Details for: KISS1R

Gene ID: 84634

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: KISS1R

Ensembl ID: ENSG00000116014

Description: KISS1 receptor

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • extravillous trophoblast CL0008036
    CSI 3.86
    rCSI 4.78%
    PRS 99.02
  • suprabasal keratinocyte CL4033013
    CSI 2.94
    rCSI 4.81%
    PRS 92.91
  • retinal ganglion cell CL0000740
    CSI 2.16
    rCSI 4.77%
    PRS 98.05
  • type B pancreatic cell CL0000169
    CSI 1.79
    rCSI 3.96%
    PRS 99.22
  • melanocyte of skin CL1000458
    CSI 1.33
    rCSI 1.81%
    PRS 92.49

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
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  • Node Size: Proportional to Target Cell CSI magnitude
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  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [KISS1R](/details-gene/84634), also known as GPR54, is a protein-coding gene located on chromosome 19p13.3 that encodes the KiSS-1 receptor. This receptor is a G protein-coupled receptor (GPCR) that binds to kisspeptins, peptides encoded by the *KiSS-1* gene. Functionally, [KISS1R](/details-gene/84634) is a critical regulator of the neuroendocrine axis, playing an indispensable role in the onset of puberty ([Link](https://doi.org/10.1056/nejmoa035322), [Link](https://doi.org/10.1016/j.tem.2004.09.008)). Loss-of-function mutations are associated with hypogonadotropic hypogonadism ([Link](https://omim.org/entry/176400), [Link](https://doi.org/10.1073/pnas.1834399100)). Beyond its role in reproductive function, the KISS1/[KISS1R](/details-gene/84634) signaling axis has been identified as a potent metastasis suppressor in several cancers, including melanoma and breast cancer ([Link](https://doi.org/10.1038/35079135)). Expression data highlights its significant role in specialized cell types, with its highest significance observed in [extravillous trophoblast](/details-cell/CL0008036)s, suggesting a key function in placental biology. ## Cellular Roles and Expression Landscape The expression profile of [KISS1R](/details-gene/84634) indicates a highly specialized function across diverse tissues. **Overall**, its most significant expression is found in [extravillous trophoblast](/details-cell/CL0008036) (CSI: 3.86), a cell type critical for placental implantation and uterine invasion. This is consistent with research demonstrating that kisspeptin signaling via [KISS1R](/details-gene/84634) acts as a physiological inhibitor of trophoblast migration, thereby regulating the extent of placental invasion during pregnancy ([Link](https://doi.org/1242/jcs.00971)). Beyond the placenta, [KISS1R](/details-gene/84634) shows significant expression in several other distinct cell populations. It is a notable marker in epidermal cells, including [suprabasal keratinocyte](/details-cell/CL4033013) (CSI: 2.94) and [melanocyte of skin](/details-cell/CL1000458) (CSI: 1.33), which aligns with its initial discovery as a metastasis suppressor in melanoma. The receptor is also significantly expressed in neuronal and endocrine cells, such as the [retinal ganglion cell](/details-cell/CL0000740) (CSI: 2.16) and the insulin-producing [type B pancreatic cell](/details-cell/CL0000169) (CSI: 1.79). This diverse expression pattern suggests that while [KISS1R](/details-gene/84634) is famed for its role in the hypothalamus for puberty regulation, it also performs crucial, context-specific functions in placental development, skin homeostasis, and sensory and metabolic tissues. ## Pathways and Molecular Function [KISS1R](/details-gene/84634) functions primarily as a [G protein-coupled peptide receptor activity](/details-go/GO0008528) located on the [cell surface](/details-go/GO0009986) and [plasma membrane](/details-go/GO0005886). Its engagement by kisspeptin ligands initiates the [G protein-coupled receptor signaling pathway](/details-go/GO0007186) and the [neuropeptide signaling pathway](/details-go/GO0007218). Reactome pathway analysis further