LGR4

Summary

LGR4 (leucine rich repeat containing G protein-coupled receptor 4, HGNC:13299) is a protein-coding gene on chromosome 11p14.1, encoding Leucine-rich repeat-containing G-protein coupled receptor 4 (Q9BXB1). Receptor for R-spondins that potentiates the canonical Wnt signaling pathway and is involved in the formation of various organs.

The protein encoded by this gene is a G-protein coupled receptor that binds R-spondins and activates the Wnt signaling pathway. This Wnt signaling pathway activation is necessary for proper development of many organs of the body.

Source: NCBI Gene 55366 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic disease (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 13
• Clinical variants (ClinVar): 150 total — 2 pathogenic
• Phenotypes (HPO): 7
• Druggable target: yes
• MANE Select transcript: NM_018490

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13299
Approved symbol	LGR4
Name	leucine rich repeat containing G protein-coupled receptor 4
Location	11p14.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000205213
Ensembl biotype	protein_coding
OMIM	606666
Entrez	55366

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 10 protein_coding, 3 retained_intron

ENST00000379214, ENST00000389858, ENST00000480977, ENST00000489910, ENST00000527773, ENST00000530658, ENST00000894858, ENST00000894859, ENST00000894860, ENST00000894861, ENST00000894862, ENST00000937759, ENST00000937760

RefSeq mRNA: 2 — MANE Select: NM_018490 NM_001346432, NM_018490

CCDS: CCDS31449, CCDS86187

Canonical transcript exons

ENST00000379214 — 18 exons

Exon	Start	End
ENSE00001480120	27365961	27369143
ENSE00001480121	27371615	27371698
ENSE00001480129	27378697	27378768
ENSE00001480132	27380271	27380339
ENSE00001480134	27380640	27380711
ENSE00001480136	27380895	27380966
ENSE00001480139	27382188	27382256
ENSE00001480142	27384336	27384407
ENSE00001480146	27385253	27385468
ENSE00001480150	27391094	27391165
ENSE00001480153	27392447	27392518
ENSE00001507130	27372283	27372398
ENSE00001784942	27412789	27412860
ENSE00001913600	27472118	27472790
ENSE00003341228	27376299	27376370
ENSE00003422528	27373551	27373676
ENSE00003457094	27373975	27374046
ENSE00003688371	27377158	27377223

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 96.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.3238 / max 277.9385, expressed in 1427 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
119063	2.4450	1051
119062	1.9346	800
119061	1.1303	605
119064	0.9245	524
119060	0.4058	211
119065	0.2778	115
119059	0.2058	77

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	96.23	gold quality
body of pancreas	UBERON:0001150	96.20	gold quality
hair follicle	UBERON:0002073	95.86	gold quality
gingival epithelium	UBERON:0001949	95.17	gold quality
rectum	UBERON:0001052	94.65	gold quality
decidua	UBERON:0002450	93.95	gold quality
colonic mucosa	UBERON:0000317	93.81	gold quality
pancreas	UBERON:0001264	93.69	gold quality
gingiva	UBERON:0001828	93.47	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.17	gold quality
placenta	UBERON:0001987	92.80	gold quality
choroid plexus epithelium	UBERON:0003911	92.35	gold quality
metanephros	UBERON:0000081	92.34	gold quality
metanephric glomerulus	UBERON:0004736	92.13	gold quality
germinal epithelium of ovary	UBERON:0001304	92.12	gold quality
nephron tubule	UBERON:0001231	91.95	gold quality
renal glomerulus	UBERON:0000074	91.88	gold quality
kidney epithelium	UBERON:0004819	91.60	gold quality
palpebral conjunctiva	UBERON:0001812	91.54	gold quality
kidney	UBERON:0002113	91.13	gold quality
cortex of kidney	UBERON:0001225	91.12	gold quality
right uterine tube	UBERON:0001302	91.07	gold quality
liver	UBERON:0002107	91.04	gold quality
tibia	UBERON:0000979	91.03	gold quality
jejunal mucosa	UBERON:0000399	90.80	gold quality
islet of Langerhans	UBERON:0000006	90.09	gold quality
renal medulla	UBERON:0000362	90.08	gold quality
metanephros cortex	UBERON:0010533	89.69	gold quality
endometrium	UBERON:0001295	89.64	gold quality
right atrium auricular region	UBERON:0006631	89.53	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	18.01
E-ANND-3	yes	15.97
E-MTAB-8271	yes	7.30

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
AR	Activation
ESR1	Activation

Upstream regulators (CollecTRI, top): STAT3

miRNA regulators (miRDB)

126 targeting LGR4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-302E	99.96	70.74	2669

Literature-anchored findings (GeneRIF, showing 40)

