Affinage

LGR5

Leucine-rich repeat-containing G-protein coupled receptor 5 · UniProt O75473

Length
907 aa
Mass
100.0 kDa
Annotated
2026-06-10
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LGR5 is a seven-transmembrane R-spondin receptor that marks and maintains multipotent, self-renewing adult stem cells, defined originally as the cycling crypt base columnar cells that regenerate all intestinal epithelial lineages and self-organize into crypt-villus organoids from single cells (PMID:17934449, PMID:19329995). Mechanistically, R-spondin-bound LGR5 forms a supercomplex with the Wnt co-receptors FZD5 and LRP6 to enhance LRP6 phosphorylation and potentiate Wnt/β-catenin signaling (PMID:22473993, PMID:33262293); this complex internalizes via clathrin/dynamin, but endocytosis is dispensable for signaling, as C-terminal truncation increases activity while reducing internalization (PMID:22473993, PMID:27207778). Within the Wnt module, the R-spondin/LGR5 interaction tunes signal strength by neutralizing the transmembrane E3 ligases RNF43/ZNRF3 that remove Wnt receptors, yet unlike its paralog LGR4, full-length LGR5 does not itself bind RNF43/ZNRF3—a distinction conferred by the seven-transmembrane domain (PMID:24532711, PMID:33262293, PMID:37402772). Beyond Wnt potentiation, LGR5 engages additional outputs: its C-terminus drives ligand-independent, TROY-dependent NF-κB activation that supports organoid growth, and it activates G12/13-Rho-SRF signaling and shapes actin-rich cytoneme-like protrusions (PMID:33001511, PMID:23912594, PMID:25653388). LGR5 receptor abundance is constrained post-translationally by NEDD4/NEDD4L-mediated proteasomal and lysosomal degradation, loss of which heightens R-spondin sensitivity and accelerates tumorigenesis (PMID:31867777). In tissue, LGR5+ stem cell behavior is governed by niche inputs—Paneth-cell-derived signals, Notch, YAP, IL-17A/ATOH1, and distinct Wnt versus R-spondin roles—that couple self-renewal to differentiation and regeneration (PMID:21113151, PMID:26271103, PMID:26503053, PMID:35081371, PMID:28467820), and LGR5 expression is itself a transcriptional output of Wnt/Hippo and other regulators (PMID:34826093).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2007 High

    Established that LGR5 is not just a Wnt target but a functional marker of bona fide adult stem cells, answering what cell population sustains the intestinal epithelium.

    Evidence Inducible Cre knock-in lineage tracing in mouse intestine in vivo

    PMID:17934449

    Open questions at the time
    • Does not define LGR5's biochemical signaling activity
    • Marker function does not establish whether LGR5 protein is required for stemness
  2. 2009 High

    Showed LGR5+ cells are intrinsically multipotent and niche-independent for organization, by reconstituting crypt-villus organoids from single sorted cells.

    Evidence Single-cell sorting and 3D organoid culture in vitro

    PMID:19329995

    Open questions at the time
    • Culture requires exogenous Wnt/R-spondin/EGF, so cell-autonomous signaling roles remain unresolved
    • Does not address LGR5 receptor mechanism
  3. 2010 High

    Defined the cellular niche and population dynamics of LGR5+ stem cells, establishing Paneth cells as signal providers and symmetric neutral-drift division as the renewal mode.

    Evidence Genetic Paneth ablation, co-culture, and multicolor clonal fate mapping in vivo

    PMID:20887898 PMID:21113151

    Open questions at the time
    • Niche signals identified are paracrine ligands, not LGR5-direct receptor events
    • Does not connect division dynamics to LGR5 signaling output
  4. 2012 High

    Resolved how LGR5 acts within the Wnt machinery, showing it forms an internalizing LRP6/FZD5 supercomplex but that endocytosis is uncoupled from β-catenin potentiation.

    Evidence Co-IP, endocytosis inhibitors, C-terminal deletion, Wnt luciferase reporters

    PMID:22473993

    Open questions at the time
    • Mechanism by which the complex enhances LRP6 phosphorylation not detailed here
    • Role of the C-terminal tail in negative regulation left open
  5. 2013 Medium

    Identified a Wnt-independent LGR5 output, showing ligand-independent G12/13-Rho-SRF activation.

    Evidence SRF-RE reporter, dominant-negative RhoA/G12-13, siRNA knockdown, overexpression

    PMID:23912594

    Open questions at the time
    • Relies on overexpression; physiological relevance in stem cells untested
    • Single lab, no in vivo confirmation
  6. 2014 High

    Placed LGR5 mechanistically as the receptor that tunes Wnt signal strength via the R-spondin/RNF43/ZNRF3 feedback loop.

