Affinage

LGR4

Leucine-rich repeat-containing G-protein coupled receptor 4 · UniProt Q9BXB1

Length
951 aa
Mass
104.5 kDa
Annotated
2026-06-10
100 papers in source corpus 44 papers cited in narrative 44 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LGR4 is a leucine-rich-repeat-containing seven-transmembrane receptor that functions as the high-affinity engagement receptor for R-spondins to potentiate Wnt/β-catenin signaling, and serves more broadly as a hub for stem cell maintenance, development, immune regulation, and metabolic homeostasis across many tissues (PMID:21693646, PMID:27088858, PMID:21508962). R-spondins bind the concave surface of the horseshoe-shaped LGR4 ectodomain through their two furin-like cysteine-rich domains in a one-site binding mode, as resolved by multiple crystal structures (PMID:23756652, PMID:23891289, PMID:25480784). Rather than coupling to heterotrimeric G proteins or β-arrestin upon R-spondin stimulation, LGR4 acts non-canonically: through its seven-transmembrane domain it forms a constitutive complex with the membrane E3 ubiquitin ligases ZNRF3/RNF43, and R-spondin engagement drives clearance of these ligases to protect Wnt receptors and enhance LRP6 phosphorylation, with LGR4 serving as the "engagement" receptor and ZNRF3/RNF43 as the "effector" receptors in a dual-receptor model (PMID:21693646, PMID:24165923, PMID:33262293). Downstream, RSPO-LGR4 recruits the scaffold IQGAP1 to bridge the receptor to the Wnt signalosome and promote MEK1/2-mediated LRP5/6 phosphorylation, also driving actin/cytoneme-based protrusions (PMID:24639526, PMID:25653388). Beyond R-spondins, LGR4 binds additional ligands—RANKL, where it competes with RANK and activates Gαq-GSK3β signaling to suppress NFATc1 and osteoclastogenesis (PMID:27064449); nidogen-2, which biased-activates Gαq-PKCα-AMPKα1 signaling to counteract vascular calcification (PMID:36354004); and norrin, which stimulates LGR4-dependent Wnt signaling (PMID:23444378). LGR4 also signals independently of Wnt by directly interacting with EGFR to block its ubiquitination and sustain its activation (PMID:34099494). Through these activities LGR4 governs intestinal, gastric, mammary, and leukemic stem cell self-renewal, liver metabolic zonation, osteoblast/osteoclast balance, macrophage polarization, and reproductive development, and its mutations cause delayed puberty via impaired Wnt/β-catenin signaling in GnRH neurons (PMID:27088858, PMID:21508962, PMID:32493844, PMID:32559496).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2011 High

    Established LGR4 as the high-affinity R-spondin receptor that potentiates Wnt/β-catenin signaling through a non-canonical mechanism that does not use classical GPCR effectors, resolving how RSPOs amplify Wnt.

    Evidence Binding, LRP6 phosphorylation, G-protein and β-arrestin coupling assays in mammalian cells and Xenopus, plus domain mapping and siRNA depletion

    PMID:21693646 PMID:21909076 PMID:22815884

    Open questions at the time
    • Did not resolve the structural basis of the RSPO interface
    • The intracellular effector translating ligand binding into Wnt potentiation was unidentified
  2. 2013 High

    Defined the atomic basis of receptor-ligand recognition, showing RSPO furin-like domains dock onto the concave face of the LGR4 horseshoe ectodomain via a one-site binding mode.

    Evidence X-ray crystallography of LGR4 ECD alone and with RSPO1, with mutagenesis validation; confirmed by independent structures

    PMID:23756652 PMID:23891289 PMID:25480784

    Open questions at the time
    • Structures covered the ectodomain only, not the seven-transmembrane region or full-length receptor
    • Did not explain how ligand binding signals across the membrane
  3. 2013 High

    Resolved the downstream signaling machinery, establishing a dual-receptor model where LGR4 engages RSPO and clears the E3 ligases ZNRF3/RNF43, and identifying IQGAP1 as the intracellular scaffold linking LGR4 to the Wnt signalosome.

    Evidence Mutagenesis of distinct binding motifs, Co-IP, membrane clearance assays, in vitro ternary complex reconstitution, and MEK/LRP6 phosphorylation assays

    PMID:24050775 PMID:24165923 PMID:24639526

    Open questions at the time
    • Stoichiometry of the receptor-ligase complex was not yet defined
    • Constitutive versus ligand-dependent assembly of the complex was unclear
  4. 2020 Medium

    Distinguished LGR4 from LGR5 mechanistically, showing LGR4 forms a constitutive ZNRF3/RNF43 complex via its seven-transmembrane domain as a 2:2 dimer accommodating bivalent RSPO, whereas LGR5 does not bind the E3 ligases.

    Evidence Co-IP, proximity ligation, TR-FRET, domain-swapping, and monovalent/bivalent RSPO binding assays in whole cells

    PMID:33262293 PMID:37402772

    Open questions at the time
    • No full-length structure of the receptor-ligase dimer
    • Functional consequences of dimerization for signaling output not fully mapped
  5. 2016 High

    Expanded LGR4 beyond Wnt by identifying it as a second RANKL receptor that competes with RANK and signals via Gαq-GSK3β to suppress osteoclastogenesis, revealing a G-protein-coupled mode distinct from RSPO signaling.

    Evidence Binding competition, Lgr4 KO and conditional KO mice, osteoclast differentiation, Gαq/GSK3-β signaling assays, and in vivo soluble LGR4-ECD therapy

    PMID:27064449

    Open questions at the time
    • Why RANKL triggers Gαq coupling while RSPO does not was unexplained
    • Structural basis of RANKL–LGR4 interaction not determined
  6. 2022 High

    Identified nidogen-2 as a further endogenous ligand activating biased Gαq-PKCα-AMPKα1 signaling, demonstrating that LGR4 integrates multiple ligands into distinct G-protein-dependent outputs in the vasculature.

