LGR5 is a leucine-rich repeat-containing seven-transmembrane receptor of the glycoprotein hormone receptor-like (rhodopsin family) group, with a large N-terminal ectodomain of 17 leucine-rich repeats that binds the secreted R-spondins (RSPO1-4). It marks Wnt-dependent adult stem cells of the intestinal crypt, stomach, hair follicle and other epithelia. R-spondin binding by LGR4/5/6 potentiates canonical Wnt/beta-catenin signaling by enhancing Wnt-induced LRP6 phosphorylation, in part by recruiting and neutralizing the E3 ligases RNF43/ZNRF3 that otherwise degrade Frizzled and LRP receptors; LGR5 does not activate heterotrimeric G proteins or beta-arrestin. LGR5 reaches the plasma membrane, where its ectodomain is exposed for ligand binding, but it is constitutively internalized by dynamin-dependent endocytosis and retromer-mediated retrograde transport, so at steady state it is predominantly intracellular in the trans-Golgi network.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004888 transmembrane signaling receptor activity | IDA PMID:21693646 R-spondins function as ligands of the orphan receptors LGR4 ... | ACCEPT | Summary: LGR5 is a transmembrane receptor for R-spondins. Reason: R-spondins bind the LGR5 ectodomain with high affinity (crystal structure of the RSPO1-LGR5 ectodomain complex) and LGR5 mediates RSPO potentiation of Wnt/beta-catenin signaling; LGR5 can substitute for LGR4. Supporting Evidence: PMID:21693646 Here we demonstrate that LGR4 and LGR5 bind the R-spondins with high affinity and mediate the potentiation of Wnt/Ξ²-catenin signaling by enhancing Wnt-induced LRP6 phosphorylation. PMID:22815884 We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5 PMID:23809763 Ecto-LGR5 binds Rspo1 at its concave leucine-rich-repeat (LRR) surface, forming a dimeric 2:2 complex. |
| GO:0004888 transmembrane signaling receptor activity | IDA PMID:22815884 R-Spondin potentiates Wnt/Ξ²-catenin signaling through orphan... | ACCEPT | Summary: LGR5 is a transmembrane receptor for R-spondins. Reason: R-spondins bind the LGR5 ectodomain with high affinity (crystal structure of the RSPO1-LGR5 ectodomain complex) and LGR5 mediates RSPO potentiation of Wnt/beta-catenin signaling; LGR5 can substitute for LGR4. Supporting Evidence: PMID:21693646 Here we demonstrate that LGR4 and LGR5 bind the R-spondins with high affinity and mediate the potentiation of Wnt/Ξ²-catenin signaling by enhancing Wnt-induced LRP6 phosphorylation. PMID:22815884 We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5 PMID:23809763 Ecto-LGR5 binds Rspo1 at its concave leucine-rich-repeat (LRR) surface, forming a dimeric 2:2 complex. |
| GO:0004888 transmembrane signaling receptor activity | IEA GO_REF:0000107 | ACCEPT | Summary: LGR5 is a transmembrane receptor for R-spondins. Reason: R-spondins bind the LGR5 ectodomain with high affinity (crystal structure of the RSPO1-LGR5 ectodomain complex) and LGR5 mediates RSPO potentiation of Wnt/beta-catenin signaling; LGR5 can substitute for LGR4. Supporting Evidence: PMID:21693646 Here we demonstrate that LGR4 and LGR5 bind the R-spondins with high affinity and mediate the potentiation of Wnt/Ξ²-catenin signaling by enhancing Wnt-induced LRP6 phosphorylation. PMID:22815884 We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5 PMID:23809763 Ecto-LGR5 binds Rspo1 at its concave leucine-rich-repeat (LRR) surface, forming a dimeric 2:2 complex. |
| GO:0004930 G protein-coupled receptor activity | IDA NOT PMID:21693646 R-spondins function as ligands of the orphan receptors LGR4 ... | ACCEPT | Summary: Curated NOT annotation; LGR5 does not enable canonical G-protein-coupled receptor activity. Reason: This is a curated NOT (negated) annotation, and the evidence supports the negation. The cited studies show directly that R-spondin-stimulated LGR5/LGR4 do not couple to heterotrimeric G proteins or beta-arrestin. Keep it as the machine-readable record that LGR5 lacks canonical GPCR activity; its actual receptor function is transmembrane signaling receptor activity. The positive TAS assertion of GPCR activity is the row that is contradicted and REMOVEd below. Supporting Evidence: PMID:21693646 Interestingly, neither receptor is coupled to heterotrimeric G proteins or to Ξ²-arrestin when stimulated by the R-spondins, indicating a unique mechanism of action. PMID:22815884 No coupling between LGR4 and heterotrimeric G proteins could be detected in RSPO-treated cells |