• GPR48 may play an important role in invasiveness and metastasis of carcinoma and might represent a potential prognostic marker or therapeutic target. (PMID:17178856)
• Testicular efferent ducts in the mutant mouse are dramatically shortened and less convoluted than in the wild-type animal, providing an explanation to the phenotype observed in LGR4KO. (PMID:19301269)
• Data show that GPR48 shRNA can inhibit in vitro invasion and in vivo metastasis of HeLa cells efficiently. (PMID:19550120)
• LGR4 and LGR5 bind the R-spondins with high affinity and mediate the potentiation of Wnt/beta-catenin signaling by enhancing Wnt-induced LRP6 phosphorylation. (PMID:21693646)
• R-Spondin potentiates Wnt/beta-catenin signaling through orphan receptors LGR4 and LGR5 (PMID:22815884)
• Multi-functional norrin is a ligand for the LGR4 receptor. (PMID:23444378)
• Lgr4/Gpr48 plays a critical role in modulating the TLR2/4 signaling pathway and represents a useful therapeutic approach of targeting Lgr4/Gpr48 in TLR2/4-associated septic shock and autoimmune diseases. (PMID:23589304)
• the c.376C>T mutation is associated with low BMD and osteoporotic fractures, electrolyte imbalance, late onset of menarche, reduced testosterone levels, and an increased risk of squamous cell carcinoma of the skin and biliary tract cancer (PMID:23644456)
• Upregulation of GPR48 resulted in increased phosphorylation of glycogen synthase kinase 3beta. (PMID:23803691)
• GPR48 overexpression promotes cancer cell proliferation via activation of Wnt signaling. (PMID:24083742)
• Lgr4 overexpression promoted glioma cell proliferation through activation of Wnt signaling. (PMID:24083766)
• A functional low-frequency human LGR4 variant (A750T) has been associated with body mass index in a Chinese obese-versus-control study. (PMID:24212090)
• Lgr4, which regulates eye, kidney, testis, ovary, and uterine organ development as well as mental development through genetic and epigenetic surveillance, is a novel candidate gene for the pathogenesis of AGR syndrome (PMID:24519938)
• RSPO-LGR4 not only induces the clearance of RNF43/ZNRF3 to increase Wnt receptor levels but also recruits IQGAP1 into the Wnt signaling complex. (PMID:24639526)
• the LGR4-Rspo1 complex crystal structure shows divergent mechanisms of ligand recognition by leucine-rich repeat G-protein-coupled receptors (PMID:25480784)
• These findings suggest that aberrant RSPO3-LGR4 signaling potentially acts as a driving mechanism in the aggressiveness of Keap1-deficient lung ADs. (PMID:25531322)
• LGR4 promotes tumorigenesis of prostate cancer via PI3K/Akt signaling pathway. (PMID:25636507)
• miR-218 directly targets LGR4 and modulated the PI3K/Akt and Wnt/beta-catenin pathways in the LNCaP-IL-6+ cells. (PMID:26986507)
• LGR4 is another receptor for RANKL. LGR4 competes with RANK to bind RANKL and suppresses canonical RANK signaling during osteoclast differentiation. (PMID:27064449)
• A mechanistic understanding of RANKL-LGR4 interaction has provided new insight into LGR4 mediated RANKL signaling in osteoporosis and other diseases (PMID:27178473)
• Lgr4 is a critical positive factor for skin tumorigenesis by mediating the activation of MEK1/ERK1/2 and Wnt/beta-catenin pathways. (PMID:27693558)
• Lgr4 activates Jmjd2a/AR signaling pathway to promote interaction AR with PSA promoter, causing reduction of prostate cancer apoptosis and cell cycle arrest. (PMID:27743893)
• The LGR4 A750T variant is correlated with central obesity-related characteristics in young subjects. (PMID:27925416)
• miR-34a gene expression upregulation inhibits ARPE-19 cell proliferation, migration and adhesion partly by suppressing LGR4 expression. (PMID:27977785)
• Loss of LGR4 abrogated RSPO3-regulated osteogenesis and RSPO3-induced ERK1/2 signalling inhibition. (PMID:28220828)
• Data (including data from studies using transgenic/knockout mice) suggest that LGR4 is key protein necessary for prostate cancer epithelial-mesenchymal transition and metastasis; LGR4 expression is elevated in human prostate cancer cell lines with metastatic potential; LGR4 silencing in prostate cancer cell line impairs cell migration and invasion without affecting cell proliferation. (PMID:28768769)
• High LGR4 expression is associated with osteoarthritis. (PMID:28777797)
• the host protein leucine-rich repeat-containing G protein-coupled receptor 4 (Lgr4) is essential for VSV and VSV-G pseudotyped lentivirus (VSVG-LV) to infect susceptible cells. (PMID:28842478)
• findings support a crucial role of the Wnt signaling component LGR4 in breast cancer initiation, metastasis, and breast cancer stem cell. (PMID:29269400)
• Luciferase reporter assay was performed to confirm that LGR4 is a direct target gene of miR-137 with a potential binding site in the 3’UTR of LGR4. (PMID:29786747)
• The miR-193a-3p regulates osteoblast differentiation by modulating LGR4/ATF4 signaling and suggests that the miR-193a-3p/LGR4/ATF4 regulation axis may play an important role in regulating bone remodeling. (PMID:30100064)
• High expression of LGR4 is associated with Primary intestinal-type carcinomas than diffuse tumours. (PMID:30803215)
• MicroRNA-34a negatively controls LGR4, thereby inhibiting the migration and invasion of uveal melanoma cells. Ultimately, both miR-34a and LGR4 impact the aggressiveness of uveal melanoma with alterations in the markers of the epithelial-mesenchymal transition. (PMID:31661551)
• LGR4 overexpression is associated with clinical parameters and poor prognosis of serous ovarian cancer. (PMID:32176632)
• LGR4, Not LGR5, Enhances hPSC Hematopoiesis by Facilitating Mesoderm Induction via TGF-Beta Signaling Activation. (PMID:32375050)
• Association between LGR4 polymorphisms and peak bone mineral density and body composition. (PMID:32399675)
• LGR4 deficiency results in delayed puberty through impaired Wnt/beta-catenin signaling. (PMID:32493844)
• Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia. (PMID:32559496)
• MicroRNA137 regulates hypoxiamediated migration and epithelialmesenchymal transition in prostate cancer by targeting LGR4 via the EGFR/ERK signaling pathway. (PMID:32626928)
• LGR4 maintains HGSOC cell epithelial phenotype and stem-like traits. (PMID:32980127)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	lgr4	ENSDARG00000060542
mus_musculus	Lgr4	ENSMUSG00000050199
rattus_norvegicus	Lgr4	ENSRNOG00000005715
drosophila_melanogaster	Con	FBGN0005775
drosophila_melanogaster	kek3	FBGN0028370
caenorhabditis_elegans	lron-9	WBGENE00011971
caenorhabditis_elegans		WBGENE00020649