    Evidence Membrane interactome, Co-IP, SPR, G-protein signaling assays, and in vivo vascular calcification models with LGR4 KO

    PMID:36354004

    Open questions at the time
    • Ligand-binding site on LGR4 for nidogen-2 not structurally defined
    • How distinct ligands selectively bias different G-protein pathways unresolved
  7. 2021 High

    Established a Wnt-independent function whereby LGR4 directly binds EGFR and blocks its ubiquitination and degradation, decoupling LGR4's oncogenic activity from its canonical Wnt-potentiating role.

    Evidence Wnt-deactivation experiments, Wnt-incompetent LGR4 mutants, Co-IP, ubiquitination assays, and in vivo metastasis models

    PMID:34099494

    Open questions at the time
    • Whether EGFR stabilization requires a ligand or is constitutive is unclear
    • Earlier reports of EGFR-pathway effects via HB-EGF transactivation versus direct interaction not reconciled
  8. 2020 Medium

    Linked LGR4 to human disease by showing LGR4 mutations cause delayed puberty through impaired Wnt/β-catenin signaling required for GnRH neuron formation and migration.

    Evidence Whole-exome sequencing, LGR4 mutant protein trafficking/degradation assays, Lgr4 KO mice, zebrafish knockdown, and Wnt reporter lineage tracing

    PMID:32493844

    Open questions at the time
    • Single-cohort genetic evidence
    • Direct rescue of the neuronal phenotype by wild-type LGR4 not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single receptor selects among R-spondin (non-G-protein), RANKL/nidogen-2 (Gαq-coupled), and EGFR-stabilizing modes from the same seven-transmembrane scaffold remains unresolved.
  • No full-length structure capturing transmembrane signaling states
  • Determinants of ligand-biased G-protein coupling versus E3-ligase recruitment are unknown
  • Mechanism switching between Wnt-dependent and Wnt-independent outputs is uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 3 GO:0048018 receptor ligand activity 2 GO:0060090 molecular adaptor activity 1
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 3
Partners
EGFRIQGAP1NID2RNF43RSPO1RSPO2RSPO3ZNRF3
Complex memberships
LGR4–ZNRF3/RNF43 receptor complexRSPO–LGR4–ZNRF3 ternary complex