| GO:0004930 G protein-coupled receptor activity | IDA NOT PMID:22815884 R-Spondin potentiates Wnt/Ξ²-catenin signaling through orphan... | ACCEPT | Summary: Curated NOT annotation; LGR5 does not enable canonical G-protein-coupled receptor activity. Reason: This is a curated NOT (negated) annotation, and the evidence supports the negation. The cited studies show directly that R-spondin-stimulated LGR5/LGR4 do not couple to heterotrimeric G proteins or beta-arrestin. Keep it as the machine-readable record that LGR5 lacks canonical GPCR activity; its actual receptor function is transmembrane signaling receptor activity. The positive TAS assertion of GPCR activity is the row that is contradicted and REMOVEd below. Supporting Evidence: PMID:21693646 Interestingly, neither receptor is coupled to heterotrimeric G proteins or to Ξ²-arrestin when stimulated by the R-spondins, indicating a unique mechanism of action. PMID:22815884 No coupling between LGR4 and heterotrimeric G proteins could be detected in RSPO-treated cells |
| GO:0004930 G protein-coupled receptor activity | TAS PMID:9642114 Identification and cloning of an orphan G protein-coupled re... | REMOVE | Summary: GPCR activity inferred from LGR5's seven-transmembrane architecture. Reason: Although LGR5 belongs structurally to the GPCR superfamily, the cited studies explicitly show that R-spondin-stimulated LGR5/LGR4 do not couple to heterotrimeric G proteins or beta-arrestin. G protein-coupled receptor activity (activation of a G protein) is therefore contradicted; its receptor function is captured by transmembrane signaling receptor activity. Supporting Evidence: PMID:21693646 Interestingly, neither receptor is coupled to heterotrimeric G proteins or to Ξ²-arrestin when stimulated by the R-spondins, indicating a unique mechanism of action. PMID:22815884 No coupling between LGR4 and heterotrimeric G proteins could be detected in RSPO-treated cells |
| GO:0005515 protein binding | IPI PMID:21693646 R-spondins function as ligands of the orphan receptors LGR4 ... | MODIFY | Summary: LGR5 binds R-spondins (RSPO1, RSPO2). Reason: Following the protein-binding policy, the informative activity is the receptor function for R-spondins, shown by ectodomain binding and RSPO-dependent signaling. (One row, PMID:29769720, reports RSPO2 can act independently of LGR4-6 in limb development; the binding itself is not disputed.) Proposed replacements: transmembrane signaling receptor activity Supporting Evidence: PMID:23809763 Ecto-LGR5 binds Rspo1 at its concave leucine-rich-repeat (LRR) surface, forming a dimeric 2:2 complex. PMID:22815884 We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5 |
| GO:0005515 protein binding | IPI PMID:21727895 Lgr5 homologues associate with Wnt receptors and mediate R-s... | MODIFY | Summary: LGR5 binds R-spondins (RSPO1, RSPO2). Reason: Following the protein-binding policy, the informative activity is the receptor function for R-spondins, shown by ectodomain binding and RSPO-dependent signaling. (One row, PMID:29769720, reports RSPO2 can act independently of LGR4-6 in limb development; the binding itself is not disputed.) Proposed replacements: transmembrane signaling receptor activity Supporting Evidence: PMID:23809763 Ecto-LGR5 binds Rspo1 at its concave leucine-rich-repeat (LRR) surface, forming a dimeric 2:2 complex. PMID:22815884 We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5 |
| GO:0005515 protein binding | IPI PMID:22815884 R-Spondin potentiates Wnt/Ξ²-catenin signaling through orphan... | MODIFY | Summary: LGR5 binds R-spondins (RSPO1, RSPO2). Reason: Following the protein-binding policy, the informative activity is the receptor function for R-spondins, shown by ectodomain binding and RSPO-dependent signaling. (One row, PMID:29769720, reports RSPO2 can act independently of LGR4-6 in limb development; the binding itself is not disputed.) Proposed replacements: transmembrane signaling receptor activity Supporting Evidence: PMID:23809763 Ecto-LGR5 binds Rspo1 at its concave leucine-rich-repeat (LRR) surface, forming a dimeric 2:2 complex. PMID:22815884 We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5 |
| GO:0005515 protein binding | IPI PMID:23809763 Structure of stem cell growth factor R-spondin 1 in complex ... | MODIFY | Summary: LGR5 binds R-spondins (RSPO1, RSPO2). Reason: Following the protein-binding policy, the informative activity is the receptor function for R-spondins, shown by ectodomain binding and RSPO-dependent signaling. (One row, PMID:29769720, reports RSPO2 can act independently of LGR4-6 in limb development; the binding itself is not disputed.) Proposed replacements: transmembrane signaling receptor activity Supporting Evidence: PMID:23809763 Ecto-LGR5 binds Rspo1 at its concave leucine-rich-repeat (LRR) surface, forming a dimeric 2:2 complex. PMID:22815884 We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5 |
