Affinage

LGR4

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

Length
951 aa
Mass
104.5 kDa
Annotated
2026-04-28
100 papers in source corpus 39 papers cited in narrative 39 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LGR4 is a leucine-rich repeat-containing G protein-coupled receptor that serves as a high-affinity receptor for R-spondins and potentiates Wnt/β-catenin signaling by forming ternary complexes with the E3 ubiquitin ligases ZNRF3/RNF43, driving their membrane clearance and thereby stabilizing Wnt receptors (PMID:21693646, PMID:24165923, PMID:33262293). Structurally, the LGR4 extracellular domain adopts a horseshoe-shaped leucine-rich repeat fold that engages R-spondin furin-like domains on its concave surface, and its seven-transmembrane domain uniquely mediates constitutive interaction with ZNRF3/RNF43 independently of R-spondin (PMID:23756652, PMID:33262293). Beyond canonical Wnt potentiation, LGR4 functions as a receptor for RANKL, norrin, and nidogen-2, engaging Gαq, cAMP-PKA-CREB, NF-κB, and ERK/STAT3 pathways to regulate osteoclastogenesis, erythropoiesis, innate immunity, macrophage polarization, and vascular calcification (PMID:27064449, PMID:18955481, PMID:29967265, PMID:36354004). LGR4 also directly interacts with EGFR through a Wnt-independent mechanism that blocks EGFR ubiquitination and sustains EGFR signaling, promoting cancer cell metastasis (PMID:34099494).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2008 Medium

    Before the R-spondin connection was established, LGR4 was shown to be an orphan GPCR that regulated definitive erythropoiesis through cAMP-PKA-CREB-ATF4 signaling and keratinocyte EGFR transactivation, establishing its coupling to classical GPCR second messengers and crosstalk with receptor tyrosine kinases.

    Evidence Lgr4 knockout mice with hematopoietic and eyelid developmental phenotypes, signaling pathway analysis

    PMID:18487371 PMID:18955481

    Open questions at the time
    • Endogenous ligand unknown at the time
    • cAMP-PKA pathway coupling not confirmed with purified receptor reconstitution
    • EGFR transactivation mechanism not fully defined
  2. 2011 High

    The identification of R-spondins as high-affinity LGR4 ligands resolved the orphan receptor problem and established a new paradigm: LGR4 potentiates Wnt/β-catenin signaling not through classical G protein coupling but through a unique mechanism involving enhanced LRP6 phosphorylation.

    Evidence Binding assays, LRP6 phosphorylation, G protein and β-arrestin coupling assays, gain/loss-of-function in mammalian cells and Xenopus

    PMID:21693646 PMID:21909076 PMID:22815884

    Open questions at the time
    • Downstream effector mechanism of Wnt potentiation not yet defined
    • Relative contributions of LGR4 vs LGR5 in vivo unclear
  3. 2013 High

    Crystal structures of the LGR4 ectodomain–RSPO1 complex revealed a TLR-like horseshoe architecture engaging R-spondin furin-like repeats on its concave surface, providing the atomic basis for ligand recognition and explaining conservation across LGR4-6.

    Evidence X-ray crystallography with functional mutagenesis from multiple independent groups

    PMID:23756652 PMID:23891289 PMID:25480784

    Open questions at the time
    • No full-length receptor structure including transmembrane domain
    • Structural basis for ZNRF3/RNF43 interaction unknown
  4. 2013 High

    The mechanism of Wnt potentiation was resolved: R-spondin simultaneously binds LGR4 and ZNRF3/RNF43 through distinct motifs, forming a ternary complex that triggers membrane clearance of the E3 ligases and prevents Frizzled/LRP ubiquitination; intracellularly, LGR4 recruits IQGAP1 to the Wnt signalosome to drive MEK1/2-mediated LRP5/6 phosphorylation.

    Evidence Mutagenesis of R-spondin dual-binding motifs, co-immunoprecipitation of ternary complex, ZNRF3 clearance assays, IQGAP1 pulldown and signaling assays, in vitro reconstitution of ternary complexes

    PMID:24050775 PMID:24165923 PMID:24639526

    Open questions at the time
    • Stoichiometry of ternary complex in native membranes unclear
    • Role of clathrin-mediated endocytosis in ternary complex turnover not fully resolved
  5. 2013 Medium

    LGR4-dependent Wnt/β-catenin signaling was shown to be essential for intestinal stem cell maintenance, Paneth cell differentiation, spermatogenesis, mammary gland development, and myogenic differentiation, establishing LGR4 as a master amplifier of Wnt signaling across multiple stem/progenitor cell compartments.