    Evidence Receptor-ligand and E3-ligase neutralization biochemistry; Co-IP and reporter assays in cancer cells

    PMID:24476626 PMID:24532711

    Open questions at the time
    • Whether LGR5 itself binds the E3 ligases was not yet distinguished from paralogs
    • Context-dependent positive vs negative effects unresolved
  7. 2015 Medium

    Extended LGR5 cell biology to membrane morphology and gastric/niche regulation, linking it to cytoneme formation and Notch-dependent gastric stem cell homeostasis.

    Evidence Live-cell imaging of cytonemes; Notch manipulation with Lgr5-Cre and gastric organoids

    PMID:25653388 PMID:26271103

    Open questions at the time
    • Cytoneme function based on overexpression imaging
    • Notch acts on LGR5+ cells but not via LGR5 receptor itself
  8. 2017 High

    Dissected non-interchangeable Wnt vs R-spondin roles and identified TGFβ cross-talk, showing Wnt maintains LGR5 expression/competency while R-spondin drives expansion, and LGR5 can couple to TGFβ receptors.

    Evidence Synthetic non-lipidated Wnt analogue, RSPO gain-of-function, lineage tracing; LGR5-TGFβR Co-IP with orthotopic model

    PMID:28467820 PMID:28939678

    Open questions at the time
    • TGFβ coupling shown in cancer cells (Medium); generality to normal stem cells unclear
    • Molecular basis of LGR5-TGFβR complex undefined
  9. 2019 High

    Defined post-translational control of LGR5, showing NEDD4/NEDD4L degrade the receptor to restrain R-spondin sensitivity and tumorigenesis.

    Evidence Genetic Nedd4/Nedd4l deletion, organoid assays, degradation Western blots, ApcMin model

    PMID:31867777

    Open questions at the time
    • Ubiquitination sites on LGR5 not mapped
    • Balance between proteasomal and lysosomal routes unresolved
  10. 2020 High

    Mechanistically separated LGR5 from LGR4, establishing that LGR5 does not bind RNF43/ZNRF3 but instead enhances LRP6 phosphorylation, and that its C-terminus drives TROY-dependent NF-κB signaling.

    Evidence Co-IP, PLA, competition binding, TR-FRET, domain-swap mutagenesis; NF-κB reporter and TROY Co-IP with organoid growth assays

    PMID:33001511 PMID:33262293

    Open questions at the time
    • How the 7TM domain selects against E3-ligase binding not structurally resolved
    • NF-κB branch validated in single lab (Medium)
  11. 2023 Medium

    Provided structural-level rationale for paralog divergence, showing LGR4 forms a 2:2 complex with RNF43/ZNRF3 enabling bivalent RSPO sensing while LGR5 homodimers do not.

    Evidence Whole-cell binding affinity assays, Co-IP, structural modeling

    PMID:37402772

    Open questions at the time
    • No experimental high-resolution structure of LGR5 complexes
    • Functional consequence of monovalent/bivalent equivalence in LGR5 stem cells untested
  12. 2024 High

    Connected LGR5+ identity to mechanical and metastatic cancer-stem-cell phenotypes through ERM downregulation.

    Evidence Patient-derived organoids, scRNA-seq, atomic force microscopy, ERM knockdown/overexpression

    PMID:38637494

    Open questions at the time
    • Whether ERM downregulation is downstream of LGR5 signaling per se is not established
    • Link to specific LGR5 signaling branch (Wnt/NF-κB/Rho) undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how LGR5's multiple signaling outputs (Wnt potentiation, NF-κB, G12/13-Rho, TGFβ coupling) are integrated and balanced within a single stem cell to control self-renewal versus differentiation.
  • No unified structural model of LGR5 distinguishing its branch-specific conformations
  • Quantitative contribution of each branch to stem-cell maintenance in vivo unknown

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
Localization
GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3
Partners
FZD5LRP6NEDD4RNF43RSPO1RSPO2TROYZNRF3
Complex memberships
Wnt signalosome (LGR5-FZD5-LRP6)