Evidence

Reading pass · 44 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 LGR4 binds R-spondins (RSPOs) with high affinity and mediates potentiation of Wnt/β-catenin signaling by enhancing Wnt-induced LRP6 phosphorylation. Neither LGR4 nor LGR5 couples to heterotrimeric G proteins or β-arrestin when stimulated by RSPOs, indicating a unique non-canonical GPCR mechanism. Binding assays, LRP6 phosphorylation assays, G-protein and β-arrestin coupling assays in mammalian cells Proceedings of the National Academy of Sciences of the United States of America High 21693646
2011 R-spondins bind to LGR4 and LGR5 via their Furin domains and promote both Wnt/β-catenin and Wnt/PCP signaling. R-spondin-triggered β-catenin signaling via LGR4 requires Clathrin-mediated (not Caveolin-mediated) endocytosis. Gain- and loss-of-function experiments in mammalian cells and Xenopus embryos; domain mapping; endocytosis inhibitor experiments EMBO reports High 21909076
2012 LGR4 is the cognate receptor for R-spondin; siRNA depletion of LGR4 completely abolishes RSPO-induced β-catenin signaling. RSPO binds the extracellular domain of LGR4. No coupling of LGR4 to heterotrimeric G proteins was detected in RSPO-treated cells. Unbiased siRNA screen, overexpression/depletion, binding assays with extracellular domain, G-protein coupling assay, Lgr4-/- crypt culture PloS one High 22815884
2013 Crystal structure of LGR4 ectodomain (ECD) alone and in complex with RSPO1 N-terminal fragment (two furin-like cysteine-rich domains, FU-CRD1 and FU-CRD2) was determined. LGR4-ECD adopts a TLR horseshoe structure and uses its concave surface near the N-termini to bind RSPO1. Both FU-CRD1 and FU-CRD2 contribute to LGR4 binding. Critical RSPO1 residues for biological activity were identified by mutagenesis. X-ray crystallography of LGR4 ECD–RSPO1 complex; mutagenesis and cellular binding/signaling assays Genes & development High 23756652
2013 Crystal structure of Lgr4 ectodomain alone and bound to Rspo1 was determined. The receptor adopts an extended horseshoe LRR architecture and binds Rspo1 furin-like repeats via its concave side, providing molecular details of receptor activation. X-ray crystallography of Lgr4 ECD and Lgr4–Rspo1 complex Structure High 23891289
2014 Crystal structure of LGR4–Rspo1 complex determined using hybrid LRR technique. Rspo1 binds in the concave surface of LGR4 through electrostatic and hydrophobic interactions. All Rspo1-binding residues are conserved in LGR4–6, suggesting identical binding surface. LGR4 uses a one-site binding model distinct from the two-step mechanism of LGR1–3. X-ray crystallography with hybrid LRR fusion protein; structural comparison The Journal of biological chemistry High 25480784
2013 R-spondin interacts with ZNRF3/RNF43 and LGR4 through distinct motifs. Both LGR4 and ZNRF3 binding motifs are required for R-spondin-induced LGR4/ZNRF3 complex formation, ZNRF3 membrane clearance, and Wnt signaling activation. LGR4 functions as an engagement receptor while ZNRF3/RNF43 function as effector receptors in a dual receptor model. Mutagenesis of distinct binding motifs, Co-IP, membrane clearance assays, Wnt signaling assays EMBO reports High 24165923
2013 RSPO-LGR4 recruits the intracellular scaffold protein IQGAP1, which bridges RSPO-LGR4 to the Wnt signalosome through enhanced IQGAP1–DVL interaction following RSPO stimulation. This complex potentiates canonical Wnt/β-catenin signaling via MEK1/2-mediated LRP5/6 phosphorylation and non-canonical signaling through actin dynamics regulation. Co-IP identification of IQGAP1 as LGR4-interacting protein, pulldown, RSPO stimulation assays, MEK/LRP6 phosphorylation assays, actin dynamics assays Proceedings of the National Academy of Sciences of the United States of America High 24639526
2013 Reconstitution of RSPO:LGR4:ZNRF3 ternary complexes was achieved with bacterially produced recombinant proteins. RSPO2 and RSPO3 formed detectable ternary complexes with LGR4 LRR1-14 and ZNRF3 ECD; RSPO4:ZNRF3 complexes were not detected. RSPOs bound LGR4 with nanomolar affinities in order RSPO4 > RSPO2 > RSPO3 > RSPO1. In vitro reconstitution with recombinant proteins, TR-FRET binding assay, native gel electrophoretic mobility shift assay, cell-based signaling assay Biochemistry High 24050775
2016 LGR4 is a second receptor for RANKL (in addition to RANK). LGR4 competes with RANK to bind RANKL and suppresses canonical RANK signaling. RANKL binding to LGR4 activates Gαq and GSK3-β signaling, suppressing NFATc1 expression and activity to negatively regulate osteoclastogenesis. Soluble LGR4 ECD binds RANKL and inhibits osteoclast differentiation in vivo. Binding competition assays, Lgr4 knockout and conditional knockout mice, osteoclast differentiation assays, Gαq/GSK3-β signaling assays, in vivo osteoporosis models with LGR4-ECD treatment Nature medicine High 27064449
2020 Full-length LGR4 forms a tight constitutive complex with ZNRF3 and RNF43 even without RSPO, whereas LGR5 does not interact with either E3 ligase with or without RSPO. The seven-transmembrane domain of LGR4 confers interaction with E3 ligases (shown by domain-swapping experiments). LGR4 and LGR5 exist as homodimers on the cell surface; LGR5 interacts with FZD and LRP6 to enhance LRP6 phosphorylation. Coimmunoprecipitation, proximity ligation assay, competition binding, time-resolved FRET, domain-swapping experiments in whole cells Science signaling High 33262293