    Evidence Lgr4 knockout and conditional knockout mice, ex vivo crypt cultures, genetic epistasis with Apc(min/+), Sox2 and follistatin as downstream targets identified by ChIP and promoter analysis

    PMID:21508962 PMID:23533175 PMID:23712846 PMID:24344199

    Open questions at the time
    • Relative contributions of LGR4 vs LGR5 in each tissue not fully delineated
    • Whether RSPO isoform selectivity differs across tissues not resolved
  6. 2016 High

    LGR4 was identified as a second receptor for RANKL that signals through Gαq-GSK3β to suppress NFATc1 and osteoclastogenesis, revealing a Wnt-independent G protein-coupled signaling axis and establishing LGR4 as a multi-ligand receptor.

    Evidence Co-immunoprecipitation, competition binding with RANK, Gαq signaling assays, conditional knockout mice, soluble LGR4-ECD treatment in vivo

    PMID:27064449

    Open questions at the time
    • Structural basis for RANKL–LGR4 interaction unknown
    • Whether RANKL and RSPO signaling through LGR4 are mutually exclusive not tested
  7. 2016 High

    The RSPO-LGR4/5-ZNRF3/RNF43 module was demonstrated to control hepatic metabolic zonation by maintaining the Wnt/β-catenin gradient across the liver lobule, showing that the ternary complex mechanism operates in terminally differentiated tissue homeostasis, not only in stem cells.

    Evidence Liver-specific LGR4/5 conditional knockout, recombinant RSPO1 treatment reversibly expanding the Wnt zone

    PMID:27088858

    Open questions at the time
    • Whether RSPO dosage titrates zone boundaries quantitatively not fully modeled
    • Relative contributions of LGR4 vs LGR5 in hepatocytes not separated
  8. 2018 High

    LGR4 was shown to regulate macrophage polarization: RSPO-LGR4-ERK-STAT3 signaling promotes M2 polarization of tumor-associated macrophages, while LGR4-CREB-driven AP-1 transactivation governs pro-inflammatory macrophage programs, demonstrating context-dependent immune signaling outputs.

    Evidence Macrophage-specific Lgr4 conditional knockout mice, tumor models, cardiac injury models, transcriptomics, AP-1 and CREB activity assays

    PMID:29967265 PMID:32600176

    Open questions at the time
    • How the same receptor achieves opposing macrophage polarization outcomes (M2 vs pro-inflammatory) in different contexts not mechanistically reconciled
    • Whether RSPO is the relevant ligand in both contexts not confirmed
  9. 2020 High

    Domain-swap experiments revealed that the LGR4 seven-transmembrane domain constitutively interacts with ZNRF3/RNF43 even without R-spondin, distinguishing LGR4 mechanistically from LGR5, which instead enhances Wnt signaling by interacting with FZD-LRP6; both receptors exist as dimers.

    Evidence Co-immunoprecipitation, proximity ligation, time-resolved FRET, domain-swap chimeras between LGR4 and LGR5

    PMID:33262293

    Open questions at the time
    • Structure of TM domain–ZNRF3 interface not determined
    • Functional significance of LGR4 dimerization not established
  10. 2021 High

    A Wnt-independent LGR4-EGFR axis was uncovered: LGR4 physically interacts with EGFR and blocks its ubiquitination, sustaining EGFR activation to drive cancer metastasis; LGR4 mutants defective in Wnt potentiation retain full pro-metastatic capacity, functionally separating Wnt and EGFR outputs of LGR4.

    Evidence Co-immunoprecipitation, EGFR ubiquitination assay, Wnt-signaling-dead LGR4 mutants, in vivo xenograft metastasis

    PMID:34099494

    Open questions at the time
    • Which LGR4 domain mediates EGFR interaction unknown
    • Whether EGFR-protective function occurs in normal physiology or is cancer-specific not tested
  11. 2022 High

    Nidogen-2 was identified as a novel endogenous ligand of LGR4, engaging Gαq-PKCα-AMPKα1 biased signaling to counteract vascular smooth muscle cell osteogenic transition and calcification, expanding the ligand repertoire beyond R-spondins and RANKL.