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Lgr5 marks cycling crypt base columnar (CBC) cells at the intestinal crypt bottom; lineage-tracing using an inducible Cre knock-in allele demonstrated that these Lgr5+ CBC cells are self-renewing, multipotent stem cells that generate all epithelial lineages of the small intestine and colon over a 60-day period. Knock-in allele reporter mice; inducible Cre/Rosa26-lacZ lineage tracing in vivo Nature High 17934449
2009 Single sorted Lgr5+ stem cells can self-organize into crypt-villus organoids in vitro, generating all differentiated epithelial cell types and maintaining the Lgr5+ stem-cell hierarchy, demonstrating that the intestinal crypt-villus unit is a self-organizing structure that does not require a non-epithelial mesenchymal niche. Single-cell sorting of Lgr5+ cells, 3D organoid culture, lineage tracing in vitro Nature High 19329995
2010 Paneth cells constitute the niche for Lgr5+ stem cells by physically interdigitating with them and providing essential niche signals (EGF, TGF-α, Wnt3, Dll4); genetic removal of Paneth cells in vivo results in concomitant loss of Lgr5+ stem cells, and co-culture of sorted Lgr5+ stem cells with Paneth cells markedly improves organoid formation. Co-culture assays, genetic Paneth cell ablation in vivo, FACS sorting, organoid formation assay Nature High 21113151
2010 Lgr5-high stem cells in the intestinal crypt divide symmetrically and undergo neutral drift dynamics; crypt clonality is achieved stochastically rather than through asymmetric division, as shown by multicolor clonal fate mapping. Multicolor Cre-reporter fate mapping (Rainbow mouse); quantitative clonal tracing Cell High 20887898
2012 LGR5, upon co-stimulation with R-spondin1 and Wnt3a, forms a supercomplex with Wnt co-receptors LRP6 and Fzd5, which is internalized via a dynamin- and clathrin-dependent pathway; deletion of the LGR5 C-terminal tail increases signaling activity and decreases endocytosis, indicating that internalization is not required for Wnt/β-catenin potentiation. Co-immunoprecipitation, endocytosis inhibitors, C-terminal deletion mutagenesis, luciferase Wnt reporter assays Molecular and cellular biology High 22473993
2014 The R-spondin/Lgr5/Rnf43 module regulates Wnt signal strength: Lgr5 and homologs Lgr4/Lgr6 are receptors for R-spondins; the Lgr5/R-spondin complex acts by neutralizing RNF43 and ZNRF3, two transmembrane E3 ligases (themselves Wnt target genes) that remove Wnt receptors from the stem cell surface, constituting a negative Wnt feedback loop that is relieved by R-spondin. Biochemical characterization, review synthesizing multiple experimental findings including receptor identification and E3 ligase neutralization Genes & development High 24532711
2014 RSPO2 interacts with LGR5 to stabilize membrane-associated ZNRF3, thereby inhibiting Wnt/β-catenin signaling in colorectal cancer cells; the RSPO2-induced inhibition of Wnt signaling is dependent on LGR5, revealing a LGR5-dependent negative feedback mechanism. Co-immunoprecipitation, LGR5 knockdown, Wnt reporter assays, cell proliferation assays Nature communications Medium 24476626
2015 Lgr5 and Lgr4 promote formation of ultra-long actin-rich cytoneme-like membrane protrusions (exceeding 80 µm) by stabilizing nascent filopodia from a lamellipodial-like network; these cytonemes serve as conduits for transit of signaling effectors including myosin X (Myo10) and β-arrestin-2 (Arrb2). Live-cell imaging, overexpression of Lgr4/Lgr5, fluorescent reporter constructs for cargo tracking Journal of cell science Medium 25653388
2013 LGR5/GPR49 overexpression activates the G12/13-Rho GTPase signaling pathway in a ligand-independent manner; LGR5-induced SRF-RE reporter activity is blocked by Rho inhibitor C3 transferase, RhoA-N19 mutant, and Gα12/13 knockdown. R-spondin ligands did not activate this Rho pathway in the presence of LGR5. SRF-RE luciferase reporter assay, dominant-negative mutants, siRNA knockdown of Gα12/13, LGR5 overexpression Molecules and cells Medium 23912594
2019 The HECT-domain E3 ubiquitin ligases NEDD4 and NEDD4L are expressed in intestinal crypt stem cell regions and negatively regulate LGR5 receptor and DVL2 by targeting them for proteasomal and lysosomal degradation; loss of Nedd4/Nedd4l enhances ISC proliferation, increases sensitivity to R-spondin stimulation, and accelerates tumor development. Genetic deletion of Nedd4/Nedd4l, organoid assays, Western blotting for protein degradation, ApcMin tumor model The EMBO journal High 31867777