Paralogs (22): CHADL (ENSG00000100399), LGI1 (ENSG00000108231), LGR6 (ENSG00000133067), CHAD (ENSG00000136457), LRIG3 (ENSG00000139263), LGR5 (ENSG00000139292), LRIG1 (ENSG00000144749), LRRTM2 (ENSG00000146006), LRIT1 (ENSG00000148602), LGI2 (ENSG00000153012), LGI4 (ENSG00000153902), LRRC52 (ENSG00000162763), ELFN2 (ENSG00000166897), LGI3 (ENSG00000168481), LRG1 (ENSG00000171236), CPN2 (ENSG00000178772), LRIT3 (ENSG00000183423), LRRC26 (ENSG00000184709), LRIG2 (ENSG00000198799), ELFN1 (ENSG00000225968), LRRC24 (ENSG00000254402), TRIL (ENSG00000255690)

Protein

Protein identifiers

Leucine-rich repeat-containing G-protein coupled receptor 4 — Q9BXB1 (reviewed: Q9BXB1)

Alternative names: G-protein coupled receptor 48

All UniProt accessions (2): Q9BXB1, E9PK51

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for R-spondins that potentiates the canonical Wnt signaling pathway and is involved in the formation of various organs. Upon binding to R-spondins (RSPO1, RSPO2, RSPO3 or RSPO4), associates with phosphorylated LRP6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. In contrast to classical G-protein coupled receptors, does not activate heterotrimeric G-proteins to transduce the signal. Its function as activator of the Wnt signaling pathway is required for the development of various organs, including liver, kidney, intestine, bone, reproductive tract and eye. May also act as a receptor for norrin (NDP), such results however require additional confirmation in vivo. Required during spermatogenesis to activate the Wnt signaling pathway in peritubular myoid cells. Required for the maintenance of intestinal stem cells and Paneth cell differentiation in postnatal intestinal crypts. Acts as a regulator of bone formation and remodeling. Involved in kidney development; required for maintaining the ureteric bud in an undifferentiated state. Involved in the development of the anterior segment of the eye. Required during erythropoiesis. Also acts as a negative regulator of innate immunity by inhibiting TLR2/TLR4 associated pattern-recognition and pro-inflammatory cytokine production. Plays an important role in regulating the circadian rhythms of plasma lipids, partially through regulating the rhythmic expression of MTTP. Required for proper development of GnRH neurons (gonadotropin-releasing hormone expressing neurons) that control the release of reproductive hormones from the pituitary gland.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in multiple steroidogenic tissues: placenta, ovary, testis and adrenal. Expressed also in spinal cord, thyroid, stomach, trachea, heart, pancreas, kidney, prostate and spleen.