2023 LGR4 and RNF43/ZNRF3 form a 2:2 dimer complex that accommodates bivalent RSPO binding with high affinity; LGR5 forms a homodimer that does not complex with E3 ligases and shows similar affinity for monovalent and bivalent RSPO forms. Co-expression of ZNRF3 with LGR4 (but not LGR5) greatly increased binding affinity for monovalent RSPO. Whole-cell binding assays with monovalent/bivalent RSPO ligands, TR-FRET, co-expression experiments Scientific reports Medium 37402772
2013 Norrin (Norrie disease gene product, vertebrate ortholog of insect burs/pburs) is a ligand for LGR4 that stimulates Wnt signaling mediated by LGR4 but not by LGR5 or LGR6 in mammalian cells. Binding studies showed norrin interactions with LGR4, 5, and 6. Mutagenesis categorized Norrie disease mutations into subgroups with distinct defects in signaling through three binding partners. Cell-based Wnt signaling assays, binding studies, site-directed mutagenesis of norrin Journal of cell science Medium 23444378
2022 Nidogen-2 is a novel endogenous ligand of LGR4 (KD ~26.77 nM, measured by surface plasmon resonance). Nidogen-2 binding to LGR4 biased-activates Gαq–PKCα–AMPKα1 signaling to counteract VSMC osteogenic transition and vascular calcification. LGR4 deficiency in VSMCs abolished the protective effect of nidogen-2. Unbiased membrane protein interactome, Co-IP, flow cytometric binding assay, surface plasmon resonance, G protein signaling assays, VSMC calcification assays, in vivo vascular calcification models with LGR4 KO Circulation research High 36354004
2022 RSPO2 and RANKL both signal through LGR4 to modulate the WNT inhibitor DKK1 via Gαq and β-catenin signaling, promoting osteoclastic premetastatic niche formation. Soluble LGR4-ECD acting as a decoy receptor for RSPO2 and RANKL reduced bone metastasis in a mouse model. Unbiased GPCR ligand/agonist screening, binding assays, signaling pathway analysis (Gαq, β-catenin, DKK1), mouse bone metastasis models with LGR4-ECD treatment The Journal of clinical investigation Medium 34847079
2016 LGR4/5 LOF in liver disrupts Wnt/β-catenin signaling and hepatic metabolic zonation. The RSPO-LGR4/5-ZNRF3/RNF43 module is a master regulator of Wnt/β-catenin-mediated liver zonation; RSPO1-induced expansion of Wnt signaling gradient requires LGR4/5. Liver-specific Lgr4/5 LOF mice, RSPO1 protein treatment, ZNRF3/RNF43 LOF mice, functional Wnt reporter assays in liver Nature cell biology High 27088858
2014 LGR4 potentiates Wnt/β-catenin signaling through IQGAP1 in lung adenocarcinomas with aberrant RSPO3 expression. Knockdown of LGR4 or IQGAP1 reduced tumor growth and metastasis in vivo. Knockdown of LGR4/IQGAP1 in lung cancer cell lines, in vitro proliferation/migration assays, in vivo xenograft/metastasis models Oncogene Medium 25531322
2021 LGR4 promotes cancer cell metastasis through a Wnt-independent mechanism involving direct interaction with EGFR. LGR4 blocks EGFR ubiquitination and degradation, resulting in persistent EGFR activation. LGR4 mutants unable to potentiate Wnt signaling still promoted breast cancer migration/invasion in vitro and metastasis in vivo. Pharmacological and genetic Wnt deactivation, LGR4 mutant overexpression, multiomic screening, Co-IP of LGR4-EGFR, ubiquitination assays, in vitro migration/invasion, in vivo metastasis models Cancer research High 34099494
2008 Gpr48/LGR4 inactivation impairs definitive erythropoiesis at midgestation through down-regulation of the ATF4 signaling pathway via the cAMP-PKA-CREB pathway. Gpr48-/- fetal livers showed decreased c-Myc and cyclin D1 expression with suppressed proliferation. Gpr48-/- mice, histological analysis, blood smear assays, real-time PCR for hemoglobin chains and signaling components, proliferation/apoptosis assays The Journal of biological chemistry Medium 18955481
2008 GPR48/LGR4 regulates epithelial cell proliferation and migration during eyelid development through activation of the EGFR signaling pathway. Phosphorylation of EGFR was dramatically decreased in Gpr48-/- keratinocytes and developing eyelids, causing reduced F-actin formation, delayed leading-edge extension, and EOB phenotype. Gpr48-/- mice, histology, scanning EM, scratch assay, Western blot and immunostaining for EGFR phosphorylation Investigative ophthalmology & visual science Medium 18487371
2010 GPR48/LGR4 mediates keratinocyte proliferation through HB-EGF-mediated EGFR transactivation. HB-EGF was reduced in Gpr48-/- cell culture medium; addition of HB-EGF restored EGFR, ERK, and STAT3 phosphorylation and cell proliferation. EGFR tyrosine kinase inhibitor AG1478 blocked GPR48-mediated cellular processes. EGFR inhibitor treatment, conditioned media immunodepletion of EGFR ligands, HB-EGF supplementation rescue, Western blot for EGFR/ERK/STAT3 phosphorylation FEBS letters Medium 20732323
2013 Lgr4 ablation reduces adiposity and promotes white-to-brown fat switch by potentiating brown adipocyte differentiation, partly through Rb1 reduction. Lgr4 homozygous mutant mice show increased energy expenditure and express BAT markers in WAT depots. Lgr4 homozygous mutant mice, stromal vascular fraction differentiation assays, Rb1 expression analysis, metabolic phenotyping Nature cell biology Medium 24212090