2020 Unlike LGR4, full-length LGR5 does not interact with E3 ligases RNF43 or ZNRF3 (with or without RSPO), as shown by Co-IP, proximity ligation, competition binding, and time-resolved FRET assays; instead, LGR5 interacts with FZD and LRP6 of the Wnt signalosome to enhance LRP6 phosphorylation and potentiate Wnt/β-catenin signaling. Domain-swapping revealed the LGR4 seven-transmembrane domain confers E3 ligase interaction. Co-immunoprecipitation, proximity ligation assay, competition binding, time-resolved FRET, domain-swap mutagenesis Science signaling High 33262293
2023 LGR4 forms a 2:2 homodimer complex with RNF43/ZNRF3 that accommodates bivalent RSPO binding, whereas LGR5 forms a homodimer that does not interact with these E3 ligases; monovalent and bivalent RSPO2 have nearly identical affinity for LGR5, in contrast to LGR4. Co-expression of ZNRF3 with LGR4 greatly increases monovalent RSPO affinity but has no effect when co-expressed with LGR5. Whole-cell binding affinity assays, co-immunoprecipitation, structural modeling Scientific reports Medium 37402772
2020 LGR5 and LGR4 constitutively activate NF-κB signaling in a ligand-independent manner through their C-termini; the C-termini of LGR5/4 interact with the adaptor protein TROY, which is required for NF-κB activation. Overexpression of a C-terminal deletion mutant of LGR5 inhibits organoid growth and budding, while an R-spondin-binding-deficient mutant of LGR5 still promotes organoid growth via NF-κB. C-terminal deletion and binding-domain mutagenesis, luciferase NF-κB reporter, co-immunoprecipitation with TROY, intestinal organoid growth assays FASEB journal Medium 33001511
2017 R-spondin1/LGR5 directly activates TGFβ signaling cooperatively with TGFβ type II receptor in colon cancer cells; upon RSPO1 stimulation, LGR5 forms complexes with TGFβ receptors, enhancing TGFβ-mediated growth inhibition and apoptosis. LGR5 knockdown attenuated downstream TGFβ signaling and increased metastasis in an orthotopic colon cancer model. Co-immunoprecipitation (LGR5-TGFβR complex), siRNA knockdown, orthotopic xenograft model, downstream signaling assays Cancer research Medium 28939678
2017 Wnt and R-spondin ligands have qualitatively distinct, non-interchangeable roles in Lgr5+ ISC self-renewal: Wnt proteins cannot induce ISC self-renewal but confer basal competency by maintaining RSPO receptor (LGR5) expression, while RSPO ligands actively drive stem-cell expansion. This was shown using a non-lipidated Wnt analogue and genetic/organoid approaches. In vivo genetic Wnt loss-of-function, non-lipidated Wnt analogue, RSPO gain-of-function, Lgr5+ ISC organoid culture, single-cell lineage tracing Nature High 28467820
2015 Notch signaling is intrinsic to the gastric epithelium and is essential for homeostasis of LGR5+ antral stem cells; Notch inhibition reduces proliferation and induces mucous/endocrine differentiation, while constitutive Notch activation in LGR5+ stem cells induces gland fission and tissue expansion via mTORC1 signaling. Pharmacological Notch inhibition/activation, conditional Notch activation using Lgr5-Cre, gastric organoid culture, multicolor lineage tracing The EMBO journal High 26271103
2015 Yap transiently reprograms Lgr5+ ISCs by suppressing Wnt signaling and excessive Paneth cell differentiation while promoting cell survival and inducing an Egf pathway regenerative program; Yap-deficient organoid growth is rescued by the Egfr ligand epiregulin, and Yap inactivation abolishes adenomas in Apc(Min) mice. Yap conditional knockout mice, irradiation injury model, organoid rescue assays with epiregulin, Apc(Min) tumor model Nature High 26503053
2019 R-spondin-3 (Rspo3) secreted by myofibroblasts acts on basal Lgr5+ gastric stem cells to induce their differentiation into secretory cells expressing antimicrobial factors (e.g., intelectin-1), rather than promoting proliferation; depletion of Lgr5+ cells or Rspo3 knockout leads to hypercolonization of gastric glands with H. pylori. Lgr5+ cell depletion, Rspo3 conditional knockout in myofibroblasts, systemic Rspo3 administration, H. pylori colonization assays Nature cell biology High 31235935
2017 LGR5 expression in neuroblastoma cells regulates pro-survival MEK/ERK signaling independently of Wnt; siRNA-mediated LGR5 knockdown induces apoptosis accompanied by decreased phosphorylation of MEK1/2 and ERK1/2, increased BimEL, decreased Akt signaling via a Rictor-dependent PDK1-independent mechanism, and G1 cell-cycle arrest with increased p27. siRNA knockdown, Western blotting for MEK/ERK/Akt phosphorylation, cell cycle analysis, apoptosis assays Oncotarget Medium 26517508
