Nomenclature: LGR6

Family: Class A Orphans

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

Contents

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 828 1q32.1 LGR6 leucine-rich repeat containing G protein-coupled receptor 6 7
Mouse 7 967 1 E4 Lgr6 leucine-rich repeat-containing G protein-coupled receptor 6
Rat 7 965 13q13 Lgr6 leucine-rich repeat-containing G protein-coupled receptor 6
Previous and Unofficial Names
FLJ14471
VTS20631
LGR6
leucine-rich repeat-containing G protein-coupled receptor 6
gonadotropin receptor
leucine-rich repeat-containing G-protein coupled receptor 6
LOC498233
RGD1560339
RGD1560339_predicted
similar to VTS20631
similar to VTS20631 (predicted)
A530037C04Rik
Database Links
Ensembl Gene
Entrez Gene
GPCRDB
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Natural/Endogenous Ligand(s)
R-spondins
Comments: Proposed ligands, single publication
Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Reference
R-spondin-2 {Sp: Mouse} Hs Full agonist 9.3 pIC50 5
pIC50 9.3 (IC50 5x10-10 M) [5]
R-spondin-3 {Sp: Mouse} Hs Full agonist 8.77 pIC50 5
pIC50 8.77 (IC50 1.7x10-9 M) [5]
R-spondin-1 {Sp: Mouse} Hs Full agonist 8.48 pIC50 5
pIC50 8.48 (IC50 3.3x10-9 M) [5]
R-spondin-4 {Sp: Mouse} Hs Full agonist 8.15 pIC50 5
pIC50 8.15 (IC50 7x10-9 M) [5]
Agonist Comments
The four R-spondins can bind to LGR4, LGR5, and LGR6, which specifically associate with Frizzled and LRPs—proteins that are activated by extracellular Wnt molecules- and then trigger canonical Wnt signalling to increase gene expression [4]. LGR6 is not coupled with heterotrimeric G proteins or to β-arrestin following R-spondin activation [5].
Tissue Distribution
Hair follicile pluripotent stem cell area. Lgr6 mRNA was only detected slightly in the hair follicle buldge area and the dermal papilla.
Species:  Human
Technique:  RT-PCR
References:  1
Brain, mammary gland, lung and skin. Absent in the gastrointestinal tract.
Species:  Mouse
Technique:  in situ hybridisation
References:  2,9
Testis, ovary, oviduct, uterus, thymus, small intestine, colon, spleen, kidney, adrenal, brain and heart
Species:  Rat
Technique:  Northen blot
References:  7
Tissue Distribution Comments
Lgr6 is expressed in early hair progenitor cells and becomes restricted to a limited number of cells at the central isthmus [9]. Prenatally, Lgr-6 positive cells established hair follicles, sebaceous glands and an interfollicular epidermis. Postanally, Lgr-6 positive cells established sebaceous glands and an interfollicular epidermis, whereas their contribution to hair lineages slowly decreased with age [9]. In zebrafish, Lgr6 is expressed in the notochord, Kupffer's vesicle, the most anterior region of diencephalon, otic vesicles, and the anterior and posterior lateral line primodia by 24 h post-fertilisation (hpf). From 48 to 72 hpf, Lgr6 expression is restricted to the anterior and posterior neuromasts, otic vesicles, pharyngeal arches, pectoral fin buds, and cranial cartilages such as Meckel's cartilages, ceratohyals, and trabeculae [6].
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