2011 Lgr4 gene inactivation reduces intestinal epithelial cell proliferation by 50% and Paneth cell terminal differentiation by 80%. LGR4-deficient but not LGR5-deficient crypts die in ex vivo culture with downregulation of stem cell markers and Wnt target genes including Lgr5. Partial rescue with LiCl (GSK3β inhibitor) but not Wnt agonists identifies LGR4 as a permissive factor in the intestinal Wnt pathway. Lgr4 knockout mice, ex vivo crypt culture, LiCl rescue, quantification of stem cell markers and Wnt targets EMBO reports Medium 21508962
2013 Lgr4 deficiency in macrophages increases CD14 (TLR2/4 co-receptor) expression at the transcriptional level by decreasing CREB binding activity, thereby potentiating TLR2/4-associated cytokine production and increasing susceptibility to septic shock. Lgr4-/- mice, cytokine production assays, CREB binding assays, CD14 expression analysis in Lgr4-deficient macrophages The Journal of biological chemistry Medium 23589304
2018 Lgr4 promotes macrophage M2 polarization through Rspo/Lgr4/Erk/Stat3 signaling. Myeloid-specific Lgr4 knockout mice show reduced M2 tumor-associated macrophages and increased CD8+ T cell infiltration in tumors. Blocking Rspo/Lgr4/Erk/Stat3 signaling with LGR4-ECD or anti-Rspo1 antibody overcame resistance to anti-PD-1 therapy. Myeloid-specific conditional Lgr4 KO mice, tumor models, ERK/STAT3 signaling analysis, macrophage polarization assays Cancer research Medium 29967265
2020 Macrophage-specific Lgr4 knockout mice show improved post-MI cardiac repair with reduced inflammatory macrophages. Lgr4-mediated proinflammatory programming in macrophages occurs via enhancement of CREB-mediated c-Fos, Fosl1, and Fosb transactivation to activate AP-1. Macrophage-specific Lgr4 KO mice, MI model, transcriptomic profiling, AP-1/CREB activity assays, immune cell quantification Circulation research Medium 32600176
2014 Lgr4 regulates corpus luteum maturation through WNT-mediated EGFR-ERK signaling. In Lgr4-/- granulosa-lutein cells, EGFR-ERK signaling activity is attenuated. WNT/β-catenin downstream target MMP9 is reduced, impairing activation of EGF-like factors needed for EGFR-ERK activation and steroidogenesis. Lgr4-/- mice, primary granulosa cell culture, EGFR-ERK signaling assays, MMP9 inhibitor treatment, HB-EGF rescue Endocrinology Medium 24877628
2013 LGR4 controls mammary gland development and stem cell repopulation capacity through activation of Sox2 via the Lgr4/Wnt/β-catenin/Lef1 pathway. ChIP analysis showed Sox2 expression is controlled by this pathway; Sox2 overexpression restored mammary regeneration potential of Lgr4-/- stem cells. Lgr4-/- mice, mammosphere assays, Wnt signaling analysis, ChIP assay for β-catenin/Lef1 at Sox2 promoter, Sox2 overexpression rescue, in vivo mammary regeneration assay Stem cells Medium 23712846
2013 Lgr4 is selectively expressed in peritubular myoid cells (PMCs) of testes, and Lgr4 loss arrests germ cells at meiosis I. Lgr4 in PMCs signals through Wnt/β-catenin to support spermatogenesis; re-activation of Wnt/β-catenin (Apc(min/+) cross or GSK3β inhibitor) partially rescued the Lgr4-/- testis phenotype. Lgr4-/- mice, Apc(min/+) cross, GSK3β inhibitor treatment, PMC gene expression analysis, meiosis staging Development Medium 23533175
2019 The miR-34–LGR4 axis regulates keratinocyte inflammatory response via GSK-3β-induced p65 serine 468 phosphorylation, modulating NF-κB signaling pathway activity. LGR4 was identified as a direct target of miR-34a and miR-34c mediating their proinflammatory function. Lgr4 knockout mice showed impaired wound closure with enhanced inflammation. miR-34 target validation, Lgr4 KO mice wound model, NF-κB signaling assays including p65 phosphorylation at Ser468, wound healing assays The Journal of investigative dermatology Medium 31376385
2013 RSPO-LGR4 signaling activates WNT/β-catenin pathway to induce follistatin (Fst) expression in myoblasts, which then antagonizes TGF-β signaling to promote myogenic differentiation. LGR4 depletion severely disrupts myogenic differentiation and abolishes RSPO2 response. Specific TCF/LEF1 binding sites within Fst promoter and intron 1 were required for RSPO2/WNT-induced Fst expression. LGR4 siRNA depletion in C2C12 myoblasts, RSPO2 stimulation assays, β-catenin activation/inactivation, promoter/ChIP analysis of Fst TCF/LEF1 sites Molecular and cellular biology Medium 24344199
2015 LGR4 (and LGR5) promote formation of long (>80 μm) actin-rich cytoneme-like membrane protrusions through stabilization of nascent filopodia. LGR5-induced cytonemes serve as conduits for β-arrestin-2 and Myosin X transit, linking GPCR signaling to cytoneme-based cell communication. Overexpression of Lgr4/Lgr5 in cells, live imaging, measurement of filopodial/cytoneme lengths, β-arrestin-2 and Myo10 trafficking assays Journal of cell science Medium 25653388
2020 LGR4 deficiency in mice results in delayed puberty with fewer GnRH neurons. LGR4 mutant proteins from delayed puberty patients showed impaired Wnt/β-catenin signaling due to defective protein expression, trafficking, and degradation. Lgr4 knockdown in zebrafish prevented formation and migration of GnRH neurons. Genetic lineage tracing showed strong Lgr4-mediated Wnt/β-catenin signaling activation during GnRH neuron development. Whole-exome sequencing, LGR4 mutant protein functional assays (expression/trafficking/degradation), Lgr4 KO mice, zebrafish lgr4 knockdown, genetic lineage tracing with Wnt/β-catenin reporter JCI insight Medium 32493844