    Evidence Membrane protein interactome screen, SPR binding (KD ~27 nM), G protein signaling assays, conditional knockout

    PMID:36354004

    Open questions at the time
    • Whether nidogen-2 and RSPO compete for LGR4 binding unknown
    • Structural basis for nidogen-2–LGR4 recognition not determined
  12. 2024 Medium

    LGR4-Wnt signaling was shown to transcriptionally upregulate SLC7A11 to inhibit ferroptosis, conferring acquired drug resistance in colorectal cancer; a therapeutic LGR4 monoclonal antibody reversed this resistance by sensitizing tumors to ferroptosis.

    Evidence Organoid drug resistance model, transcriptomics, LGR4-mAb treatment, ferroptosis assays

    PMID:38291304

    Open questions at the time
    • Whether SLC7A11 upregulation is a direct β-catenin/TCF target or indirect not fully dissected
    • In vivo efficacy of LGR4-mAb across tumor types not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full-length structure of LGR4 including its transmembrane domain in complex with ZNRF3/RNF43 or EGFR, how a single receptor achieves biased signaling through Gαq, cAMP, NF-κB, and β-catenin depending on ligand and cellular context, and whether the diverse ligands (R-spondins, RANKL, norrin, nidogen-2) compete for or cooperate through overlapping or distinct binding sites.
  • No full-length LGR4 structure available
  • Biased signaling mechanism across multiple ligands not reconciled
  • Functional interplay among four known ligand classes not systematically tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1266738 Developmental Biology 4 R-HSA-168256 Immune System 4 R-HSA-1643685 Disease 3
Partners
EGFRIQGAP1NID2RANKLRNF43RSPO1RSPO2ZNRF3
Complex memberships
LGR4–IQGAP1–DVL signalosomeRSPO–LGR4–ZNRF3/RNF43 ternary complex

