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Gene and Protein Information  |
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| class A G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 951 | 11p14.1 | LGR4 | leucine rich repeat containing G protein-coupled receptor 4 | 16 |
| Mouse | 7 | 951 | 2 E3 | Lgr4 | leucine-rich repeat-containing G protein-coupled receptor 4 | 16 |
| Rat | 7 | 951 | 3q34 | Lgr4 | leucine-rich repeat-containing G protein-coupled receptor 4 | |
| Previous and Unofficial Names |
| GPR48 | leucine-rich repeat-containing G protein-coupled receptor 4 | leucine-rich repeat containing G protein-coupled receptor 4 |
| Database Links |
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| Specialist databases | |
| GPCRdb | lgr4_human (Hs), lgr4_mouse (Mm), lgr4_rat (Rn) |
| Other databases | |
| Alphafold | Q9BXB1 (Hs), A2ARI4 (Mm), Q9Z2H4 (Rn) |
| CATH/Gene3D | 3.80.10.10 |
| Ensembl Gene | ENSG00000205213 (Hs), ENSMUSG00000050199 (Mm), ENSRNOG00000005715 (Rn) |
| Entrez Gene | 55366 (Hs), 107515 (Mm), 286994 (Rn) |
| Human Protein Atlas | ENSG00000205213 (Hs) |
| KEGG Gene | hsa:55366 (Hs), mmu:107515 (Mm), rno:286994 (Rn) |
| OMIM | 606666 (Hs) |
| Pharos | Q9BXB1 (Hs) |
| RefSeq Nucleotide | NM_018490 (Hs), NM_172671 (Mm), NM_173328 (Rn) |
| RefSeq Protein | NP_060960 (Hs), NP_766259 (Mm), NP_775450 (Rn) |
| SynPHARM | 9421 (in complex with R-spondin-1) |
| UniProtKB | Q9BXB1 (Hs), A2ARI4 (Mm), Q9Z2H4 (Rn) |
| Wikipedia | LGR4 (Hs) |
| Selected 3D Structures |
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| Natural/Endogenous Ligands |
| R-spondin-1 {Sp: Human} |
| R-spondin-2 {Sp: Human} |
| R-spondin-3 {Sp: Human} |
| R-spondin-4 {Sp: Human} |
| R-spondins |
| Comments: Proposed ligands, single publication |
Download all structure-activity data for this target as a CSV file 
| Agonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | Click column headers to sort | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| R-spondins bind to LGR4, which specifically associates with Frizzled and LRPs—proteins that are activated by the extracellular Wnt molecules and then trigger canonical Wnt signalling to increase gene expression [1,3,25]. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Immuno Process Associations | ||
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| Primary Transduction Mechanisms
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| Comments: Although direct Gs protein coupling has not been demonstrated, LGR4 can increase intracellular cAMP levels, which activates cAMP-dependent PKA and directly regulates Pitx2 expression through CREB transcription factor binding to the Pitx2 promoter. LGR4 does not couple to heterotrimeric G proteins or recruit arrestins when stimulated by the R-spondins, indicating a unique mechanism of action [1]. | |
| References: 17,31 |
| Tissue Distribution
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| Tissue Distribution Comments | ||||||||
| LGR4 is expressed at embryonic day 7 in the mouse indicating a potential role in development [15]. Zebrafish lgr4 is expressed in the neural plate border, Kupffer's vesicle, neural tube, otic vesicles, midbrain, eyes, forebrain, and brain ventricular zone, midbrain-hindbrain boundary, otic vesicles, pharyngeal arches, cranial cartilages, palatoquadrates, ceratohyals, cranial cavity, pectoral fin buds, brain ventricular zone, ciliary marginal zone, and digestive organs such as the intestine, liver, and pancreas (in situ hybridisation) [8]. | ||||||||
| Expression Datasets |
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| Physiological Functions
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| Physiological Functions Comments | ||||||||
| LGR4 is required for Rspo3 signalling in vivo. It is cointernalised with Rspo3 by clathrin-mediated endocytosis [6]. LGR4 enhances aldosterone responsiveness in the kidney by activating mineralocorticoid receptor expression, suggesting that LGR4 may contribute to homeostasis of electrolytes and blood pressure and may be a candidate gene for pseudohypoaldosteronism type 1 (PHA1) [29]. | ||||||||