2016 LGR5 undergoes rapid, constitutive internalization independent of ligand, and LGR5-high cancer cells exhibit properties of tumor-initiating/cancer stem cells; LGR5-targeting antibody-drug conjugates internalize to lysosomes of LGR5-expressing cells and induce cytotoxicity specifically in LGR5-high but not LGR5-negative or LGR5-knockdown cells. Receptor binding assays, cell internalization assays, cytotoxicity assays, xenograft tumor model Molecular cancer therapeutics Medium 27207778
2022 IL-17A signaling through IL-17RA in Lgr5+ intestinal stem cells induces expression of transcription factor ATOH1 to promote secretory epithelial cell lineage commitment; multiple conditional deletion models demonstrated that Paneth, tuft, goblet, and enteroendocrine cell numbers were dependent on this IL-17A/ATOH1 axis specifically in Lgr5+ cells. Multiple conditional deletion mouse models (Lgr5-Cre, ATOH1-Cre), human intestinal organoid stimulation with IL-17A Immunity High 35081371
2020 NOD2 agonist MDP protects Lgr5+ intestinal stem cells against oxidative stress-induced death via mitophagy; MDP-induced cytoprotection requires both NOD2 and ATG16L1; the mechanism involves NOD2-dependent reduction of mitochondrial ROS through mitophagy induction, independent of NF-κB. ATG16L1 and NOD2 knockout organoids, irradiation stress model, ROS measurement, mitophagy quantification in vivo and in vitro Proceedings of the National Academy of Sciences of the United States of America High 31919280
2016 IKKα binds directly to the LGR5 promoter in basal cell carcinoma cells and upregulates LGR5 expression through activation of the STAT3 signaling pathway; STAT3 and IKKα interact functionally to drive LGR5 expression during BCC cancer progression. ChIP assay (IKKα at LGR5 promoter), STAT3 pathway inhibition, IKKα knockdown, tumor growth assays Oncotarget Medium 27049829
2015 SOX9 directly transcriptionally upregulates LGR5 expression in glioblastoma cells; knockdown of SOX9 suppresses LGR5 expression, proliferation, and tumorigenicity of glioblastoma cells, establishing a SOX9-LGR5 regulatory axis. SOX9 knockdown, luciferase reporter (LGR5 promoter), ChIP, LGR5 KD functional assays Biochemical and biophysical research communications Medium 25770425
2017 LGR5 knockdown in human pluripotent stem cells (hPSCs) reduces cardiomyocyte-associated markers and impairs cardiac differentiation, while promoting endothelial cell differentiation with increased nuclear translocation of β-catenin and upregulation of Wnt signaling-related genes, indicating LGR5 modulates hPSC lineage fate through Wnt/β-catenin regulation. LGR5 siRNA knockdown during hPSC differentiation, qRT-PCR, immunostaining, functional tube formation and LDL uptake assays Stem cell reports Medium 28793247
2024 LGR5+ colorectal cancer stem cells are mechanically stiffer, adhere better to ECM, move slower, display higher nuclear YAP, and form larger transendothelial gaps compared to LGR5- cells; these differences are largely explained by downregulation of membrane-to-cortex attachment proteins Ezrin/Radixin/Moesin (ERMs) in LGR5+ cells. Patient-derived organoids, single-cell RNA-seq, atomic force microscopy, live-cell imaging, ERM knockdown/overexpression Nature communications High 38637494
2023 Loss of LGR5 expression (through chemotherapy, LGR5-targeted ADC treatment, or gene ablation) in colorectal cancer cells activates STAT3 via increased MET (mesenchymal-epithelial transition factor) receptor activity; LGR5 overexpression decreased MET-STAT3 activity, and STAT3 inhibition suppressed MET phosphorylation, suggesting a feedback mechanism between LGR5, MET, and STAT3. LGR5 gene ablation, LGR5 overexpression, Western blotting, MET/STAT3 inhibition, tumor organoids and xenograft model Molecular cancer therapeutics Medium 36921315
2022 Quiescent (slow-cycling) LGR5+p27+ cells exist in the human colon and display lineage-forming capability in vivo; TGFβ signaling regulates the quiescent state of these LGR5+ cells, as shown by orthotopic xenotransplantation and lineage tracing of LGR5-tdTomato/LGR5-iCaspase9 knock-in human colon organoids. Single-cell RNA-seq, genome-engineered human organoid knock-ins (LGR5-tdTomato, LGR5-iCaspase9, p27-mVenus), orthotopic xenotransplantation, EdU pulse-chase, TGFβ pathway manipulation Gastroenterology High 35963362
2021 REGγ enhances transcriptional activation of Lgr5 via potentiation of both Wnt and Hippo signaling pathways; TEAD4 alone or cooperating with TCF4 directly enhances Lgr5 expression, and silencing TEAD4 drastically attenuates β-catenin/TCF4-dependent Lgr5 expression. Conditional ablation of REGγ in Lgr5+ stem cells impairs intestinal crypt proliferation and delays regeneration after irradiation. Conditional REGγ knockout in Lgr5+ cells, TEAD4 and TCF4 co-transfection/silencing, luciferase reporter assays for Lgr5 promoter, irradiation injury model Science China. Life sciences Medium 34826093