Evidence

Reading pass · 39 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 LGR4 and LGR5 bind R-spondins (RSPOs) with high affinity and mediate potentiation of Wnt/β-catenin signaling by enhancing Wnt-induced LRP6 phosphorylation; neither receptor couples to heterotrimeric G proteins or β-arrestin upon RSPO stimulation, indicating a unique signaling mechanism. Binding assays, LRP6 phosphorylation assays, G protein coupling assays, β-arrestin assays Proceedings of the National Academy of Sciences of the United States of America High 21693646
2011 LGR4 and LGR5 bind R-spondins via their Furin domains and promote R-spondin-mediated Wnt/β-catenin and Wnt/PCP signaling; R-spondin-triggered β-catenin signaling requires Clathrin-mediated endocytosis, whereas Wnt3a-mediated signaling requires Caveolin-mediated endocytosis. Gain- and loss-of-function experiments in mammalian cells and Xenopus embryos, endocytosis inhibitor assays EMBO reports High 21909076
2013 Crystal structure of LGR4 extracellular domain (ECD) in complex with RSPO1 N-terminal fragment reveals that LGR4-ECD adopts a TLR horseshoe structure and uses its concave surface near the N-terminus to bind RSPO1; both FU-CRD1 and FU-CRD2 domains of RSPO1 contribute to LGR4 binding. X-ray crystallography, binding assays, mutagenesis Genes & development High 23756652
2013 Crystal structure of LGR4 ectodomain alone and in complex with Rspo1 shows an extended horseshoe LRR architecture that binds ligand furin-like repeats via its concave side through electrostatic and hydrophobic interactions. X-ray crystallography Structure High 23891289
2014 Crystal structure of LGR4-Rspo1 complex confirms concave surface as the sole binding site for R-spondins; all Rspo1-binding residues are conserved in LGR4-6, suggesting identical binding surface; LGR4-6 use a one-site binding model distinct from group A and C LGR members. X-ray crystallography, structural analysis 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, membrane clearance of ZNRF3, and Wnt signaling activation; LGR4/5 serve as engagement receptors while ZNRF3/RNF43 are effector receptors. Mutagenesis, co-immunoprecipitation, ZNRF3 membrane clearance assay, Wnt signaling assay EMBO reports High 24165923
2013 RSPO-LGR4 signaling functions via the intracellular scaffold protein IQGAP1: LGR4 interacts with IQGAP1, which bridges RSPO-LGR4 to the Wnt signalosome through enhanced IQGAP1-DVL interaction following RSPO stimulation, promoting MEK1/2-mediated LRP5/6 phosphorylation for canonical Wnt and actin dynamics regulation for non-canonical Wnt signaling. Co-immunoprecipitation, pulldown, signaling assays, actin dynamics assays Proceedings of the National Academy of Sciences of the United States of America High 24639526
2012 LGR4 is the cognate receptor of RSPO identified by unbiased siRNA screen; RSPO binds the extracellular domain of LGR4; LGR4 depletion abolishes RSPO-induced β-catenin signaling; overexpression of LGR5 can compensate for LGR4 loss; no coupling to heterotrimeric G proteins detected. siRNA screen, binding assay, β-catenin signaling assay, G protein coupling assay, crypt culture PloS one High 22815884
2013 Recombinant RSPO proteins bind LGR4 LRR1-14 with nanomolar affinities (order RSPO4>RSPO2>RSPO3>RSPO1); ternary RSPO:LGR4:ZNRF3 complexes form for RSPO2 and RSPO3; stronger signaling potencies of RSPO2 and RSPO3 result from strong binding of both LGR4 and ZNRF3. TR-FRET binding assay, native gel electrophoretic mobility shift assay, cell-based signaling assay, in vitro reconstitution with bacterially expressed proteins Biochemistry High 24050775
2016 LGR4 is a second receptor for RANKL that competes with RANK to bind RANKL; RANKL binding to LGR4 activates the Gαq and GSK3-β signaling pathway, suppressing NFATc1 expression and activity to negatively regulate osteoclastogenesis; LGR4 extracellular domain (ECD) binds RANKL and inhibits osteoclast differentiation in vivo. Co-immunoprecipitation, competition binding, Gαq signaling assays, osteoclast differentiation assays, conditional knockout mice, in vivo ECD treatment Nature medicine High 27064449