| Physiological Consequences of Altering Gene Expression
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| Physiological Consequences of Altering Gene Expression Comments | ||||||||||
| Lgr4 null mouse fetuses displayed transient anemia during midgestation and abnormal definitive erythropoiesis, possibly because ATF4, a key transcription factor in erythropoiesis, is down-regulated [26]. Conditional knockout of Lgr4 leads to impaired ductal elongation and branchingmorphogenesis in mouse mammary glands [24]. Conditional knockout of Lgr4 in the oviduct impaired embryonic development due to impaired secretion of growth factors [21]. Conditional deletion of Lgr4 in theintestinal epithelium of adult mice impaired Wnt target gene expression and resulted in the rapid demise of intestinal crypts, thus phenocopying Wnt pathway inhibition [1]. Lgr4 is required for Paneth cell differentiation and maintenance of intestinal stem cells ex vivo [23]. | ||||||||||
| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinically-Relevant Mutations and Pathophysiology
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| Gene Expression and Pathophysiology Comments | |
| Role in kidney development suggests that LGR4 may be involved in hereditary kidney disease [11]. LGR4 expression is upregulated in human colon carcinoma cells, correlated with lymph node metastasis and inversely associated with p27 expression [4]. LGR4 is significantly overexpressed in squamous cell carcinoma [7]. LGR4 is a permissive factor in the Wnt pathway in the intestine and, as such, a potential target for intestinal cancer therapy [23]. |
| Biologically Significant Variants
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1. 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]
2. Damond F, Benard A, Ruelle J, Alabi A, Kupfer B, Gomes P, Rodes B, Albert J, Böni J, Garson J et al.. (2008) Quality control assessment of human immunodeficiency virus type 2 (HIV-2) viral load quantification assays: results from an international collaboration on HIV-2 infection in 2006. J Clin Microbiol, 46 (6): 2088-91. [PMID:18434556]
3. 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]
4. Gao Y, Kitagawa K, Hiramatsu Y, Kikuchi H, Isobe T, Shimada M, Uchida C, Hattori T, Oda T, Nakayama K et al.. (2006) Up-regulation of GPR48 induced by down-regulation of p27Kip1 enhances carcinoma cell invasiveness and metastasis. Cancer Res, 66 (24): 11623-31. [PMID:17178856]
5. Gao Y, Shan ZY, Wang H, Zhang HM, Teng WP. (2009) Inhibitory effect of shRNA targeting GPR48 on invasion and metastasis of human cervical carcinoma cell line HeLa. Ai Zheng, 28 (2): 104-7. [PMID:19550120]
6. Glinka A, Dolde C, Kirsch N, Huang YL, Kazanskaya O, Ingelfinger D, Boutros M, Cruciat CM, Niehrs C. (2011) LGR4 and LGR5 are R-spondin receptors mediating Wnt/β-catenin and Wnt/PCP signalling. EMBO Rep, 12 (10): 1055-61. [PMID:21909076]
7. Gugger M, White R, Song S, Waser B, Cescato R, Rivière P, Reubi JC. (2008) GPR87 is an overexpressed G-protein coupled receptor in squamous cell carcinoma of the lung. Dis Markers, 24 (1): 41-50. [PMID:18057535]
8. Hirose K, Shimoda N, Kikuchi Y. (2011) Expression patterns of lgr4 and lgr6 during zebrafish development. Gene Expr Patterns, 11 (7): 378-83. [PMID:21570488]
9. Hsu SY, Liang SG, Hsueh AJ. (1998) Characterization of two LGR genes homologous to gonadotropin and thyrotropin receptors with extracellular leucine-rich repeats and a G protein-coupled, seven-transmembrane region. Mol Endocrinol, 12 (12): 1830-45. [PMID:9849958]
10. 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]
11. Kato S, Matsubara M, Matsuo T, Mohri Y, Kazama I, Hatano R, Umezawa A, Nishimori K. (2006) Leucine-rich repeat-containing G protein-coupled receptor-4 (LGR4, Gpr48) is essential for renal development in mice. Nephron Exp Nephrol, 104 (2): e63-75. [PMID:16785743]