2016 LGR4 expression in multiple myeloma plasma cells is driven by IL-6/STAT3 signaling, allowing MM cells to hijack osteoblast-derived R-spondins and stabilize Wnt co-receptors via inhibition of RNF43/ZNRF3 E3 ligase activity, dramatically increasing Wnt sensitivity. IL-6/STAT3 signaling analysis, LGR4 overexpression in MM cells, R-spondin binding assays, Wnt receptor stabilization assays Proceedings of the National Academy of Sciences of the United States of America Medium 28028233
2022 In gastric stem cells, Rspo3 signaling via Lgr4 (not Lgr5) drives proliferation of stem cells and induces NF-κB activity. Upon H. pylori exposure, Lgr4-driven NF-κB activation causes expansion of the gland base module and chemokine expression in stem cells, leading to hyperplasia and neutrophil recruitment. Conditional Lgr4 KO mice, H. pylori infection model, NF-κB reporter assays, conditional Lgr5 KO comparison The EMBO journal Medium 35767364
2014 LGR4-dependent Wnt/β-catenin signaling transcriptionally upregulates SLC7A11 (a ferroptosis inhibitor), and LGR4-mAb treatment blocks this pathway, sensitizing chemoresistant colorectal cancer cells to ferroptosis. Monoclonal antibody (LGR4-mAb) treatment, colorectal cancer organoid biobank, transcriptomic analysis, SLC7A11 expression assays, ferroptosis sensitivity assays Nature cancer Medium 38291304
2020 RSPO-LGR4 signaling upregulates key self-renewal genes and is essential for leukemia stem cell (LSC) self-renewal in HOXA9-dependent AML. LGR4 is epigenetically upregulated and cooperates with HOXA9. Blocking RSPO3-LGR4 interaction with anti-RSPO3 antibody impairs self-renewal and induces differentiation in patient-derived xenografts without affecting normal HSCs. Patient-derived xenograft (PDX) models, anti-RSPO3 antibody (OMP-131R10) treatment, epigenetic analysis, self-renewal assays, differentiation assays Cancer cell Medium 32559496
2021 Lgr4 promotes aerobic glycolysis and osteoblast differentiation via canonical Wnt/β-catenin signaling by inducing pyruvate dehydrogenase kinase 1 (pdk1) expression. Lgr4 osteoblast-specific KO mice exhibited decreased bone mass and strength with impaired glycolysis. Osteoblast-specific Lgr4 KO mice (Lgr4osb-/-), glucose/lactate metabolism assays, Wnt/β-catenin activation rescue, pdk1 expression analysis Journal of bone and mineral research Medium 33950533
2013 LGR4 in the hypothalamic arcuate nucleus co-localizes with NPY, POMC, and BDNF neurons. Intracerebroventricular injection of Rspo1 or Rspo3 (ligands acting through LGR4) inhibited food intake, with Rspo1 decreasing NPY and increasing POMC expression. Rspo1 and Rspo3 mRNAs were down-regulated by fasting and up-regulated by insulin. In situ hybridization, intracerebroventricular injection, food intake measurement, neuropeptide expression assays Endocrinology Medium 24280058
2014 LGR4 acts as a link between the peripheral circadian clock and lipid metabolism by regulating circadian expression of Mttp (microsomal triglyceride transfer protein) in hepatocytes, thereby controlling plasma triglyceride rhythms. Lgr4 mutant mice, measurement of respiratory exchange ratio and plasma lipid rhythms, circadian gene expression analysis in liver and primary hepatocytes Journal of molecular endocrinology Medium 24353284
2018 LGR4 activation by Rspo1 in hepatocytes reduces TNFα-induced cell death by inhibiting NF-κB nuclear translocation. LGR4 knockdown increased NF-κB-p65 nuclear translocation and caspase-3 levels after acute injury. IKKβ overexpression attenuated Rspo1 protection, and β-catenin disruption reversed protective effects. Liver-specific Lgr4 KO mice, primary hepatocyte culture, TNFα treatment, NF-κB signaling assays, IKKβ overexpression, β-catenin disruption, HIRI and LPS/D-Gal liver injury models American journal of physiology. Gastrointestinal and liver physiology Medium 30406697
2020 Rspo1/Rspo3-LGR4 signaling inhibits hepatic cholesterol synthesis via the AMPKα-SREBP2 pathway. LGR4 knockdown increased hepatic cholesterol synthesis and decreased AMPKα phosphorylation. AMPKα agonist/antagonist experiments confirmed AMPKα as the downstream mediator of Rspos-LGR4 effects on SREBP2 nuclear translocation. Lgr4 and Rspo1/3 knockdown mice, AMPKα agonist/antagonist treatment, AMPKα shRNA, SREBP2 nuclear translocation assays, cholesterol synthesis measurements FASEB journal Medium 32926477
2014 LGR4/GPR48 inactivation down-regulates histone demethylases Jmjd2a and Fbxl10 through cAMP-CREB signaling pathways in embryonic fibroblasts and urinary/reproductive tissues, contributing to WAGR/AGR syndrome-like defects. Lgr4-/- mice, gene expression analysis in MEFs and tissues, cAMP-CREB pathway assays The Journal of biological chemistry Medium 24519938
2006 LGR4/GPR48 loss in male mice leads to failed tube elongation and convolution of efferent ducts and epididymis with dramatically reduced cell proliferation. In efferent ducts, LGR4 inactivation decreases estrogen receptor (ESR1) and SLC9A3 expression, causing water reabsorption failure and rete testis dilation. LGR4 KO mice, histology, cell proliferation assays, gene expression analysis for ESR1 and SLC9A3 Biology of reproduction Medium 17079737