2020 Full-length LGR4 forms a tight complex with ZNRF3 and RNF43 even without RSPO, whereas LGR5 does not interact with either E3 ligase; the seven-transmembrane domain of LGR4 confers interaction with E3 ligases; LGR5 potentiates Wnt signaling by interacting with FZD and LRP6 to enhance LRP6 phosphorylation; LGR4 and LGR5 exist as dimers on the cell surface. Co-immunoprecipitation, proximity ligation assay, competition binding, time-resolved FRET, domain-swapping experiments Science signaling High 33262293
2016 The RSPO-LGR4/5-ZNRF3/RNF43 module controls hepatic Wnt/β-catenin-mediated metabolic liver zonation; liver-specific LGR4/5 loss disrupts Wnt/β-catenin signaling and zonation; pathway activation with recombinant RSPO1 expanded the hepatic Wnt/β-catenin gradient in a reversible and LGR4/5-dependent manner. Conditional knockout mice, RSPO1 recombinant protein treatment, reporter assays, histology Nature cell biology High 27088858
2013 Norrin (Norrie disease gene product) is a ligand for LGR4 that stimulates Wnt signaling mediated specifically by LGR4 (not LGR5/6) in mammalian cells; mutagenesis of norrin revealed distinct residues required for LGR4 signaling versus Frizzled4 signaling versus BMP antagonism. Cell-based Wnt signaling assay, binding studies, mutagenesis Journal of cell science Medium 23444378
2022 Nidogen-2 is a novel endogenous ligand of LGR4 (KD = 26.77 nM) that biased-activates LGR4-Gαq-PKCα-AMPKα1 signaling to counteract VSMC osteogenic transition and vascular calcification; LGR4 deficiency in VSMCs abolishes the protective effect of nidogen-2. Membrane protein interactome, co-immunoprecipitation, surface plasmon resonance, flow cytometric binding assay, G protein signaling assays, conditional knockout Circulation research High 36354004
2018 Lgr4 promotes macrophage M2 polarization through Rspo/Lgr4/Erk/Stat3 signaling; macrophage-specific Lgr4 knockout reduces M2 tumor-associated macrophages and increases CD8+ T lymphocyte infiltration in the tumor microenvironment. Macrophage-conditional knockout mice (Lgr4fl/fl Lyz2cre/+), tumor models, signaling pathway analysis Cancer research High 29967265
2020 Lgr4 governs a pro-inflammatory program in macrophages via enhancing CREB-mediated c-Fos, Fosl1, and Fosb transactivation to activate AP-1 in inflammatory macrophages; macrophage-specific Lgr4 knockout improves cardiac repair after myocardial infarction. Macrophage-specific conditional knockout mice, transcriptomic profiling, AP-1 activity assays, CREB activation assays Circulation research High 32600176
2013 Lgr4 ablation promotes white-to-brown fat transition partially through retinoblastoma 1 gene (Rb1) reduction; Lgr4 mutant mice show increased energy expenditure with brown-like adipocytes in WAT depots. Lgr4 mutant mice, brown adipocyte differentiation assays from stromal vascular fraction, Rb1 expression analysis Nature cell biology High 24212090
2008 Gpr48/LGR4 regulates definitive erythropoiesis through the cAMP-PKA-CREB pathway, which controls ATF4 expression; Gpr48-/- fetal livers show decreased definitive erythroid precursors with reduced c-Myc and cyclin D1 expression. Knockout mice, real-time PCR, histology, blood smear assay, signaling pathway analysis The Journal of biological chemistry Medium 18955481
2008 GPR48/LGR4 mediates keratinocyte proliferation and migration during eyelid development through activation of EGFR signaling; GPR48 regulates EGFR phosphorylation, and GPR48 inactivation results in decreased EGFR phosphorylation and reduced F-actin formation. Knockout mice, in vitro scratch assay, Western blot, immunostaining, scanning electron microscopy Investigative ophthalmology & visual science Medium 18487371
2010 GPR48/LGR4 mediates keratinocyte proliferation via HB-EGF-mediated EGFR transactivation; HB-EGF is reduced in Gpr48-/- cell culture medium and its addition restores EGFR, ERK, and STAT3 phosphorylation as well as cell proliferation. EGFR inhibitor treatment, conditioned media immunodepletion, HB-EGF reconstitution, Western blot FEBS letters Medium 20732323