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 5642 19329995
2007 Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 4597 17934449
2010 Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 1998 21113151
2010 Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 1580 20887898
2010 Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell stem cell 1256 20085740
2013 In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 1231 23354049
2012 Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5⁺ stem cell. Nature medicine 646 22406745
2012 The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent '+4' cell markers. The EMBO journal 634 22692129
2017 A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer. Nature 631 28358093
2017 Visualization and targeting of LGR5+ human colon cancer stem cells. Nature 577 28355176
2015 Yap-dependent reprogramming of Lgr5(+) stem cells drives intestinal regeneration and cancer. Nature 526 26503053
2014 The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength. Genes & development 526 24532711
2013 Niche-independent high-purity cultures of Lgr5+ intestinal stem cells and their progeny. Nature methods 459 24292484
2017 Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal. Nature 354 28467820
2017 Anatomically and Functionally Distinct Lung Mesenchymal Populations Marked by Lgr5 and Lgr6. Cell 300 28886383
2009 Wnt signaling, lgr5, and stem cells in the intestine and skin. The American journal of pathology 277 19197002
2020 Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer. Cell stem cell 249 32169167
2014 Lgr5 marks stem/progenitor cells in ovary and tubal epithelia. Nature cell biology 179 24997521
2012 LGR5 interacts and cointernalizes with Wnt receptors to modulate Wnt/β-catenin signaling. Molecular and cellular biology 174 22473993
2003 Overexpression of orphan G-protein-coupled receptor, Gpr49, in human hepatocellular carcinomas with beta-catenin mutations. Hepatology (Baltimore, Md.) 174 12601349
2006 Identification of overexpression of orphan G protein-coupled receptor GPR49 in human colon and ovarian primary tumors. Cancer biology & therapy 156 16575208
2014 Stem cells marked by the R-spondin receptor LGR5. Gastroenterology 137 24859206
2011 Dynamic expression of Lgr5, a Wnt target gene, in the developing and mature mouse cochlea. Journal of the Association for Research in Otolaryngology : JARO 132 21472479
2022 Functional patient-derived organoid screenings identify MCLA-158 as a therapeutic EGFR × LGR5 bispecific antibody with efficacy in epithelial tumors. Nature cancer 126 35469014
2022 LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma. Cell 123 35381199
2008 G-protein-coupled receptor GPR49 is up-regulated in basal cell carcinoma and promotes cell proliferation and tumor formation. The American journal of pathology 123 18688030
2020 Lgr5+ telocytes are a signaling source at the intestinal villus tip. Nature communications 120 32321913
2018 Targeting LGR5 in Colorectal Cancer: therapeutic gold or too plastic? British journal of cancer 116 29844449
2018 Recent Advances in Lgr5+ Stem Cell Research. Trends in cell biology 115 29477614
2014 RSPO2-LGR5 signaling has tumour-suppressive activity in colorectal cancer. Nature communications 107 24476626
2011 Lgr5 and Lgr6 as markers to study adult stem cell roles in self-renewal and cancer. Oncogene 107 22002312
2016 LGR5-Targeted Antibody-Drug Conjugate Eradicates Gastrointestinal Tumors and Prevents Recurrence. Molecular cancer therapeutics 98 27207778
2015 Notch signaling regulates gastric antral LGR5 stem cell function. The EMBO journal 90 26271103
2019 Lgr5+ pericentral hepatocytes are self-maintained in normal liver regeneration and susceptible to hepatocarcinogenesis. Proceedings of the National Academy of Sciences of the United States of America 84 31488716
2019 Lgr5 in cancer biology: functional identification of Lgr5 in cancer progression and potential opportunities for novel therapy. Stem cell research & therapy 83 31358061
2019 NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor. The EMBO journal 82 31867777
2014 Functional roles of Lgr4 and Lgr5 in embryonic gut, kidney and skin development in mice. Developmental biology 82 24680895
2017 LGR5 promotes cancer stem cell traits and chemoresistance in cervical cancer. Cell death & disease 80 28880275