Disease relevance. Osteoporosis (OSTEOP) [MIM:166710] A systemic skeletal disorder characterized by decreased bone mass and deterioration of bone microarchitecture without alteration in the composition of bone. The result is fragile bones and an increased risk of fractures, even after minimal trauma. Osteoporosis is a chronic condition of multifactorial etiology and is usually clinically silent until a fracture occurs. Disease susceptibility may be associated with variants affecting the gene represented in this entry. A LGR4 nonsense mutation creating a stop codon after position 126 (c.376C>T) is strongly associated with low bone mineral density and osteoporotic fractures. This mutation probably causes degradation of the transcript by nonsense-mediated decay (NMD). The c.376C>T mutation is also associated with electrolyte imbalance, late onset of menarche and reduced testosterone levels, as well as an increased risk of squamous cell carcinoma of the skin and biliary tract cancer. Delayed puberty, self-limited (DPSL) [MIM:619613] A condition defined as the absence of testicular enlargement in boys or breast development in girls at an age that is 2-2.5 SD later than the population mean. DPSL is often familial and is highly heritable, most commonly seen with an autosomal dominant inheritance pattern. The disease may be caused by variants affecting the gene represented in this entry.

Polymorphism. Genetic variations in LGR4 define the bone mineral density quantitative trait locus 17 (BMND17) [MIM:615311]. Variance in bone mineral density influences bone mass, contributes to size determination in the general population, and is a susceptibility factor for osteoporotic fractures.

Similarity. Belongs to the G-protein coupled receptor 1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BXB1-1	1	yes
Q9BXB1-2	2

RefSeq proteins (2): NP_001333361, NP_060960* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR000372	LRRNT	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR002131	Gphrmn_rcpt_fam	Family
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR032675	LRR_dom_sf	Homologous_superfamily

Pfam: PF00001, PF00560, PF01462, PF13855

UniProt features (122 total): strand 29, helix 17, turn 15, repeat 15, topological domain 8, sequence variant 8, transmembrane region 7, sequence conflict 7, disulfide bond 6, glycosylation site 5, signal peptide 1, chain 1, domain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

23 structures.

PDB	Method	Resolution (Å)
4QXE	X-RAY DIFFRACTION	2.2
4QXF	X-RAY DIFFRACTION	2.25
4KT1	X-RAY DIFFRACTION	2.5
9KGK	ELECTRON MICROSCOPY	2.63
8XUM	ELECTRON MICROSCOPY	2.9
9UOK	ELECTRON MICROSCOPY	3.05
8XT9	ELECTRON MICROSCOPY	3.1
8XFS	ELECTRON MICROSCOPY	3.2
8XFP	ELECTRON MICROSCOPY	3.21
8XFT	ELECTRON MICROSCOPY	3.24
9KB8	ELECTRON MICROSCOPY	3.25
8WVY	ELECTRON MICROSCOPY	3.29
8WVX	ELECTRON MICROSCOPY	3.32
8WVV	ELECTRON MICROSCOPY	3.35
8Y69	ELECTRON MICROSCOPY	3.38
8WVW	ELECTRON MICROSCOPY	3.53
9KB6	ELECTRON MICROSCOPY	3.53
9KB9	ELECTRON MICROSCOPY	3.59
8WVU	ELECTRON MICROSCOPY	3.61
9KHH	ELECTRON MICROSCOPY	3.65
9S37	ELECTRON MICROSCOPY	3.94
9S38	ELECTRON MICROSCOPY	3.94
9KB7	ELECTRON MICROSCOPY	3.97

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BXB1-F1	79.35	0.59

Antibody-complex structures (SAbDab): 11 — 8XFP, 8XFS, 8XFT, 8XT9, 8XUM, 8Y69, 9KGK, 9KHH, 9S37, 9S38, 9UOK

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 920

Disulfide bonds (6): 29–35, 33–43, 339–364, 470–522, 471–476, 618–693

Glycosylation sites (5): 68, 199, 294, 314, 505

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-4641263	Regulation of FZD by ubiquitination
R-HSA-162582	Signal Transduction
R-HSA-195721	Signaling by WNT
R-HSA-201681	TCF dependent signaling in response to WNT

MSigDB gene sets: 264 (showing top): GOBP_CIRCADIAN_RHYTHM, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_METANEPHRIC_NEPHRON_MORPHOGENESIS, GOBP_EPITHELIUM_DEVELOPMENT, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_REGULATION_OF_MORPHOGENESIS_OF_A_BRANCHING_STRUCTURE, GOBP_METANEPHROS_DEVELOPMENT, GOBP_METANEPHRIC_EPITHELIUM_DEVELOPMENT, GOBP_MALE_GENITALIA_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_CIRCADIAN_REGULATION_OF_GENE_EXPRESSION, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_MALE_GAMETE_GENERATION, GOBP_KIDNEY_EPITHELIUM_DEVELOPMENT