classifies it within [Class a/1 (rhodopsin-like receptors)](https://reactome.org/content/detail/R-HSA-373076), a major family of GPCRs. Upon ligand binding ([Gpcr ligand binding](https://reactome.org/content/detail/R-HSA-500792)), [KISS1R](/details-gene/84634) preferentially couples to the Gq/11 family of G proteins, activating downstream [G alpha (q) signalling events](https://reactome.org/content/detail/R-HSA-416476). This leads to the activation of phospholipase C, subsequent production of inositol triphosphate and diacylglycerol, and a rise in intracellular calcium levels, ultimately modulating cellular processes such as proliferation, migration, and hormone secretion. ## Research Directions The role of [KISS1R](/details-gene/84634) appears to be highly context-dependent, acting as a key developmental signal in the neuroendocrine system while also serving as a potent regulator of cell invasion in both physiological (placentation) and pathological (cancer metastasis) settings. Several publications have documented the loss of [KISS1R](/details-gene/84634) expression in advanced cancers like esophageal squamous cell carcinoma ([Link](https://doi.org/10.1158/1078-0432.ccr-1519-02)) and hepatocellular carcinoma ([Link](https://doi.org/10.1007/s00432-003-0469-z)), suggesting its downregulation is a critical step in tumor progression. Conversely, it has been found to be overexpressed in papillary thyroid cancer, where it promotes MAP kinase signaling ([Link](https://doi.org/10.1210/jcem.87.5.8626)). This dual role provides fertile ground for further investigation. **Proposed Hypotheses:** 1. Given its high significance in [extravillous trophoblast](/details-cell/CL0008036)s and its known role in limiting their invasion, dysregulation of [KISS1R](/details-gene/84634) signaling contributes to pathologies of placentation. Reduced signaling may lead to excessive invasion as seen in placenta accreta, while over-activity could result in shallow implantation associated with pre-eclampsia. 2. The loss of [KISS1R](/details-gene/84634) expression in [melanocyte of skin](/details-cell/CL1000458) is a key event in the transition from primary to metastatic melanoma. Epigenetic silencing (e.g., via promoter methylation) of the [KISS1R](/details-gene/84634) gene may serve as a biomarker for metastatic potential and a mechanism that allows melanoma cells to escape suppressive signaling. **Experimental Approach:** To test the first hypothesis, one could utilize an *in vitro* model of trophoblast invasion. Specifically, CRISPR-Cas9 could be used to knock out or knockdown [KISS1R](/details-gene/84634) in a human [extravillous trophoblast](/details-cell/CL0008036) cell line (e.g., HTR-8/SVneo). The invasive capacity of these modified cells could then be quantitatively assessed against control cells using a Matrigel-coated transwell invasion assay. Furthermore, RNA-sequencing of the [KISS1R](/details-gene/84634)-deficient cells would identify downstream transcriptional changes, particularly in genes related to cell adhesion, matrix metalloproteinase activity, and epithelial-to-mesenchymal transition, providing mechanistic insight into how [KISS1R](/details-gene/84634) signaling controls invasion. **Therapeutic Potential:** The therapeutic potential of targeting [KISS1R](/details-gene/84634) is complex and context-dependent. For metastatic cancers characterized by loss of [KISS1R](/details-gene/84634) function, **activation** of the pathway using stable kisspeptin analogs could represent a novel anti-metastatic therapy. Conversely, in cancers like papillary thyroid cancer where [KISS1R](/details-gene/84634) is overexpressed and pro-proliferative, **inhibition** with a small molecule antagonist or a targeted antibody could be beneficial. A major challenge for systemic therapies is the central role of [KISS1R](/details-gene/84634) in regulating the reproductive axis, meaning that any therapeutic agent would need to be highly targeted to tumor tissue to avoid significant endocrine side effects.