There should be a chart of expression data here, you may need to enable JavaScript!
Functional Assay Comments
Stimulation of LGR6 with R-spondin 1-3 enhances Wnt/β-catenin signalling [5].
Physiological Functions
Lgr6 positive cells mediate would healing, including the formation of new hair follicles.
Species:  Mouse
Tissue:  Skin
References:  9
LGR6-positive hair follicle cells are able to differentiate into mesenchymal lineages (adipocytes, chondrocytes, muscle cells) or neurons (βIII-tubulin) using defined cell-culture conditions.
Species:  Mouse
Tissue:  Isolated hair follicle stem cells
References:  8
Physiological Consequences of Altering Gene Expression
Cells expressing LGR6 show increased cell migration when treated with R-spondin-1 and Wnt3a.
Species:  Human
Tissue:  HeLa cells
Technique:  Gene overexpression
References:  5
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Lgr6tm1Cle Lgr6tm1Cle/Lgr6tm1Cle
Not Specified
MGI:2441805  MP:0002169 no abnormal phenotype detected PMID: 20223988 
Lgr6tm2.1(cre/ERT2)Cle Lgr6tm2.1(cre/ERT2)Cle/Lgr6tm2.1(cre/ERT2)Cle
Not Specified
MGI:2441805  MP:0002169 no abnormal phenotype detected PMID: 20223988 
Clinically-Relevant Mutations and Pathophysiology Comments
LGR6 mutations have been detected in colon cancer, pancreatic cancer and ovarian cancer [5]. LGR6 is hypermethylated in up to 50% of colon cancer samples. LGR6 truncation mutant has been identified in ovarian cancer. These data imply that LGR6 may act as tumour suppressor for colon and ovarian cancer [5].
Biologically Significant Variants
Type:  Naturally occurring SNPs.
Species:  Human
Description:  A669E, low frequency (<10% in all tested populations)
SNP accession: 
Type:  SNP
Species:  Human
Change:  S9L
Global MAF (%):  42
Subpopulation MAF (%):  AFR|AMR|ASN|EUR: 51|48|27|47
Minor allele count:  T=0.424/927
SNP accession: 
Validation:  1000 Genomes, HapMap, Frequency
Type:  SNP
Species:  Human
Change:  A464S
Global MAF (%):  4
Subpopulation MAF (%):  AFR|AMR: 17|2
Minor allele count:  T=0.043/93
SNP accession: 
Validation:  1000 Genomes, HapMap, Frequency
Type:  SNP
Species:  Human
Change:  V540A
Global MAF (%):  38
Subpopulation MAF (%):  AFR|AMR|ASN|EUR: 64|31|25|36
Minor allele count:  T=0.385/840
SNP accession: 
Validation:  1000 Genomes, Frequency
References:  3
Type:  SNP
Species:  Human
Change:  V723M
Global MAF (%):  9
Subpopulation MAF (%):  AFR|AMR|ASN|EUR: 8|12|6|10
Minor allele count:  A=0.087/190
SNP accession: 
Validation:  1000 Genomes, Frequency
Biologically Significant Variant Comments
Variant numbering based on RefSeq Protein NP_067649
General Comments
LGR6 is a member of type B leucine-rich repeat containing G protein-coupled receptor [6]. LGR6 was shown to mark a population of multipotent stem cells in mouse skin that can give rise to all lineages of skin; however LGR6-knockout mice are healthy and fertile [9].
Available Assays
DiscoveRx PathHunter® CHO-K1 LGR6 β-Arrestin Orphan GPCR Cell Line (Cat no. 93-0527C2A)
PathHunter® eXpress LGR6 CHO-K1 β-Arrestin Orphan GPCR Assay (Cat no. 93-0527E2ACP1M)
more info

REFERENCES

1. Amoh Y, Aki R, Hamada Y, Niiyama S, Eshima K, Kawahara K, Sato Y, Tani Y, Hoffman RM, Katsuoka K. (2012) Nestin-positive hair follicle pluripotent stem cells can promote regeneration of impinged peripheral nerve injury. J. Dermatol.39 (1): 33-8. [PMID:22098554]

2. Barker N, Clevers H. (2010) Leucine-rich repeat-containing G-protein-coupled receptors as markers of adult stem cells. Gastroenterology138 (5): 1681-96. [PMID:20417836]

3. Clark HF, Gurney AL, Abaya E, Baker K, Baldwin D, Brush J, Chen J, Chow B, Chui C, Crowley C et al.. (2003) The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. Genome Res.13 (10): 2265-70. [PMID:12975309]

4. de Lau W, Barker N, Low TY, Koo BK, Li VS, Teunissen H, Kujala P, Haegebarth A, Peters PJ, van de Wetering M et al.. (2011) Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature476 (7360): 293-7. [PMID:21727895]

5. Gong X, Carmon KS, Lin Q, Thomas A, Yi J, Liu Q. (2012) LGR6 is a high affinity receptor of R-spondins and potentially functions as a tumor suppressor. PLoS ONE7 (5): e37137. [PMID:22615920]

6. Hirose K, Shimoda N, Kikuchi Y. (2011) Expression patterns of lgr4 and lgr6 during zebrafish development. Gene Expr. Patterns11 (7): 378-83. [PMID:21570488]

7. Hsu SY, Kudo M, Chen T, Nakabayashi K, Bhalla A, van der Spek PJ, van Duin M, Hsueh AJ. (2000) The three subfamilies of leucine-rich repeat-containing G protein-coupled receptors (LGR): identification of LGR6 and LGR7 and the signaling mechanism for LGR7. Mol Endocrinol14: 1257-1271. [PMID:10935549]

8. Nath M, Offers M, Hummel M, Seissler J. (2011) Isolation and in vitro expansion of Lgr6-positive multipotent hair follicle stem cells. Cell Tissue Res.344 (3): 435-44. [PMID:21484413]

9. Snippert HJ, Haegebarth A, Kasper M, Jaks V, van Es JH, Barker N, van de Wetering M, van den Born M, Begthel H, Vries RG, Stange DE, Toftgård R, Clevers H. (2010) Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin. Science327 (5971): 1385-9. [PMID:20223988]

To cite this database page, please use the following:

Anthony P. Davenport, Stephen Alexander, Joanna L. Sharman, Adam J. Pawson, Helen E. Benson, Amy E. Monaghan, Wen Chiy Liew, Chido Mpamhanga, Jim Battey, Richard V. Benya, Robert T. Jensen, Sadashiva Karnik, Evi Kostenis, Eliot Spindel, Laura Storjohann, Kalyan Tirupula, Tom I. Bonner, Richard Neubig, Jean-Philippe Pin, Michael Spedding, Anthony Harmar.
Class A Orphans: LGR6. Last modified on 09/08/2013. Accessed on 18/04/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=149.

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