2021 LGR4 promotes cancer metastasis through a Wnt-independent axis: LGR4 interacts with EGFR and blocks EGFR ubiquitination and degradation, resulting in persistent EGFR activation; LGR4 mutants unable to potentiate Wnt signaling still promote cancer cell migration and invasion. Co-immunoprecipitation, EGFR ubiquitination assay, Wnt pathway inhibition (pharmacological and genetic), in vitro migration/invasion, in vivo xenograft metastasis Cancer research High 34099494
2013 Lgr4 is required for Paneth cell differentiation and intestinal stem cell maintenance; LGR4-deficient crypts cultured ex vivo die rapidly with downregulation of stem cell markers and Wnt target genes; partial rescue achieved with LiCl but not Wnt agonists. Lgr4 gene inactivation, ex vivo crypt culture, histology, marker gene analysis EMBO reports Medium 21508962
2013 Lgr4 regulates Wnt/β-catenin signaling in peritubular myoid cells (PMCs) to support spermatogenesis; Lgr4 loss attenuates Wnt/β-catenin signaling in PMCs; reactivation by crossing with Apc(min/+) or GSK3β inhibitor partially rescues the Lgr4-/- testicular phenotype. Conditional knockout mice, signaling analysis, genetic rescue (Apc(min/+) cross), pharmacological rescue (GSK3β inhibitor) Development High 23533175
2013 Lgr4 protects against inflammatory bowel disease through Wnt/β-catenin signaling; Lgr4 deficiency reduces Paneth and stem cells; crossing with Apc(min/+) mice or GSK3β inhibitor treatment partially restores Paneth cell number and reduces DSS-induced mortality. Hypomorphic mouse model, DSS colitis, genetic rescue (Apc(min/+)), pharmacological rescue, histology The Journal of biological chemistry Medium 23393138
2013 Lgr4/Gpr48 negatively regulates TLR2/4-associated innate immunity by suppressing CD14 expression; Lgr4 deletion increases CD14 expression through decreased cAMP-response element-binding protein (CREB) activity, enhancing TLR2/4-associated cytokine production. Lgr4 knockout macrophages, TLR signaling assays, CREB activity assay, CD14 expression analysis The Journal of biological chemistry Medium 23589304
2014 Lgr4 regulates corpus luteum maturation through WNT-mediated EGFR-ERK signaling; Lgr4-deficient granulosa-lutein cells show attenuated EGFR-ERK signaling; Wnt/β-catenin target MMP9 activates EGF-like factors to facilitate ERK activation and luteinization. Lgr4-/- mice, ovarian granulosa cell culture, EGFR-ERK signaling assays, MMP9 inhibitor, HB-EGF rescue Endocrinology Medium 24877628
2013 RSPO-LGR4 signaling in myoblasts activates Wnt/β-catenin pathway to upregulate follistatin (Fst) expression via TCF/LEF1 binding sites in the Fst promoter and intron 1; LGR4 depletion severely disrupts myogenic differentiation and diminishes RSPO2 response. siRNA depletion, luciferase reporter assay with TCF/LEF1 site mutagenesis, C2C12 differentiation assay, in vivo β-catenin activation/inactivation Molecular and cellular biology Medium 24344199
2013 Lgr4 regulates mammary gland development and stem cell activity through the Wnt/β-catenin/Lef1 pathway, which controls Sox2 expression; Sox2 overexpression restores in vivo mammary regeneration potential of Lgr4-/- mammary stem cells. Lgr4-/- mice, mammosphere formation, chromatin immunoprecipitation, Wnt3a rescue, Sox2 overexpression rescue Stem cells Medium 23712846
2014 LGR4 inactivation down-regulates histone demethylases Jmjd2a and Fbxl10 through the cAMP-CREB signaling pathway, contributing to AGR syndrome-like developmental defects (aniridia, polycystic kidney disease, genitourinary anomalies, mental retardation) in Lgr4-/- mice. Lgr4-/- mice, cAMP-CREB pathway analysis, gene expression in MEF cells and tissues The Journal of biological chemistry Medium 24519938
2015 LGR4 and LGR5 promote formation of long actin-rich cytoneme-like membrane protrusions (>80 μm) through stabilization of nascent filopodia; LGR5-induced cytonemes serve as conduits for transit of myosin X (Myo10) and β-arrestin-2 (Arrb2). Live cell imaging, overexpression, fluorescent protein tagging of cargo proteins Journal of cell science Medium 25653388