| GO:0005515 protein binding | IPI PMID:29769720 RSPO2 inhibition of RNF43 and ZNRF3 governs limb development... | MODIFY | Summary: LGR5 binds R-spondins (RSPO1, RSPO2). Reason: Following the protein-binding policy, the informative activity is the receptor function for R-spondins, shown by ectodomain binding and RSPO-dependent signaling. (One row, PMID:29769720, reports RSPO2 can act independently of LGR4-6 in limb development; the binding itself is not disputed.) Proposed replacements: transmembrane signaling receptor activity Supporting Evidence: PMID:23809763 Ecto-LGR5 binds Rspo1 at its concave leucine-rich-repeat (LRR) surface, forming a dimeric 2:2 complex. PMID:22815884 We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5 |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | MODIFY | Summary: UniProt mapping to the Golgi apparatus. Reason: The Golgi pool of LGR5 is specifically the trans-Golgi network membrane reached by retrograde transport, a term already carried by the gene. Proposed replacements: trans-Golgi network membrane Supporting Evidence: PMID:23439653 reaches a steady-state distribution in the TGN within 2 h |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: LGR5 is a multi-pass plasma membrane receptor with an extracellular ligand-binding ectodomain. Reason: R-spondins bind LGR5 at the cell surface via its extracellular LRR domain, so the plasma membrane is the functional site; however LGR5 is constitutively endocytosed and at steady state is mostly intracellular. Supporting Evidence: PMID:22815884 We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5 PMID:23439653 LGR5 is rapidly internalized from the plasma membrane into early endosomes |
| GO:0005886 plasma membrane | IDA PMID:21693646 R-spondins function as ligands of the orphan receptors LGR4 ... | ACCEPT | Summary: LGR5 is a multi-pass plasma membrane receptor with an extracellular ligand-binding ectodomain. Reason: R-spondins bind LGR5 at the cell surface via its extracellular LRR domain, so the plasma membrane is the functional site; however LGR5 is constitutively endocytosed and at steady state is mostly intracellular. Supporting Evidence: PMID:22815884 We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5 PMID:23439653 LGR5 is rapidly internalized from the plasma membrane into early endosomes |
| GO:0005886 plasma membrane | IDA PMID:22815884 R-Spondin potentiates Wnt/Ξ²-catenin signaling through orphan... | ACCEPT | Summary: LGR5 is a multi-pass plasma membrane receptor with an extracellular ligand-binding ectodomain. Reason: R-spondins bind LGR5 at the cell surface via its extracellular LRR domain, so the plasma membrane is the functional site; however LGR5 is constitutively endocytosed and at steady state is mostly intracellular. Supporting Evidence: PMID:22815884 We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5 PMID:23439653 LGR5 is rapidly internalized from the plasma membrane into early endosomes |
| GO:0005886 plasma membrane | IDA PMID:23439653 Constitutive internalization of the leucine-rich G protein-c... | ACCEPT | Summary: LGR5 is a multi-pass plasma membrane receptor with an extracellular ligand-binding ectodomain. Reason: R-spondins bind LGR5 at the cell surface via its extracellular LRR domain, so the plasma membrane is the functional site; however LGR5 is constitutively endocytosed and at steady state is mostly intracellular. Supporting Evidence: PMID:22815884 We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5 PMID:23439653 LGR5 is rapidly internalized from the plasma membrane into early endosomes |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: LGR5 is a multi-pass plasma membrane receptor with an extracellular ligand-binding ectodomain. Reason: R-spondins bind LGR5 at the cell surface via its extracellular LRR domain, so the plasma membrane is the functional site; however LGR5 is constitutively endocytosed and at steady state is mostly intracellular. Supporting Evidence: PMID:22815884 We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5 PMID:23439653 LGR5 is rapidly internalized from the plasma membrane into early endosomes |