12. Kato S, Mohri Y, Matsuo T, Ogawa E, Umezawa A, Okuyama R, Nishimori K. (2007) Eye-open at birth phenotype with reduced keratinocyte motility in LGR4 null mice. FEBS Lett, 581 (24): 4685-90. [PMID:17850793]
13. Krusche CA, Kroll T, Beier HM, Classen-Linke I. (2007) Expression of leucine-rich repeat-containing G-protein-coupled receptors in the human cyclic endometrium. Fertil Steril, 87 (6): 1428-37. [PMID:17274992]
14. Lambot MA, Mendive F, Laurent P, Van Schoore G, Noël JC, Vanderhaeghen P, Vassart G. (2009) Three-dimensional reconstruction of efferent ducts in wild-type and Lgr4 knock-out mice. Anat Rec (Hoboken), 292 (4): 595-603. [PMID:19301269]
15. Loh ED, Broussard SR, Kolakowski LF. (2001) Molecular characterization of a novel glycoprotein hormone G-protein-coupled receptor. Biochem Biophys Res Commun, 282 (3): 757-64. [PMID:11401528]
16. Loh ED, Broussard SR, Liu Q, Copeland NG, Gilbert DJ, Jenkins NA, Kolakowski LF. (2000) Chromosomal localization of GPR48, a novel glycoprotein hormone receptor like GPCR, in human and mouse with radiation hybrid and interspecific backcross mapping. Cytogenet Cell Genet, 89 (1-2): 2-5. [PMID:10894923]
17. 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]
18. Mazerbourg S, Bouley DM, Sudo S, Klein CA, Zhang JV, Kawamura K, Goodrich LV, Rayburn H, Tessier-Lavigne M, Hsueh AJ. (2004) Leucine-rich repeat-containing, G protein-coupled receptor 4 null mice exhibit intrauterine growth retardation associated with embryonic and perinatal lethality. Mol Endocrinol, 18 (9): 2241-54. [PMID:15192078]
19. Mendive F, Laurent P, Van Schoore G, Skarnes W, Pochet R, Vassart G. (2006) Defective postnatal development of the male reproductive tract in LGR4 knockout mice. Dev Biol, 290 (2): 421-34. [PMID:16406039]
20. Mohri Y, Kato S, Umezawa A, Okuyama R, Nishimori K. (2008) Impaired hair placode formation with reduced expression of hair follicle-related genes in mice lacking Lgr4. Dev Dyn, 237 (8): 2235-42. [PMID:18651655]
21. Mohri Y, Oyama K, Akamatsu A, Kato S, Nishimori K. (2011) Lgr4-deficient mice showed premature differentiation of ureteric bud with reduced expression of Wnt effector Lef1 and Gata3. Dev Dyn, 240 (6): 1626-34. [PMID:21523854]
22. Mohri Y, Umezu T, Hidema S, Tomisawa H, Akamatsu A, Kato S, Nawa A, Nishimori K. (2010) Reduced fertility with impairment of early-stage embryos observed in mice lacking Lgr4 in epithelial tissues. Fertil Steril, 94 (7): 2878-81. [PMID:20638054]
23. Mustata RC, Van Loy T, Lefort A, Libert F, Strollo S, Vassart G, Garcia MI. (2011) Lgr4 is required for Paneth cell differentiation and maintenance of intestinal stem cells ex vivo. EMBO Rep, 12 (6): 558-64. [PMID:21508962]
24. Oyama K, Mohri Y, Sone M, Nawa A, Nishimori K. (2011) Conditional knockout of Lgr4 leads to impaired ductal elongation and branching morphogenesis in mouse mammary glands. Sex Dev, 5 (4): 205-12. [PMID:21791950]
25. 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]
26. 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]
27. Van Schoore G, Mendive F, Pochet R, Vassart G. (2005) Expression pattern of the orphan receptor LGR4/GPR48 gene in the mouse. Histochem Cell Biol, 124 (1): 35-50. [PMID:16028069]
28. Wang D, Huang B, Zhang S, Yu X, Wu W, Wang X. (2013) Structural basis for R-spondin recognition by LGR4/5/6 receptors. Genes Dev, 27 (12): 1339-44. [PMID:23756652]
29. Wang J, Li X, Ke Y, Lu Y, Wang F, Fan N, Sun H, Zhang H, Liu R, Yang J et al.. (2012) GPR48 increases mineralocorticoid receptor gene expression. J Am Soc Nephrol, 23 (2): 281-93. [PMID:22135314]
30. Wang Z, Jin C, Li H, Li C, Hou Q, Liu M, Dong Xda E, Tu L. (2010) GPR48-Induced keratinocyte proliferation occurs through HB-EGF mediated EGFR transactivation. FEBS Lett, 584 (18): 4057-62. [PMID:20732323]
31. 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]
32. Yamashita R, Takegawa Y, Sakumoto M, Nakahara M, Kawazu H, Hoshii T, Araki K, Yokouchi Y, Yamamura K. (2009) Defective development of the gall bladder and cystic duct in Lgr4- hypomorphic mice. Dev Dyn, 238 (4): 993-1000. [PMID:19301403]