2020 Innate immune receptor NOD2 mediates LGR5+ intestinal stem cell protection against ROS cytotoxicity via mitophagy stimulation. Proceedings of the National Academy of Sciences of the United States of America 79 31919280
2022 IL-17RA-signaling in Lgr5+ intestinal stem cells induces expression of transcription factor ATOH1 to promote secretory cell lineage commitment. Immunity 73 35081371
2019 Population and Single-Cell Analysis of Human Cardiogenesis Reveals Unique LGR5 Ventricular Progenitors in Embryonic Outflow Tract. Developmental cell 71 30713072
2020 LGR5 marks targetable tumor-initiating cells in mouse liver cancer. Nature communications 69 32327656
2015 LGR5 regulates pro-survival MEK/ERK and proliferative Wnt/β-catenin signalling in neuroblastoma. Oncotarget 69 26517508
2019 R-spondin-3 induces secretory, antimicrobial Lgr5+ cells in the stomach. Nature cell biology 68 31235935
2011 Expression of LGR5, an intestinal stem cell marker, during each stage of colorectal tumorigenesis. Anticancer research 63 21273608
2018 Identification, isolation and characterization of human LGR5-positive colon adenoma cells. Development (Cambridge, England) 62 29467240
2017 Stem cell plasticity enables hair regeneration following Lgr5+ cell loss. Nature cell biology 62 28553937
2021 A tumour-resident Lgr5+ stem-cell-like pool drives the establishment and progression of advanced gastric cancers. Nature cell biology 61 34857912
2017 R-Spondin1/LGR5 Activates TGFβ Signaling and Suppresses Colon Cancer Metastasis. Cancer research 56 28939678
2014 YY1 is indispensable for Lgr5+ intestinal stem cell renewal. Proceedings of the National Academy of Sciences of the United States of America 55 24821761
2022 Identification of Quiescent LGR5+ Stem Cells in the Human Colon. Gastroenterology 45 35963362
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
2011 Chaetoglobosin Fex from the marine-derived endophytic fungus inhibits induction of inflammatory mediators via Toll-like receptor 4 signaling in macrophages. Biological & pharmaceutical bulletin 39 22130243
2023 Lgr5-expressing secretory cells form a Wnt inhibitory niche in cartilage critical for chondrocyte identity. Cell stem cell 38 37683603
2022 AQP5 complements LGR5 to determine the fates of gastric cancer stem cells through regulating ULK1 ubiquitination. Journal of experimental & clinical cancer research : CR 38 36372898
2021 αSMA+ fibroblasts suppress Lgr5+ cancer stem cells and restrain colorectal cancer progression. Oncogene 38 34108617
2024 Notoginsenoside R1 promotes Lgr5+ stem cell and epithelium renovation in colitis mice via activating Wnt/β-Catenin signaling. Acta pharmacologica Sinica 36 38491161
2016 Characterization of Lgr5+ progenitor cell transcriptomes in the apical and basal turns of the mouse cochlea. Oncotarget 36 27070092
2014 Structure and function of LGR5: an enigmatic G-protein coupled receptor marking stem cells. Protein science : a publication of the Protein Society 35 24677446
2018 LGR5 and BMI1 Increase Pig Intestinal Epithelial Cell Proliferation by Stimulating WNT/β-Catenin Signaling. International journal of molecular sciences 34 29601474
2016 Co-expression of Lgr5 and CXCR4 characterizes cancer stem-like cells of colorectal cancer. Oncotarget 34 27835894
2013 Intestinal stem cell marker LGR5 expression during gastric carcinogenesis. World journal of gastroenterology 32 24379591
2021 TNFα Induces LGR5+ Stem Cell Dysfunction In Patients With Crohn's Disease. Cellular and molecular gastroenterology and hepatology 31 34700029
2017 LGR5 and LGR6 in stem cell biology and ovarian cancer. Oncotarget 31 29416699
2017 Fluoride export (FEX) proteins from fungi, plants and animals are 'single barreled' channels containing one functional and one vestigial ion pore. PloS one 28 28472134
2021 REGγ drives Lgr5+ stem cells to potentiate radiation induced intestinal regeneration. Science China. Life sciences 27 34826093
2020 MEX3A regulates Lgr5+ stem cell maintenance in the developing intestinal epithelium. EMBO reports 26 32052574
2020 Hyaluronic acid promotes Lgr5+ stem cell proliferation and crypt fission through TLR4 and PGE2 transactivation of EGFR. American journal of physiology. Gastrointestinal and liver physiology 26 32538139
2020 LGR5+ epithelial tumor stem-like cells generate a 3D-organoid model for ameloblastoma. Cell death & disease 25 32382005
2016 LGR5 expression is controled by IKKα in basal cell carcinoma through activating STAT3 signaling pathway. Oncotarget 25 27049829