| GO:0005886 plasma membrane | TAS PMID:9642114 Identification and cloning of an orphan G protein-coupled re... | ACCEPT | Summary: LGR5 is a multi-pass plasma membrane receptor with an extracellular ligand-binding ectodomain. Reason: R-spondins bind LGR5 at the cell surface via its extracellular LRR domain, so the plasma membrane is the functional site; however LGR5 is constitutively endocytosed and at steady state is mostly intracellular. Supporting Evidence: PMID:22815884 We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5 PMID:23439653 LGR5 is rapidly internalized from the plasma membrane into early endosomes |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-4641205 | ACCEPT | Summary: LGR5 is a multi-pass plasma membrane receptor with an extracellular ligand-binding ectodomain. Reason: R-spondins bind LGR5 at the cell surface via its extracellular LRR domain, so the plasma membrane is the functional site; however LGR5 is constitutively endocytosed and at steady state is mostly intracellular. Supporting Evidence: PMID:22815884 We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5 PMID:23439653 LGR5 is rapidly internalized from the plasma membrane into early endosomes |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-4641206 | ACCEPT | Summary: LGR5 is a multi-pass plasma membrane receptor with an extracellular ligand-binding ectodomain. Reason: R-spondins bind LGR5 at the cell surface via its extracellular LRR domain, so the plasma membrane is the functional site; however LGR5 is constitutively endocytosed and at steady state is mostly intracellular. Supporting Evidence: PMID:22815884 We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5 PMID:23439653 LGR5 is rapidly internalized from the plasma membrane into early endosomes |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-4641246 | ACCEPT | Summary: LGR5 is a multi-pass plasma membrane receptor with an extracellular ligand-binding ectodomain. Reason: R-spondins bind LGR5 at the cell surface via its extracellular LRR domain, so the plasma membrane is the functional site; however LGR5 is constitutively endocytosed and at steady state is mostly intracellular. Supporting Evidence: PMID:22815884 We further demonstrated that RSPO binds to the extracellular domain of LGR4 and LGR5 PMID:23439653 LGR5 is rapidly internalized from the plasma membrane into early endosomes |
| GO:0007186 G protein-coupled receptor signaling pathway | IEA GO_REF:0000002 | REMOVE | Summary: GPCR signaling assigned from family membership. Reason: LGR5 signals by potentiating Wnt/LRP6 signaling without G protein or beta-arrestin coupling; there is no evidence for a G protein-coupled signaling pathway downstream of LGR5. Supporting Evidence: PMID:21693646 Interestingly, neither receptor is coupled to heterotrimeric G proteins or to Ξ²-arrestin when stimulated by the R-spondins, indicating a unique mechanism of action. |
| GO:0007186 G protein-coupled receptor signaling pathway | TAS PMID:9642114 Identification and cloning of an orphan G protein-coupled re... | REMOVE | Summary: GPCR signaling assigned from family membership. Reason: LGR5 signals by potentiating Wnt/LRP6 signaling without G protein or beta-arrestin coupling; there is no evidence for a G protein-coupled signaling pathway downstream of LGR5. Supporting Evidence: PMID:21693646 Interestingly, neither receptor is coupled to heterotrimeric G proteins or to Ξ²-arrestin when stimulated by the R-spondins, indicating a unique mechanism of action. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: LGR5 is a multi-pass membrane protein. Reason: True but general; the functional membrane is the plasma membrane, already accepted (with a large steady-state TGN pool). Proposed replacements: plasma membrane Supporting Evidence: PMID:23439653 LGR5 is rapidly internalized from the plasma membrane into early endosomes |
| GO:0016500 protein-hormone receptor activity | IEA GO_REF:0000002 | MODIFY | Summary: Protein-hormone receptor activity from the glycoprotein hormone receptor-like LRR family signature. Reason: LGR5 shares the LRR ectodomain architecture with glycoprotein hormone receptors, but its ligands are the R-spondin growth factors, not protein hormones. The receptor essence is right; transmembrane signaling receptor activity is the appropriate term. Proposed replacements: transmembrane signaling receptor activity Supporting Evidence: PMID:21693646 Here we demonstrate that LGR4 and LGR5 bind the R-spondins with high affinity and mediate the potentiation of Wnt/Ξ²-catenin signaling by enhancing Wnt-induced LRP6 phosphorylation. |
| GO:0030177 positive regulation of Wnt signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: LGR5 positively potentiates canonical Wnt/beta-catenin signaling upon R-spondin binding. Reason: R-spondin-bound LGR5 enhances Wnt-induced LRP6 phosphorylation and beta-catenin signaling, and Lgr4/5 loss phenocopies Wnt inhibition in intestinal crypts; this is the core biological role. Supporting Evidence: PMID:21693646 Here we demonstrate that LGR4 and LGR5 bind the R-spondins with high affinity and mediate the potentiation of Wnt/Ξ²-catenin signaling by enhancing Wnt-induced LRP6 phosphorylation. PMID:21727895 Lgr5 homologues are facultative Wnt receptor components that mediate Wnt signal enhancement by soluble R-spondin proteins. |
