LGR4, LGR5, LGR6 | G protein-coupled receptors | IUPHAR/BPS Guide to MALARIA PHARMACOLOGY

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LGR4, LGR5, LGR6 C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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This set of orphan GPCRs contain leucine rich repeat domains which suggests potential for participation in protein-protein interactions.

Receptors

LGR4 C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

147

Nomenclature

LGR4

Previous and unofficial names

GPR48 | leucine-rich repeat-containing G protein-coupled receptor 4 | leucine-rich repeat containing G protein-coupled receptor 4

Genes

LGR4 (Hs), Lgr4 (Mm), Lgr4 (Rn)

Ensembl ID

ENSG00000205213 (Hs), ENSMUSG00000050199 (Mm), ENSRNOG00000005715 (Rn)

UniProtKB AC

Q9BXB1 (Hs), A2ARI4 (Mm), Q9Z2H4 (Rn)

Principal transduction

Endogenous agonists

R-spondin-2 (RSPO2, Q6UXX9) [2]

R-spondin-1 (RSPO1, Q2MKA7) [2]

R-spondin-3 (RSPO3, Q9BXY4) [2]

R-spondin-4 (RSPO4, Q2I0M5) [2]

Comment

LGR4 does not couple to heterotrimeric G proteins or recruit arrestins when stimulated by the R-spondins, indicating a unique mechanism of action. R-spondins bind to LGR4, which specifically associates with Frizzled and LDL receptor-related proteins (LRPs) that are activated by the extracellular Wnt molecules and then trigger canonical Wnt signalling to increase gene expression [2,4,9]. Gene disruption leads to multiple developmental disorders [6,8,11,16].

LGR5 C Show summary »« Hide summary More detailed page go icon to follow link

Target Id

148

Nomenclature

LGR5

Previous and unofficial names

GPR49 | FEX | GPR67 | orphan G protein-coupled receptor HG38 | leucine-rich repeat-containing G protein-coupled receptor 5 | leucine-rich repeat containing G protein-coupled receptor 5

Genes

LGR5 (Hs), Lgr5 (Mm), Lgr5 (Rn)

Ensembl ID

ENSG00000139292 (Hs), ENSMUSG00000020140 (Mm), ENSRNOG00000004221 (Rn)

UniProtKB AC

O75473 (Hs), Q9Z1P4 (Mm)

Principal transduction

Endogenous agonists

R-spondin-2 (RSPO2, Q6UXX9) [2]

R-spondin-1 (RSPO1, Q2MKA7) [2]

R-spondin-3 (RSPO3, Q9BXY4) [2]

R-spondin-4 (RSPO4, Q2I0M5) [2]

Comment

The four R-spondins can bind to LGR4, LGR5, and LGR6, which specifically associate with Frizzled and LDL receptor-related proteins (LRPs), proteins that are activated by extracellular Wnt molecules and which then trigger canonical Wnt signalling to increase gene expression [2,4].

LGR6 C Show summary »« Hide summary More detailed page go icon to follow link

Comments

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References

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1. Barker N, Huch M, Kujala P, van de Wetering M, Snippert HJ, van Es JH, Sato T, Stange DE, Begthel H, van den Born M, Danenberg E, van den Brink S, Korving J, Abo A, Peters PJ, Wright N, Poulsom R, Clevers H. (2010) Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell, 6 (1): 25-36. [PMID:20085740]

2. Carmon KS, Gong X, Lin Q, Thomas A, Liu Q. (2011) R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. Proc Natl Acad Sci USA, 108 (28): 11452-7. [PMID:21693646]

3. Chen Q, Zheng H. (2024) Targeting LGR4-Wnt activates ferroptosis and reverses drug resistance in colorectal cancer. Nat Cancer, 5 (4): 542-543. [PMID:38355778]

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. Nature, 476 (7360): 293-7. [PMID:21727895]

5. Herpers B, Eppink B, James MI, Cortina C, Cañellas-Socias A, Boj SF, Hernando-Momblona X, Glodzik D, Roovers RC, van de Wetering M et al.. (2022) Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors. Nat Cancer, 3 (4): 418-436. [PMID:35469014]