2020 LGR4 deficiency delays puberty by impairing Wnt/β-catenin signaling in GnRH neuron development; Lgr4-/- mice have fewer GnRH neurons; lgr4 knockdown in zebrafish prevents GnRH neuron formation and migration; Lgr4-mediated Wnt/β-catenin activation during GnRH neuron development confirmed by genetic lineage tracing. LGR4 mutant functional characterization, conditional KO mice, zebrafish morpholino knockdown, genetic lineage tracing with Wnt reporter JCI insight Medium 32493844
2022 RSPO2 and RANKL signal through LGR4 to promote osteoclastic premetastatic niche formation; LGR4 modulates DKK1 expression through Gαq and β-catenin signaling; DKK1 facilitates osteoclast precursor recruitment via suppression of LRP5 (not LRP6); soluble LGR4-ECD decoy receptor alleviates bone metastasis. GPCR ligand/agonist screening, signaling pathway analysis, conditional models, in vivo bone metastasis model, LGR4-ECD treatment The Journal of clinical investigation Medium 34847079
2019 The miR-34-LGR4 axis regulates keratinocyte inflammatory response; miR-34a and miR-34c target LGR4 directly; LGR4 regulates GSK-3β-induced p65 serine 468 phosphorylation to modulate NF-κB signaling pathway activity; Lgr4 knockout mice show impaired wound closure with enhanced inflammation. miRNA mimic transfection, wound healing assay, Lgr4 KO mice, NF-κB phosphorylation analysis The Journal of investigative dermatology Medium 31376385
2020 RSPO-LGR4 signaling is required for H. pylori-induced gastric hyperplasia; LGR4 regulates Lgr5 expression and drives NF-κB activity in proliferative stem cells; Lgr4-driven NF-κB activation upon H. pylori exposure causes expansion of the gland base module and chemokine expression inducing neutrophil recruitment. Conditional knockout mice, reporter assays for NF-κB activity, H. pylori infection model The EMBO journal Medium 35767364
2020 Rspo1/Rspo3-LGR4 signaling inhibits hepatic cholesterol synthesis via the AMPKα-SREBP2 pathway; LGR4 knockdown increases hepatic cholesterol synthesis and decreases AMPKα phosphorylation; AMPKα activation/inhibition abolishes effects of LGR4 deficiency or RSPO treatment. Liver-specific knockdown mice, in vitro hepatocyte assays, AMPKα agonist/antagonist/shRNA, SREBP2 nuclear translocation assay FASEB journal Medium 32926477
2018 LGR4 activation by Rspo1 protects hepatocytes from TNFα-induced cell death by inhibiting NF-κB signaling; LGR4 knockdown increases nuclear translocation of NF-κB-p65; IKKβ overexpression attenuates Rspo1 protective effects; Rspo1 potentiates β-catenin stabilization. Liver-specific LGR4 knockout, hepatocyte culture, NF-κB pathway assays, IKKβ overexpression, β-catenin stabilization assay American journal of physiology. Gastrointestinal and liver physiology Medium 30406697
2016 Lgr4 mediates skin carcinogenesis by regulating MEK/ERK and Wnt/β-catenin signaling; TPA activates MEK1, ERK1/2 and AP-1 in wild-type but not Lgr4-depleted epidermal cells; MEK1/ERK1/2 pathway activation lies upstream of Wnt/β-catenin in this context. Lgr4-/- mice, TPA-induced papilloma model, MEK/ERK and Wnt pathway inhibitors, Western blot Cancer letters Medium 27693558
2016 Aberrant LGR4 expression in multiple myeloma is driven by IL-6/STAT3 signaling, allowing myeloma cells to hijack R-spondins from osteoblasts in the bone marrow niche, resulting in Wnt co-receptor stabilization and increased sensitivity to Wnt ligands. Co-immunoprecipitation, reporter assays, IL-6/STAT3 inhibitors, R-spondin binding assays Proceedings of the National Academy of Sciences of the United States of America Medium 28028233
2024 LGR4-dependent Wnt signaling transcriptionally upregulates SLC7A11 (a key ferroptosis inhibitor) to confer acquired drug resistance in colorectal cancer; LGR4-mAb inhibits LGR4-Wnt signaling and sensitizes drug-induced ferroptosis. Organoid drug resistance model, transcriptomic analysis, LGR4 monoclonal antibody, ferroptosis assays, SLC7A11 expression analysis Nature cancer Medium 38291304