GO Biological Process (28): osteoblast differentiation (GO:0001649), negative regulation of cytokine production (GO:0001818), hair follicle development (GO:0001942), spermatogenesis (GO:0007283), Wnt signaling pathway (GO:0016055), bone mineralization (GO:0030282), male genitalia development (GO:0030539), circadian regulation of gene expression (GO:0032922), negative regulation of toll-like receptor signaling pathway (GO:0034122), intestinal stem cell homeostasis (GO:0036335), innate immune response (GO:0045087), bone remodeling (GO:0046849), digestive tract development (GO:0048565), metanephric glomerulus development (GO:0072224), metanephric nephron tubule morphogenesis (GO:0072282), positive regulation of branching involved in ureteric bud morphogenesis (GO:0090190), positive regulation of canonical Wnt signaling pathway (GO:0090263), negative regulation of cold-induced thermogenesis (GO:0120163), epithelial cell proliferation involved in renal tubule morphogenesis (GO:2001013), immune system process (GO:0002376), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), circadian rhythm (GO:0007623), cell differentiation (GO:0030154), positive regulation of Wnt signaling pathway (GO:0030177), tube morphogenesis (GO:0035239), rhythmic process (GO:0048511), epithelial cell proliferation (GO:0050673)

GO Molecular Function (4): transmembrane signaling receptor activity (GO:0004888), G protein-coupled receptor activity (GO:0004930), protein-hormone receptor activity (GO:0016500), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
TCF dependent signaling in response to WNT	1
Signal Transduction	1
Signaling by WNT	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ossification	2
negative regulation of multicellular organismal process	2
signaling receptor activity	2
cell differentiation	1
cytokine production	1
regulation of cytokine production	1
negative regulation of gene expression	1
hair cycle process	1
anatomical structure development	1
skin epidermis development	1
developmental process involved in reproduction	1
male gamete generation	1
cell surface receptor signaling pathway	1
biomineral tissue development	1
male sex differentiation	1
genitalia development	1
reproductive system development	1
circadian rhythm	1
regulation of gene expression	1
toll-like receptor signaling pathway	1
negative regulation of immune system process	1
negative regulation of signal transduction	1
regulation of toll-like receptor signaling pathway	1
homeostasis of number of cells	1
immune response	1
defense response to symbiont	1
tissue remodeling	1
tube development	1
digestive system development	1
glomerulus development	1
metanephric nephron development	1
nephron tubule morphogenesis	1
metanephric tubule morphogenesis	1
metanephric nephron tubule development	1
metanephric nephron morphogenesis	1
branching involved in ureteric bud morphogenesis	1
positive regulation of multicellular organismal process	1
regulation of branching involved in ureteric bud morphogenesis	1
positive regulation of morphogenesis of an epithelium	1
positive regulation of Wnt signaling pathway	1

Protein interactions and networks

STRING

2156 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LGR4	RSPO1	Q2MKA7	997
LGR4	ZNRF3	Q9ULT6	995
LGR4	RNF43	Q68DV7	986
LGR4	RSPO3	Q9BXY4	977
LGR4	RSPO2	Q6UXX9	951
LGR4	NDP	Q00604	947
LGR4	RSPO4	Q2I0M5	893
LGR4	TNFSF11	O14788	893
LGR4	LRP5	O75197	767
LGR4	CREB1	P16220	639
LGR4	CTNNB1	P35222	626
LGR4	LRP6	O75581	614
LGR4	PITX2	Q99697	596
LGR4	IQGAP1	P46940	582
LGR4	CCDC34	Q96HJ3	582

IntAct

57 interactions, top by confidence:

A	B	Type	Score
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
ZNRF3	RSPO1	psi-mi:“MI:0914”(association)	0.700
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
MANSC1	KLRG2	psi-mi:“MI:0914”(association)	0.530
HAVCR2	TCAF2	psi-mi:“MI:0914”(association)	0.530
ITM2A	NDUFB5	psi-mi:“MI:0914”(association)	0.530
DAAM2	SCGB2A1	psi-mi:“MI:0914”(association)	0.530
DCT	CANX	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
ZDHHC1	PIK3CA	psi-mi:“MI:0914”(association)	0.530
ZNRF3	LGR4	psi-mi:“MI:0915”(physical association)	0.500
RSPO1	LGR4	psi-mi:“MI:0915”(physical association)	0.400
LGR4	Rspo2	psi-mi:“MI:0915”(physical association)	0.400
LGR4	Rspo3	psi-mi:“MI:0915”(physical association)	0.400
LGR4	RSPO4	psi-mi:“MI:0915”(physical association)	0.400
Cep152	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350
LGR4	FZD7	psi-mi:“MI:0914”(association)	0.350
FZD5	FZD7	psi-mi:“MI:0914”(association)	0.350
FZD7	LRP5	psi-mi:“MI:0914”(association)	0.350
BIRC2	UMAD1	psi-mi:“MI:0914”(association)	0.350
PDCD1	TMEM223	psi-mi:“MI:0914”(association)	0.350
NRG1	HS6ST1	psi-mi:“MI:0914”(association)	0.350
RNF19B		psi-mi:“MI:0914”(association)	0.350
CD79B	GOLIM4	psi-mi:“MI:0914”(association)	0.350