6. Jin C, Yin F, Lin M, Li H, Wang Z, Weng J, Liu M, Da Dong X, Qu J, Tu L. (2008) GPR48 regulates epithelial cell proliferation and migration by activating EGFR during eyelid development. Invest Ophthalmol Vis Sci, 49 (10): 4245-53. [PMID:18487371]

7. Lundberg AS, Geuijen CAW, Hill S, Lammerts van Bueren JJ, Fumagalli A, de Kruif J, Silverman PB, Tabernero J. (2025) Petosemtamab, a Bispecific Antibody Targeting Epidermal Growth Factor Receptor (EGFR) and Leucine-Rich G Repeat-Containing Protein-Coupled Receptor (LGR5) Designed for Broad Clinical Applications. Cancers (Basel), 17 (10). [PMID:40427162]

8. Luo J, Zhou W, Zhou X, Li D, Weng J, Yi Z, Cho SG, Li C, Yi T, Wu X, Li XY, de Crombrugghe B, Höök M, Liu M. (2009) Regulation of bone formation and remodeling by G-protein-coupled receptor 48. Development, 136 (16): 2747-56. [PMID:19605502]

9. Ruffner H, Sprunger J, Charlat O, Leighton-Davies J, Grosshans B, Salathe A, Zietzling S, Beck V, Therier M, Isken A et al.. (2012) R-Spondin potentiates Wnt/β-catenin signaling through orphan receptors LGR4 and LGR5. PLoS ONE, 7 (7): e40976. [PMID:22815884]

10. Shimokawa M, Ohta Y, Nishikori S, Matano M, Takano A, Fujii M, Date S, Sugimoto S, Kanai T, Sato T. (2017) Visualization and targeting of LGR5⁺ human colon cancer stem cells. Nature, 545 (7653): 187-192. [PMID:28355176]

11. Song H, Luo J, Luo W, Weng J, Wang Z, Li B, Li D, Liu M. (2008) Inactivation of G-protein-coupled receptor 48 (Gpr48/Lgr4) impairs definitive erythropoiesis at midgestation through down-regulation of the ATF4 signaling pathway. J Biol Chem, 283 (52): 36687-97. [PMID:18955481]

12. Toh Y, Tu J, Wu L, Aldana A, Wen J, Liang X, Li L, Pan S, Cui J, Liu QJ. (2025) RSPO2-based peptibodies conjugated with pyrrolobenzodiazepine dimer or camptothecin analogs demonstrate potent anti-tumor activity by targeting the three receptors LGR4/5/6. bioRxiv,. [PMID:40894780]

13. Toh Y, Wu L, Tu J, Liang Z, Aldana AM, Wen JJ, Li L, Pan S, Rowe JH, Hensel ME et al.. (2025) Anti-tumor activity of camptothecin analog conjugate of an RSPO4-based peptibody targeting LGR4/5/6 in preclinical models of colorectal cancer. Br J Cancer, [Epub ahead of print]. [PMID:40825849]

14. Valenzuela-Bezanilla D, Mardones MD, Galassi M, Arredondo SB, Santibanez SH, Gutierrez-Jimenez S, Merino-Véliz N, Bustos FJ, Varela-Nallar L. (2025) RSPO/LGR signaling regulates proliferation of adult hippocampal neural stem cells. Stem Cells, 43 (1). [PMID:39432578]

15. Wang L, Hu F, Cui Q, Qiao H, Li L, Geng T, Li Y, Sun Z, Zhou S, Lan Z et al.. (2025) Structural insights into the LGR4-RSPO2-ZNRF3 complexes regulating WNT/β-catenin signaling. Nat Commun, 16 (1): 362. [PMID:39753551]

16. Weng J, Luo J, Cheng X, Jin C, Zhou X, Qu J, Tu L, Ai D, Li D, Wang J, Martin JF, Amendt BA, Liu M. (2008) Deletion of G protein-coupled receptor 48 leads to ocular anterior segment dysgenesis (ASD) through down-regulation of Pitx2. Proc Natl Acad Sci USA, 105 (16): 6081-6. [PMID:18424556]

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Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.