2019 Pten loss in Lgr5+ hair follicle stem cells promotes SCC development. Theranostics 23 31754399
2016 Lgr5 Marks Neural Crest Derived Multipotent Oral Stromal Stem Cells. Stem cells (Dayton, Ohio) 23 26865184
2013 The clinicopathological significance of Lgr5 expression in lung adenocarcinoma. Lung cancer (Amsterdam, Netherlands) 23 23915911
2012 Clinical significance of LGR5 and CD44 expression in locally advanced rectal cancer after preoperative chemoradiotherapy. International journal of oncology 23 22923071
2024 Membrane to cortex attachment determines different mechanical phenotypes in LGR5+ and LGR5- colorectal cancer cells. Nature communications 22 38637494
2021 LGR5/R-Spo1/Wnt3a axis promotes stemness and aggressive phenotype in hepatoblast-like hepatocellular carcinoma cell lines. Cellular signalling 22 33684507
2019 Loss of PKM2 in Lgr5+ intestinal stem cells promotes colitis-associated colorectal cancer. Scientific reports 22 30996297
2020 LGR5 induces β-catenin activation and augments tumour progression by activating STAT3 in human intrahepatic cholangiocarcinoma. Liver international : official journal of the International Association for the Study of the Liver 21 33249719
2011 A novel splice variant of the stem cell marker LGR5/GPR49 is correlated with the risk of tumor-related death in soft-tissue sarcoma patients. BMC cancer 21 21978106
2016 Full-length LGR5-positive cells have chemoresistant characteristics in colorectal cancer. British journal of cancer 20 27140312
2022 Glucagon-Like Peptide-2 Stimulates S-Phase Entry of Intestinal Lgr5+ Stem Cells. Cellular and molecular gastroenterology and hepatology 19 35218981
2015 SOX9-mediated upregulation of LGR5 is important for glioblastoma tumorigenicity. Biochemical and biophysical research communications 19 25770425
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
2018 Monoclonal Antibodies Reveal Dynamic Plasticity Between Lgr5- and Bmi1-Expressing Intestinal Cell Populations. Cellular and molecular gastroenterology and hepatology 18 29928673
2017 LGR5 expression is regulated by EGF in early colorectal adenomas and governs EGFR inhibitor sensitivity. British journal of cancer 18 29149105
2017 Downregulation of LGR5 Expression Inhibits Cardiomyocyte Differentiation and Potentiates Endothelial Differentiation from Human Pluripotent Stem Cells. Stem cell reports 17 28793247
2020 LGR5 constitutively activates NF-κB signaling to regulate the growth of intestinal crypts. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 33001511
2017 Expression and functional regulation of stemness gene Lgr5 in esophageal squamous cell carcinoma. Oncotarget 16 28404917
2014 LGR5 expression in oral epithelial dysplasia and oral squamous cell carcinoma. Oral surgery, oral medicine, oral pathology and oral radiology 16 25592865
2014 Overexpression of Leucine-Rich Repeat-Containing G Protein-Coupled Receptor 5 (LGR5) Represents a Typical Wnt/β-Catenin Pathway-Activated Hepatocellular Carcinoma. Liver cancer 16 26280006
2013 LGR5 is a proneural factor and is regulated by OLIG2 in glioma stem-like cells. Cellular and molecular neurobiology 16 23793848
2013 The Lgr5 transgene is expressed specifically in glycinergic amacrine cells in the mouse retina. Experimental eye research 16 24246263
2025 LGR5: An emerging therapeutic target for cancer metastasis and chemotherapy resistance. Cancer metastasis reviews 15 39821694
2023 Loss of LGR5 through Therapy-induced Downregulation or Gene Ablation Is Associated with Resistance and Enhanced MET-STAT3 Signaling in Colorectal Cancer Cells. Molecular cancer therapeutics 14 36921315
2022 Differential epithelial and stromal LGR5 expression in ovarian carcinogenesis. Scientific reports 14 35778589
2022 Elevated Expression of LGR5 and WNT Signaling Factors in Neuroblastoma Cells With Acquired Drug Resistance. Cancer investigation 14 36318235
2024 Novel immunotherapeutics against LGR5 to target multiple cancer types. EMBO molecular medicine 13 39169164
2017 Expression of LGR5 in oral squamous cell carcinoma and its correlation to vasculogenic mimicry. International journal of clinical and experimental pathology 13 31966480
2013 Leucine-rich repeat-containing G-protein coupled receptor 5/GPR49 activates G12/13-Rho GTPase pathway. Molecules and cells 13 23912594

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