| GO:0032588 trans-Golgi network membrane | IDA PMID:23439653 Constitutive internalization of the leucine-rich G protein-c... | ACCEPT | Summary: Constitutively internalized LGR5 accumulates in the trans-Golgi network at steady state. Reason: Live-cell trafficking shows LGR5 is internalized through endosomes and reaches a steady-state TGN distribution via retromer-dependent retrograde transport. Supporting Evidence: PMID:23439653 Most importantly, in cells LGR5 is predominantly intracellular, yet the mechanisms underlying this behavior have not been determined. PMID:23439653 reaches a steady-state distribution in the TGN within 2 h |
| GO:0090263 positive regulation of canonical Wnt signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: LGR5 positively potentiates canonical Wnt/beta-catenin signaling upon R-spondin binding. Reason: R-spondin-bound LGR5 enhances Wnt-induced LRP6 phosphorylation and beta-catenin signaling, and Lgr4/5 loss phenocopies Wnt inhibition in intestinal crypts; this is the core biological role. Supporting Evidence: PMID:21693646 Here we demonstrate that LGR4 and LGR5 bind the R-spondins with high affinity and mediate the potentiation of Wnt/Ξ²-catenin signaling by enhancing Wnt-induced LRP6 phosphorylation. PMID:21727895 Lgr5 homologues are facultative Wnt receptor components that mediate Wnt signal enhancement by soluble R-spondin proteins. |
| GO:0090263 positive regulation of canonical Wnt signaling pathway | IDA PMID:21693646 R-spondins function as ligands of the orphan receptors LGR4 ... | ACCEPT | Summary: LGR5 positively potentiates canonical Wnt/beta-catenin signaling upon R-spondin binding. Reason: R-spondin-bound LGR5 enhances Wnt-induced LRP6 phosphorylation and beta-catenin signaling, and Lgr4/5 loss phenocopies Wnt inhibition in intestinal crypts; this is the core biological role. Supporting Evidence: PMID:21693646 Here we demonstrate that LGR4 and LGR5 bind the R-spondins with high affinity and mediate the potentiation of Wnt/Ξ²-catenin signaling by enhancing Wnt-induced LRP6 phosphorylation. PMID:21727895 Lgr5 homologues are facultative Wnt receptor components that mediate Wnt signal enhancement by soluble R-spondin proteins. |
| GO:0090263 positive regulation of canonical Wnt signaling pathway | IDA PMID:22815884 R-Spondin potentiates Wnt/Ξ²-catenin signaling through orphan... | ACCEPT | Summary: LGR5 positively potentiates canonical Wnt/beta-catenin signaling upon R-spondin binding. Reason: R-spondin-bound LGR5 enhances Wnt-induced LRP6 phosphorylation and beta-catenin signaling, and Lgr4/5 loss phenocopies Wnt inhibition in intestinal crypts; this is the core biological role. Supporting Evidence: PMID:21693646 Here we demonstrate that LGR4 and LGR5 bind the R-spondins with high affinity and mediate the potentiation of Wnt/Ξ²-catenin signaling by enhancing Wnt-induced LRP6 phosphorylation. PMID:21727895 Lgr5 homologues are facultative Wnt receptor components that mediate Wnt signal enhancement by soluble R-spondin proteins. |
| GO:0090263 positive regulation of canonical Wnt signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: LGR5 positively potentiates canonical Wnt/beta-catenin signaling upon R-spondin binding. Reason: R-spondin-bound LGR5 enhances Wnt-induced LRP6 phosphorylation and beta-catenin signaling, and Lgr4/5 loss phenocopies Wnt inhibition in intestinal crypts; this is the core biological role. Supporting Evidence: PMID:21693646 Here we demonstrate that LGR4 and LGR5 bind the R-spondins with high affinity and mediate the potentiation of Wnt/Ξ²-catenin signaling by enhancing Wnt-induced LRP6 phosphorylation. PMID:21727895 Lgr5 homologues are facultative Wnt receptor components that mediate Wnt signal enhancement by soluble R-spondin proteins. |
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Download this section (compressed HTML)Q: What is the functional significance of LGR5's constitutive internalization and TGN localization for R-spondin sensing?
Q: Does LGR5 have signaling output beyond Wnt potentiation, given its non-canonical, G-protein-independent mechanism?
Experiment: Test whether forcing LGR5 to the plasma membrane (internalization-defective C-tail mutant) alters R-spondin sensitivity and Wnt potentiation in intestinal organoids.
Type: structure-function in organoids
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