BioGRID (312): LGR4 (Affinity Capture-MS), LGR4 (Affinity Capture-MS), RSPO4 (Reconstituted Complex), RSPO2 (Reconstituted Complex), RSPO3 (Reconstituted Complex), RSPO1 (Reconstituted Complex), LGR4 (Affinity Capture-MS), LGR4 (Affinity Capture-MS), LGR4 (Affinity Capture-MS), LGR4 (Affinity Capture-MS), LGR4 (Affinity Capture-MS), LGR4 (Affinity Capture-MS), LGR4 (Affinity Capture-MS), LGR4 (Affinity Capture-MS), LGR4 (Affinity Capture-MS)

ESM2 similar proteins: A1A4H9, A2ARI4, A4IIW9, B0BLW3, B1H234, D3ZAL8, D3ZTV3, D4A6D8, D4A7P2, D4AC13, E5DHB5, E7FE13, F1MLX5, F1MT22, F1NUK7, F7D3V9, O43155, O43300, O75473, P0DM44, P21463, P47750, P56495, Q27987, Q3UVD5, Q5R6B1, Q5R6T0, Q5RDJ4, Q66HV9, Q6RKD8, Q80ZD7, Q80ZD8, Q86UE6, Q86VH5, Q86WK6, Q8BGA3, Q8BGT1, Q8BLU0, Q8BZ81, Q8K377

Diamond homologs: A2ARI4, A8WHP9, B0BLW3, D4AC13, E5DHB5, E7FE13, F1MLX5, F1MT22, F7D3V9, O02833, O75473, P0DM44, P70193, Q3UVD5, Q5NVQ6, Q8BGX3, Q8N967, Q96JA1, Q9BXB1, Q9HBX8, Q9Z1P4, Q9Z2H4, A3KNN3, A4IFA6, A4IIW9, A6H789, A6H793, A6NJW4, E9Q7T7, G3XA59, G5EFX6, O14498, O75093, O75094, O88186, O88279, O88280, O94813, P0C6S8, P14770

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RSPO2	up-regulates	LGR4	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 74 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of FZD by ubiquitination	5	63.3×	3e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

150 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	105
Likely benign	15
Benign	6

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1321210	NM_018490.5(LGR4):c.286A>G (p.Ile96Val)	Pathogenic
1321211	NM_018490.5(LGR4):c.2531A>G (p.Asp844Gly)	Pathogenic

SpliceAI

2707 predictions. Top by Δscore:

Variant	Effect	Δscore
11:27371696:TACCT:T	acceptor_loss	1.0000
11:27371698:CCTGA:C	acceptor_loss	1.0000
11:27371699:CT:C	acceptor_loss	1.0000
11:27371700:T:C	acceptor_loss	1.0000
11:27373546:CACA:C	donor_loss	1.0000
11:27373547:ACAC:A	donor_loss	1.0000
11:27373548:CACCT:C	donor_loss	1.0000
11:27373549:ACC:A	donor_loss	1.0000
11:27373550:C:A	donor_loss	1.0000
11:27373675:CT:C	acceptor_gain	1.0000
11:27373973:A:AC	donor_gain	1.0000
11:27373974:C:CC	donor_gain	1.0000
11:27376297:A:AC	donor_gain	1.0000
11:27376298:C:CC	donor_gain	1.0000
11:27378695:A:AC	donor_gain	1.0000
11:27378696:C:CC	donor_gain	1.0000
11:27380338:CT:C	acceptor_gain	1.0000
11:27380342:T:C	acceptor_gain	1.0000
11:27380344:A:C	acceptor_gain	1.0000
11:27380350:T:TC	acceptor_gain	1.0000
11:27380893:A:AC	donor_gain	1.0000
11:27380894:C:CC	donor_gain	1.0000
11:27380894:CAT:C	donor_gain	1.0000
11:27380894:CATAG:C	donor_gain	1.0000
11:27380962:ATCCT:A	acceptor_gain	1.0000
11:27380963:TCCT:T	acceptor_gain	1.0000
11:27380964:CCTC:C	acceptor_gain	1.0000
11:27380965:CT:C	acceptor_gain	1.0000
11:27380966:TC:T	acceptor_loss	1.0000
11:27380967:C:CC	acceptor_gain	1.0000

