeutic targets for inhibiting cancer metastasis.
- This research provides insights into the regulation of cell growth, migration, and metastasis via specific GPCR pathways.
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