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 737 21693646
2011 LGR4 and LGR5 are R-spondin receptors mediating Wnt/β-catenin and Wnt/PCP signalling. EMBO reports 473 21909076
2016 LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption. Nature medicine 286 27064449
2016 The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size. Nature cell biology 265 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 169 31080135
2012 R-Spondin potentiates Wnt/β-catenin signaling through orphan receptors LGR4 and LGR5. PloS one 145 22815884
2018 Inhibition of Rspo-Lgr4 Facilitates Checkpoint Blockade Therapy by Switching Macrophage Polarization. Cancer research 130 29967265
2011 Lgr4 is required for Paneth cell differentiation and maintenance of intestinal stem cells ex vivo. EMBO reports 117 21508962
2006 Defective postnatal development of the male reproductive tract in LGR4 knockout mice. Developmental biology 111 16406039
2013 Ablation of LGR4 promotes energy expenditure by driving white-to-brown fat switch. Nature cell biology 110 24212090
2020 Lgr4 Governs a Pro-Inflammatory Program in Macrophages to Antagonize Post-Infarction Cardiac Repair. Circulation research 105 32600176
2013 Structural basis for R-spondin recognition by LGR4/5/6 receptors. Genes & development 100 23756652
2024 Targeted activation of ferroptosis in colorectal cancer via LGR4 targeting overcomes acquired drug resistance. Nature cancer 96 38291304
2014 RSPO-LGR4 functions via IQGAP1 to potentiate Wnt signaling. Proceedings of the National Academy of Sciences of the United States of America 95 24639526
2020 Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia. Cancer cell 94 32559496
2013 Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R-spondin. EMBO reports 87 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
2006 Up-regulation of GPR48 induced by down-regulation of p27Kip1 enhances carcinoma cell invasiveness and metastasis. Cancer research 74 17178856
2005 Expression pattern of the orphan receptor LGR4/GPR48 gene in the mouse. Histochemistry and cell biology 74 16028069
2022 RSPO2 and RANKL signal through LGR4 to regulate osteoclastic premetastatic niche formation and bone metastasis. The Journal of clinical investigation 68 34847079
2017 LGR4 modulates breast cancer initiation, metastasis, and cancer stem cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 68 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
2013 Multi-functional norrin is a ligand for the LGR4 receptor. Journal of cell science 64 23444378
2019 MicroRNA-34 Family Enhances Wound Inflammation by Targeting LGR4. The Journal of investigative dermatology 63 31376385
2014 Aberrant RSPO3-LGR4 signaling in Keap1-deficient lung adenocarcinomas promotes tumor aggressiveness. Oncogene 63 25531322
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
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
2013 Analysis of LGR4 receptor distribution in human and mouse tissues. PloS one 56 24205130
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 45 33950533
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
2008 GPR48 regulates epithelial cell proliferation and migration by activating EGFR during eyelid development. Investigative ophthalmology & visual science 45 18487371
2007 Eye-open at birth phenotype with reduced keratinocyte motility in LGR4 null mice. FEBS letters 45 17850793
2013 Lgr4-mediated Wnt/β-catenin signaling in peritubular myoid cells is essential for spermatogenesis. Development (Cambridge, England) 44 23533175
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 43 28028233
2015 GPCR48/LGR4 promotes tumorigenesis of prostate cancer via PI3K/Akt signaling pathway. Medical oncology (Northwood, London, England) 43 25636507
2013 Lgr4 gene deficiency increases susceptibility and severity of dextran sodium sulfate-induced inflammatory bowel disease in mice. The Journal of biological chemistry 43 23393138
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.) 38 35006616
2022 Nidogen-2 is a Novel Endogenous Ligand of LGR4 to Inhibit Vascular Calcification. Circulation research 38 36354004
2017 MicroRNA-34c promotes osteoclast differentiation through targeting LGR4. Gene 38 28130056
2020 Unlike LGR4, LGR5 potentiates Wnt-β-catenin signaling without sequestering E3 ligases. Science signaling 36 33262293
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
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
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 34 28272338
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
2013 Lgr4/Gpr48 negatively regulates TLR2/4-associated pattern recognition and innate immunity by targeting CD14 expression. The Journal of biological chemistry 32 23589304
2010 GPR48-Induced keratinocyte proliferation occurs through HB-EGF mediated EGFR transactivation. FEBS letters 32 20732323
2014 Lgr4 gene regulates corpus luteum maturation through modulation of the WNT-mediated EGFR-ERK signaling pathway. Endocrinology 31 24877628
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
2016 Association of a gain-of-function variant in LGR4 with central obesity. Obesity (Silver Spring, Md.) 29 27925416
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 29 23975934
2019 The Interplay of MicroRNA-34a, LGR4, EMT-Associated Factors, and MMP2 in Regulating Uveal Melanoma Cells. Investigative ophthalmology & visual science 28 31661551
2016 Lgr4 is crucial for skin carcinogenesis by regulating MEK/ERK and Wnt/β-catenin signaling pathways. Cancer letters 28 27693558
2021 The Role of LGR4 (GPR48) in Normal and Cancer Processes. International journal of molecular sciences 27 33946652
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
2013 Reconstitution of R-spondin:LGR4:ZNRF3 adult stem cell growth factor signaling complexes with recombinant proteins produced in Escherichia coli. Biochemistry 26 24050775
2023 LGR4: A New Receptor Member in Endocrine and Metabolic Diseases. Endocrine reviews 25 36791020
2018 Loss of Lgr4 inhibits differentiation, migration and apoptosis, and promotes proliferation in bone mesenchymal stem cells. Journal of cellular physiology 25 30536377
2013 LGR4 and its ligands, R-spondin 1 and R-spondin 3, regulate food intake in the hypothalamus of male rats. Endocrinology 25 24280058
2010 Reduced fertility with impairment of early-stage embryos observed in mice lacking Lgr4 in epithelial tissues. Fertility and sterility 25 20638054
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 25 10894923
2022 Gastric stem cells promote inflammation and gland remodeling in response to Helicobacter pylori via Rspo3-Lgr4 axis. The EMBO journal 24 35767364
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
2022 LGR4, a G Protein-Coupled Receptor With a Systemic Role: From Development to Metabolic Regulation. Frontiers in endocrinology 23 35707461
2021 A Wnt-Independent LGR4-EGFR Signaling Axis in Cancer Metastasis. Cancer research 23 34099494
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
2017 Blockade of LGR4 inhibits proliferation and odonto/osteogenic differentiation of stem cells from apical papillae. Journal of molecular histology 23 28986711
2014 LGR4 acts as a link between the peripheral circadian clock and lipid metabolism in liver. Journal of molecular endocrinology 23 24353284
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
2018 Down-regulation of miR-193a-3p promotes osteoblast differentiation through up-regulation of LGR4/ATF4 signaling. Biochemical and biophysical research communications 22 30100064
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
2022 LGR4 cooperates with PrPc to endow the stemness of colorectal cancer stem cells contributing to tumorigenesis and liver metastasis. Cancer letters 20 35561877
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
2024 Loss of the stress sensor GADD45A promotes stem cell activity and ferroptosis resistance in LGR4/HOXA9-dependent AML. Blood 19 38579286
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
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
2016 Lgr4 promotes prostate tumorigenesis through the Jmjd2a/AR signaling pathway. Experimental cell research 17 27743893
2011 Expression patterns of lgr4 and lgr6 during zebrafish development. Gene expression patterns : GEP 17 21570488