AlphaMissense

6239 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:27382197:A:T	L250H	0.999
11:27384402:A:G	L208P	0.999
11:27385253:A:G	L206P	0.999
11:27385391:A:G	L160P	0.999
11:27385397:A:G	L158P	0.999
11:27368442:A:G	C761R	0.998
11:27369087:A:G	W546R	0.998
11:27369087:A:T	W546R	0.998
11:27371628:A:C	C522W	0.998
11:27371629:C:G	C522S	0.998
11:27371630:A:T	C522S	0.998
11:27372370:A:G	C470R	0.998
11:27373598:G:C	N444K	0.998
11:27373598:G:T	N444K	0.998
11:27380271:A:G	L324P	0.998
11:27380640:A:G	L301P	0.998
11:27380696:A:C	N282K	0.998
11:27380696:A:T	N282K	0.998
11:27380904:A:G	L274S	0.998
11:27380951:A:C	N258K	0.998
11:27380951:A:T	N258K	0.998
11:27382188:A:G	L253P	0.998
11:27382197:A:G	L250P	0.998
11:27385309:G:C	N187K	0.998
11:27385309:G:T	N187K	0.998
11:27385319:A:G	L184P	0.998
11:27385325:A:G	L182P	0.998
11:27385381:G:C	N163K	0.998
11:27385381:G:T	N163K	0.998
11:27385453:G:C	N139K	0.998

dbSNP variants (sampled 300 via entrez): RS1000012674 (11:27415378 C>T), RS1000015815 (11:27474622 C>T), RS1000016333 (11:27443626 A>G), RS1000042842 (11:27428459 A>G), RS1000116512 (11:27436429 A>T), RS1000143001 (11:27390521 G>C), RS1000148953 (11:27434804 A>C), RS1000188266 (11:27436811 A>G), RS1000212609 (11:27388688 C>T), RS1000257138 (11:27383024 TAAAAAATA>T,TAAAAAATAAAAAAATA), RS1000295638 (11:27429785 G>C), RS1000355429 (11:27395343 T>C), RS1000356952 (11:27375695 A>C), RS1000361561 (11:27422786 C>A,T), RS1000382688 (11:27467916 C>A)

Disease associations

OMIM: gene MIM:606666 | disease phenotypes: MIM:619613

GenCC curated gene-disease

Disease	Classification	Inheritance
syndromic disease	Moderate	Semidominant
delayed puberty, self-limited	Limited	Unknown

Mondo (2): delayed puberty, self-limited (MONDO:0859205), syndromic disease (MONDO:0002254)

Orphanet (0):

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000044	Hypogonadotropic hypogonadism
HP:0000823	Delayed puberty
HP:0002750	Delayed skeletal maturation
HP:0030341	Decreased circulating follicle stimulating hormone concentration
HP:0030344	Decreased circulating luteinizing hormone level
HP:0040171	Decreased serum testosterone concentration

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST002011_2	Bone mineral density	1.000000e-10
GCST002493_1	Bone mineral density (paediatric, skull)	8.000000e-06
GCST002493_7	Bone mineral density (paediatric, skull)	2.000000e-17
GCST002493_8	Bone mineral density (paediatric, skull)	3.000000e-13
GCST002541_85	Menarche (age at onset)	3.000000e-11
GCST002828_23	Urate levels in obese individuals	5.000000e-06
GCST004485_23	Survival in pancreatic cancer	3.000000e-06
GCST006661_85	Male-pattern baldness	2.000000e-09
GCST006979_784	Heel bone mineral density	6.000000e-11
GCST006988_144	Blond vs. brown/black hair color	1.000000e-13
GCST008180_17	Spontaneous preterm birth with premature rupture of membranes	7.000000e-06
GCST009267_13	Dental caries (decayed, missing and filled teeth)	3.000000e-06
GCST010703_169	Brain morphology (MOSTest)	5.000000e-09

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche
EFO:0004531	urate measurement
EFO:0000638	overall survival
EFO:0009270	heel bone mineral density
EFO:0003924	hair color
EFO:0006917	spontaneous preterm birth
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D013577	Syndrome	C23.550.288.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4665590 (PROTEIN-PROTEIN INTERACTION), CHEMBL6067594 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — LGR4, LGR5, LGR6

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
R-spondin-2	Full agonist	12.52	pEC50
R-spondin-1	Full agonist	10.7	pEC50
R-spondin-4	Full agonist	10.05	pEC50
R-spondin-3	Full agonist	8.66	pKd