Genular Protein ID: 528156730

Symbol: KISSR_HUMAN

Name: KiSS-1 receptor

UniProtKB Accession Codes:

Q969F8 A5D8U2 B2RTV1 Q96QG0

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEMBL 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 1 DrugCentral 1 EMBL 11 Ensembl 1 ExpressionAtlas 1 GO 9 Gene3D 1 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 3 KEGG 1 MANE-Select 1 MIM 5 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 3 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PRINTS 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 2 RefSeq 1 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 11385580

Title: Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor.

PubMed ID: 11385580

DOI: 10.1038/35079135

PubMed ID: 11414709

Title: FMRFamide-related neuropeptides are agonists of the orphan G-protein-coupled receptor GPR54.

PubMed ID: 11414709

DOI: 10.1006/bbrc.2001.5098

PubMed ID: 11387329

Title: AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1.

PubMed ID: 11387329

DOI: 10.1074/jbc.m102743200

PubMed ID: 11457843

Title: The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54.

PubMed ID: 11457843

DOI: 10.1074/jbc.m104847200

PubMed ID: 14573733

Title: The GPR54 gene as a regulator of puberty.

PubMed ID: 14573733

DOI: 10.1056/nejmoa035322

PubMed ID: 15057824

Title: The DNA sequence and biology of human chromosome 19.

PubMed ID: 15057824

DOI: 10.1038/nature02399

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 15519892

Title: GPR54 and puberty.

PubMed ID: 15519892

DOI: 10.1016/j.tem.2004.09.008

PubMed ID: 11527393

Title: Metastin suppresses the motility and growth of CHO cells transfected with its receptor.

PubMed ID: 11527393

DOI: 10.1006/bbrc.2001.5470

PubMed ID: 12414911

Title: Transcriptional expression of genes involved in cell invasion and migration by normal and tumoral trophoblast cells.

PubMed ID: 12414911

DOI: 10.1210/jc.2002-021093

PubMed ID: 11994395

Title: Metastin receptor is overexpressed in papillary thyroid cancer and activates MAP kinase in thyroid cancer cells.

PubMed ID: 11994395

DOI: 10.1210/jcem.87.5.8626

PubMed ID: 12944565

Title: Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54.

PubMed ID: 12944565

DOI: 10.1073/pnas.1834399100

PubMed ID: 12898236

Title: Quantitative reverse transcriptase polymerase chain reaction analysis for KiSS-1 and orphan G-protein-coupled receptor (hOT7T175) gene expression in hepatocellular carcinoma.

PubMed ID: 12898236

DOI: 10.1007/s00432-003-0469-z

PubMed ID: 14977840

Title: Clinical significance of the loss of KiSS-1 and orphan G-protein-coupled receptor (hOT7T175) gene expression in esophageal squamous cell carcinoma.

PubMed ID: 14977840

DOI: 10.1158/1078-0432.ccr-1519-02

PubMed ID: 15020672

Title: Kisspeptin-10, a KiSS-1/metastin-derived decapeptide, is a physiological invasion inhibitor of primary human trophoblasts.

PubMed ID: 15020672

DOI: 10.1242/jcs.00971

PubMed ID: 15596153

Title: Activation of GPR54 promotes cell cycle arrest and apoptosis of human tumor cells through a specific transcriptional program not shared by other G(q)-coupled receptors.

PubMed ID: 15596153

DOI: 10.1016/j.bbrc.2004.11.094

PubMed ID: 15598687

Title: Two novel missense mutations in G protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism.

PubMed ID: 15598687

DOI: 10.1210/jc.2004-1418

PubMed ID: 17164310

Title: Neuroendocrine phenotype analysis in five patients with isolated hypogonadotropic hypogonadism due to a L102P inactivating mutation of GPR54.

PubMed ID: 17164310

DOI: 10.1210/jc.2006-2147

PubMed ID: 18272894

Title: A GPR54-activating mutation in a patient with central precocious puberty.

PubMed ID: 18272894

DOI: 10.1056/nejmoa073443

PubMed ID: 23643382

Title: Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.

PubMed ID: 23643382

DOI: 10.1016/j.ajhg.2013.04.008

PubMed ID: 25077900

Title: The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients.

PubMed ID: 25077900

DOI: 10.1210/jc.2014-2110

Sequence Information:

  • Length: 398
  • Mass: 42586
  • Checksum: ECAE2208848F5B06
  • Sequence:
    • MHTVATSGPN ASWGAPANAS GCPGCGANAS DGPVPSPRAV DAWLVPLFFA ALMLLGLVGN 
SLVIYVICRH KPMRTVTNFY IANLAATDVT FLLCCVPFTA LLYPLPGWVL GDFMCKFVNY 
IQQVSVQATC ATLTAMSVDR WYVTVFPLRA LHRRTPRLAL AVSLSIWVGS AAVSAPVLAL 
HRLSPGPRAY CSEAFPSRAL ERAFALYNLL ALYLLPLLAT CACYAAMLRH LGRVAVRPAP 
ADSALQGQVL AERAGAVRAK VSRLVAAVVL LFAACWGPIQ LFLVLQALGP AGSWHPRSYA 
AYALKTWAHC MSYSNSALNP LLYAFLGSHF RQAFRRVCPC APRRPRRPRR PGPSDPAAPH 
AELLRLGSHP APARAQKPGS SGLAARGLCV LGEDNAPL