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 R-spondins function as ligands of the orphan receptors LGR4 and LGR5 to regulate Wnt/beta-catenin signaling. Proceedings of the National Academy of Sciences of the United States of America 743 21693646
2011 LGR4 and LGR5 are R-spondin receptors mediating Wnt/β-catenin and Wnt/PCP signalling. EMBO reports 477 21909076
2016 LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption. Nature medicine 289 27064449
2016 The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size. Nature cell biology 269 27088858
2013 Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits. Nature 207 23644456
2019 YAP, but Not RSPO-LGR4/5, Signaling in Biliary Epithelial Cells Promotes a Ductular Reaction in Response to Liver Injury. Cell stem cell 171 31080135
2012 R-Spondin potentiates Wnt/β-catenin signaling through orphan receptors LGR4 and LGR5. PloS one 146 22815884
2018 Inhibition of Rspo-Lgr4 Facilitates Checkpoint Blockade Therapy by Switching Macrophage Polarization. Cancer research 132 29967265
2011 Lgr4 is required for Paneth cell differentiation and maintenance of intestinal stem cells ex vivo. EMBO reports 118 21508962
2013 Ablation of LGR4 promotes energy expenditure by driving white-to-brown fat switch. Nature cell biology 111 24212090
2006 Defective postnatal development of the male reproductive tract in LGR4 knockout mice. Developmental biology 111 16406039
2020 Lgr4 Governs a Pro-Inflammatory Program in Macrophages to Antagonize Post-Infarction Cardiac Repair. Circulation research 109 32600176
2024 Targeted activation of ferroptosis in colorectal cancer via LGR4 targeting overcomes acquired drug resistance. Nature cancer 103 38291304
2013 Structural basis for R-spondin recognition by LGR4/5/6 receptors. Genes & development 100 23756652
2014 RSPO-LGR4 functions via IQGAP1 to potentiate Wnt signaling. Proceedings of the National Academy of Sciences of the United States of America 97 24639526
2020 Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia. Cancer cell 96 32559496
2013 Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R-spondin. EMBO reports 89 24165923
2014 Functional roles of Lgr4 and Lgr5 in embryonic gut, kidney and skin development in mice. Developmental biology 82 24680895
2013 Lgr4 regulates mammary gland development and stem cell activity through the pluripotency transcription factor Sox2. Stem cells (Dayton, Ohio) 82 23712846
2006 LGR4 regulates the postnatal development and integrity of male reproductive tracts in mice. Biology of reproduction 78 17079737
2022 RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis. The Journal of clinical investigation 76 34847079
2006 Up-regulation of GPR48 induced by down-regulation of p27Kip1 enhances carcinoma cell invasiveness and metastasis. Cancer research 76 17178856
2005 Expression pattern of the orphan receptor LGR4/GPR48 gene in the mouse. Histochemistry and cell biology 74 16028069
2017 LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 71 29269400
2006 Leucine-rich repeat-containing G protein-coupled receptor-4 (LGR4, Gpr48) is essential for renal development in mice. Nephron. Experimental nephrology 68 16785743
2019 MicroRNA-34 Family Enhances Wound Inflammation by Targeting LGR4. The Journal of investigative dermatology 64 31376385
2014 Aberrant RSPO3-LGR4 signaling in Keap1-deficient lung adenocarcinomas promotes tumor aggressiveness. Oncogene 64 25531322
2013 Multi-functional norrin is a ligand for the LGR4 receptor. Journal of cell science 64 23444378
2009 Defective development of the gall bladder and cystic duct in Lgr4- hypomorphic mice. Developmental dynamics : an official publication of the American Association of Anatomists 60 19301403
2013 Lgr4 is a key regulator of prostate development and prostate stem cell differentiation. Stem cells (Dayton, Ohio) 59 23897697
2013 Analysis of LGR4 receptor distribution in human and mouse tissues. PloS one 57 24205130
2008 Impaired hair placode formation with reduced expression of hair follicle-related genes in mice lacking Lgr4. Developmental dynamics : an official publication of the American Association of Anatomists 57 18651655
2013 Crystal structures of Lgr4 and its complex with R-spondin1. Structure (London, England : 1993) 56 23891289
2016 LGR4 acts as a key receptor for R-spondin 2 to promote osteogenesis through Wnt signaling pathway. Cellular signalling 50 27140682
2008 Inactivation of G-protein-coupled receptor 48 (Gpr48/Lgr4) impairs definitive erythropoiesis at midgestation through down-regulation of the ATF4 signaling pathway. The Journal of biological chemistry 49 18955481
2017 RSPO3-LGR4 Regulates Osteogenic Differentiation Of Human Adipose-Derived Stem Cells Via ERK/FGF Signalling. Scientific reports 47 28220828
2021 Lgr4 promotes aerobic glycolysis and differentiation in osteoblasts via the canonical Wnt/β-catenin pathway. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 46 33950533
2008 GPR48 regulates epithelial cell proliferation and migration by activating EGFR during eyelid development. Investigative ophthalmology & visual science 46 18487371
2013 Regulation of the follistatin gene by RSPO-LGR4 signaling via activation of the WNT/β-catenin pathway in skeletal myogenesis. Molecular and cellular biology 45 24344199
2007 Eye-open at birth phenotype with reduced keratinocyte motility in LGR4 null mice. FEBS letters 45 17850793
2016 Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins. Proceedings of the National Academy of Sciences of the United States of America 44 28028233
2013 Lgr4 gene deficiency increases susceptibility and severity of dextran sodium sulfate-induced inflammatory bowel disease in mice. The Journal of biological chemistry 44 23393138
2013 Lgr4-mediated Wnt/β-catenin signaling in peritubular myoid cells is essential for spermatogenesis. Development (Cambridge, England) 44 23533175
2015 GPCR48/LGR4 promotes tumorigenesis of prostate cancer via PI3K/Akt signaling pathway. Medical oncology (Northwood, London, England) 43 25636507
2020 Unlike LGR4, LGR5 potentiates Wnt-β-catenin signaling without sequestering E3 ligases. Science signaling 40 33262293
2015 Lgr4 and Lgr5 drive the formation of long actin-rich cytoneme-like membrane protrusions. Journal of cell science 40 25653388
2022 The RSPO-LGR4/5-ZNRF3/RNF43 module in liver homeostasis, regeneration, and disease. Hepatology (Baltimore, Md.) 39 35006616
2022 Nidogen-2 is a Novel Endogenous Ligand of LGR4 to Inhibit Vascular Calcification. Circulation research 39 36354004
2017 MicroRNA-34c promotes osteoclast differentiation through targeting LGR4. Gene 38 28130056
2015 LGR4 and Its Role in Intestinal Protection and Energy Metabolism. Frontiers in endocrinology 36 26379625
2019 R-spondin 2-LGR4 system regulates growth, migration and invasion, epithelial-mesenchymal transition and stem-like properties of tongue squamous cell carcinoma via Wnt/β-catenin signaling. EBioMedicine 35 31097406
2017 Evidence of the Role of R-Spondin 1 and Its Receptor Lgr4 in the Transmission of Mechanical Stimuli to Biological Signals for Bone Formation. International journal of molecular sciences 35 28272338
2014 Emerging role for leucine-rich repeat-containing G-protein-coupled receptors LGR5 and LGR4 in cancer stem cells. Cancer management and research 35 24711713
2020 LGR4 deficiency results in delayed puberty through impaired Wnt/β-catenin signaling. JCI insight 33 32493844