CTD chemical–gene interactions

57 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation, affects cotreatment, increases expression, affects expression	5
trichostatin A	affects cotreatment, decreases expression	3
bisphenol A	decreases expression, affects expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	affects expression, decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
hydroquinone	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	increases reaction, affects binding	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
14-deoxy-11,12-didehydroandrographolide	increases expression	1
abrine	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
jinfukang	affects cotreatment, increases expression	1
Bortezomib	decreases expression, increases response to substance	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	increases methylation	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5522447	Binding	Agonist activity at LGR4 (unknown origin) by arrestin technology based assay	Identification of Novel Series of Potent and Selective Relaxin Family Peptide Receptor 1 (RXFP1) Agonists. — J Med Chem

Cellosaurus cell lines

9 cell lines: 7 cancer cell line, 1 transformed cell line, 1 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D7TJ	Ubigene A-549 LGR4 KO	Cancer cell line	Male
CVCL_D8P7	Ubigene HCT 116 LGR4 KO	Cancer cell line	Male
CVCL_D9IJ	Ubigene HEK293 LGR4 KO	Transformed cell line	Female
CVCL_E0GG	Ubigene HeLa LGR4 KO	Cancer cell line	Female
CVCL_KX87	PathHunter CHO-K1 LGR4 beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_SV49	HAP1 LGR4 (-) 1	Cancer cell line	Male
CVCL_SV50	HAP1 LGR4 (-) 2	Cancer cell line	Male
CVCL_SV51	HAP1 LGR4 (-) 3	Cancer cell line	Male
CVCL_SV52	HAP1 LGR4 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

25 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00027456	PHASE2	COMPLETED	Leptin to Treat Severe Insulin Resistance - Pilot Study
NCT00213447	Not specified	COMPLETED	T Cell Response in Hypersensitivity Syndrome
NCT02240888	Not specified	COMPLETED	Vaccination in Inflammatory Rheumatic Disease (VACCIMIL). The Impact of Antirheumatic Treatment on Antibody Response
NCT02526082	Not specified	ACTIVE_NOT_RECRUITING	Long-term Follow-up of the Helsinki Businessmen Study
NCT02637518	Not specified	UNKNOWN	Comprehensive Validation of Frailty Assessment Tools in Older Adults in Different Clinical and Social Settings
NCT02971072	Not specified	COMPLETED	Neurophysiology of Weakness and Exercise in Rotator Cuff Tendinopathy
NCT02974569	Not specified	COMPLETED	Improving Symptom Self-management in Adolescents & Young Adults With Cancer
NCT03265561	Not specified	COMPLETED	Spinal Infection Management With Structural Allograft
NCT04190342	Not specified	COMPLETED	Effects of a Traditional Chinese Exercise Program on Symptom Cluster in Breast Cancer Patients
NCT04874584	Not specified	COMPLETED	Culturally Tailored Nurse Coaching Study for Cancer Symptom Management
NCT04909489	Not specified	UNKNOWN	PDR and SKYD of Dyslipidemia’s Characteristics From the Oxidative Stress Enhancement Caused by Inhibition of Serine Metabolic Pathway
NCT05218122	Not specified	UNKNOWN	Characteristics of LKDS and PBSS of KOA Based on the Enhancement of Inflammatory Response by TGF-β/Smad Pathway Inhibited
NCT05266118	Not specified	COMPLETED	Patient Reported Symptoms the First Week After Intensive Care Unit Discharge and up to Hospital Discharge
NCT05321966	Not specified	COMPLETED	The Effect of Video Training on Symptom Burden Patients Undergoing Hemodialysis Treatment
NCT05818748	Not specified	UNKNOWN	Effect Of Virtual Reality Distraction on Symptom Control and Anxiety in Children With Leukemia
NCT05837988	Not specified	UNKNOWN	Construction of Symptom Network in Maintenance Hemodialysis Patients
NCT06143436	Not specified	UNKNOWN	TCM Constitution, Pattern Types, and Disease Factors in Primary Lung Cancer.
NCT06222008	Not specified	UNKNOWN	Study on Symptom Clusters During Chemotherapy in Ovarian Cancer Patients With Different Chinese Medicine Constitution
NCT06412107	Not specified	COMPLETED	Somatic Acupressure for Symptom Cluster Management in Breast Cancer Survivors
NCT06847360	Not specified	RECRUITING	Home-based Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) for IBS Pain
NCT07281300	Not specified	RECRUITING	Mindfulness-Oriented Respiratory Distress Symptom Intervention for Lung Cancer
NCT07315672	Not specified	RECRUITING	Acupressure for Cough in Lung Cancer Survivors
NCT07479654	Not specified	NOT_YET_RECRUITING	AI-Enabled Frailty Risk Prediction in Adult Congenital Heart Disease
NCT07495358	Not specified	NOT_YET_RECRUITING	Development and Usability Evaluation of a Knowledge Graph-Based Symptom Management System for Patients With Breast Cancer Undergoing Chemotherapy
NCT07576114	Not specified	RECRUITING	Comparison of Gluteal Muscle Activation and Core Strengthening in Dead Butt Syndrome Syndrome