2016 Ascending aortic adventitial remodeling and fibrosis are ameliorated with Apelin-13 in rats after TAC via suppression of the miRNA-122 and LGR4-β-catenin signaling. Peptides 33 27773659
2010 GPR48-Induced keratinocyte proliferation occurs through HB-EGF mediated EGFR transactivation. FEBS letters 33 20732323
2013 Lgr4/Gpr48 negatively regulates TLR2/4-associated pattern recognition and innate immunity by targeting CD14 expression. The Journal of biological chemistry 32 23589304
2014 Lgr4 gene regulates corpus luteum maturation through modulation of the WNT-mediated EGFR-ERK signaling pathway. Endocrinology 31 24877628
2013 LGR4 expressed in uterine epithelium is necessary for uterine gland development and contributes to decidualization in mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30 23975934
2013 Lgr4 promotes glioma cell proliferation through activation of Wnt signaling. Asian Pacific journal of cancer prevention : APJCP 30 24083766
2011 Lgr4-deficient mice showed premature differentiation of ureteric bud with reduced expression of Wnt effector Lef1 and Gata3. Developmental dynamics : an official publication of the American Association of Anatomists 30 21523854
2011 Conditional knockout of Lgr4 leads to impaired ductal elongation and branching morphogenesis in mouse mammary glands. Sexual development : genetics, molecular biology, evolution, endocrinology, embryology, and pathology of sex determination and differentiation 30 21791950
2021 The Role of LGR4 (GPR48) in Normal and Cancer Processes. International journal of molecular sciences 29 33946652
2019 The Interplay of MicroRNA-34a, LGR4, EMT-Associated Factors, and MMP2 in Regulating Uveal Melanoma Cells. Investigative ophthalmology & visual science 29 31661551
2016 Association of a gain-of-function variant in LGR4 with central obesity. Obesity (Silver Spring, Md.) 29 27925416
2016 Lgr4 is crucial for skin carcinogenesis by regulating MEK/ERK and Wnt/β-catenin signaling pathways. Cancer letters 28 27693558
2023 LGR4: A New Receptor Member in Endocrine and Metabolic Diseases. Endocrine reviews 27 36791020
2017 Leucine-rich repeat-containing G protein-coupled receptor 4 (Lgr4) is necessary for prostate cancer metastasis via epithelial-mesenchymal transition. The Journal of biological chemistry 27 28768769
2016 MiR-218 impedes IL-6-induced prostate cancer cell proliferation and invasion via suppression of LGR4 expression. Oncology reports 27 26986507
2016 MicroRNA let-7b induces lens epithelial cell apoptosis by targeting leucine-rich repeat containing G protein-coupled receptor 4 (Lgr4) in age-related cataract. Experimental eye research 27 27179410
2014 Crystal structure of LGR4-Rspo1 complex: insights into the divergent mechanisms of ligand recognition by leucine-rich repeat G-protein-coupled receptors (LGRs). The Journal of biological chemistry 27 25480784
2018 Loss of Lgr4 inhibits differentiation, migration and apoptosis, and promotes proliferation in bone mesenchymal stem cells. Journal of cellular physiology 26 30536377
2013 Reconstitution of R-spondin:LGR4:ZNRF3 adult stem cell growth factor signaling complexes with recombinant proteins produced in Escherichia coli. Biochemistry 26 24050775
2013 LGR4 and its ligands, R-spondin 1 and R-spondin 3, regulate food intake in the hypothalamus of male rats. Endocrinology 26 24280058
2000 Chromosomal localization of GPR48, a novel glycoprotein hormone receptor like GPCR, in human and mouse with radiation hybrid and interspecific backcross mapping. Cytogenetics and cell genetics 26 10894923
2022 Gastric stem cells promote inflammation and gland remodeling in response to Helicobacter pylori via Rspo3-Lgr4 axis. The EMBO journal 25 35767364
2010 Reduced fertility with impairment of early-stage embryos observed in mice lacking Lgr4 in epithelial tissues. Fertility and sterility 25 20638054
2021 A Wnt-Independent LGR4-EGFR Signaling Axis in Cancer Metastasis. Cancer research 24 34099494
2018 Type 2 diabetes with hypertensive patients results in changes to features of adipocytokines: Leptin, Irisin, LGR4, and Sfrp5. Clinical and experimental hypertension (New York, N.Y. : 1993) 24 30307757
2016 LGR4 Is a Direct Target of MicroRNA-34a and Modulates the Proliferation and Migration of Retinal Pigment Epithelial ARPE-19 Cells. PloS one 24 27977785
2014 LGR4 acts as a link between the peripheral circadian clock and lipid metabolism in liver. Journal of molecular endocrinology 24 24353284
2022 LGR4 cooperates with PrPc to endow the stemness of colorectal cancer stem cells contributing to tumorigenesis and liver metastasis. Cancer letters 23 35561877
2022 LGR4, a G Protein-Coupled Receptor With a Systemic Role: From Development to Metabolic Regulation. Frontiers in endocrinology 23 35707461
2021 Clinical Significance of Stem Cell Biomarkers EpCAM, LGR5 and LGR4 mRNA Levels in Lymph Nodes of Colon Cancer Patients. International journal of molecular sciences 23 35008827
2020 Lgr4 Deletion Delays the Hair Cycle and Inhibits the Activation of Hair Follicle Stem Cells. The Journal of investigative dermatology 23 32035093
2018 Down-regulation of miR-193a-3p promotes osteoblast differentiation through up-regulation of LGR4/ATF4 signaling. Biochemical and biophysical research communications 23 30100064
2017 Blockade of LGR4 inhibits proliferation and odonto/osteogenic differentiation of stem cells from apical papillae. Journal of molecular histology 23 28986711
2012 LGR4 and LGR6 are differentially expressed and of putative tumor biological significance in gastric carcinoma. Virchows Archiv : an international journal of pathology 23 22855134
2024 Loss of the stress sensor GADD45A promotes stem cell activity and ferroptosis resistance in LGR4/HOXA9-dependent AML. Blood 22 38579286
2016 LGR4 and LGR5 Function Redundantly During Human Endoderm Differentiation. Cellular and molecular gastroenterology and hepatology 22 28078320
2014 LGR4/GPR48 inactivation leads to aniridia-genitourinary anomalies-mental retardation syndrome defects. The Journal of biological chemistry 22 24519938
2018 LGR4 protects hepatocytes from injury in mouse. American journal of physiology. Gastrointestinal and liver physiology 20 30406697
2015 Lgr4 controls specialization of female gonads in mice. Biology of reproduction 20 26333992
2018 Continuous application of compressive force induces fusion of osteoclast-like RAW264.7 cells via upregulation of RANK and downregulation of LGR4. Life sciences 19 29572179
2016 LGR4 and LGR5 Regulate Hair Cell Differentiation in the Sensory Epithelium of the Developing Mouse Cochlea. Frontiers in cellular neuroscience 19 27559308
2023 LGR4 and LGR5 form distinct homodimers that only LGR4 complexes with RNF43/ZNRF3 to provide high affinity binding of R-spondin ligands. Scientific reports 18 37402772
2022 Low levels of cadmium exposure affect bone by inhibiting Lgr4 expression in osteoblasts and osteoclasts. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) 18 35772369
2020 Rspo1/Rspo3-LGR4 signaling inhibits hepatic cholesterol synthesis through the AMPKα-SREBP2 pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 18 32926477
2018 Inhibitory Effect of MiR-449b on Cancer Cell Growth and Invasion through LGR4 in Non-Small-Cell Lung Carcinoma. Current medical science 18 30128865
2011 Expression patterns of lgr4 and lgr6 during zebrafish development. Gene expression patterns : GEP 17 21570488

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