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LGR5
LGR5
LGR5
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LGR5
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesLGR5, FEX, GPR49, GPR67, GRP49, HG38, leucine-rich repeat containing G protein-coupled receptor 5, leucine rich repeat containing G protein-coupled receptor 5
External IDsOMIM: 606667; MGI: 1341817; HomoloGene: 20807; GeneCards: LGR5; OMA:LGR5 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

8549

14160

Ensembl

ENSG00000139292

ENSMUSG00000020140

UniProt

O75473

Q9Z1P4

RefSeq (mRNA)

NM_001277226
NM_001277227
NM_003667

NM_010195

RefSeq (protein)

NP_001264155
NP_001264156
NP_003658

NP_034325

Location (UCSC)Chr 12: 71.44 – 71.59 MbChr 10: 115.29 – 115.42 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) also known as G-protein coupled receptor 49 (GPR49) or G-protein coupled receptor 67 (GPR67) is a protein that in humans is encoded by the LGR5 gene.[5][6] It is a member of GPCR class A receptor proteins. R-spondin proteins are the biological ligands of LGR5. LGR5 is expressed across a diverse range of tissue such as in the muscle, placenta, spinal cord and brain and particularly as a biomarker of adult stem cells in certain tissues.[7]

Gene

[edit]

Prior to its current naming designation, LGR5 was also known as FEX, HG38, GPR49, and GPR67.[8] The Human LGR5 gene is 144,810 bases long and located at chromosome 12 at position 12q22-q23.[8] Both human, rat and mouse homologs contain 907 amino acids and seven transmembrane domains.[9] After translation, the signal peptide (amino acids 1-21) is cleaved off and the mature peptide (amino acids 22-907) inserts its transmembrane domain into the translocon membrane prior to packaging towards the plasma membrane.

Protein structure

[edit]

LGR5 is highly conserved within the mammalian clade. Sequence analyses showed that the transmembrane regions and cysteine-flanked junction between TM1 and the extracellular domain were highly conserved in sea anemone (Anthopleura elegantissima), fly (Drosophila melanogaster), worm (Caenorhabditis elegans), snail (Lymnaea stagnalis), rat (Rattus rattus) and human (Homo sapiens).[7] Homology amongst the metazoan suggests that it has been conserved across animals and was hypothesised as a chimeric fusion of an ancestral GPCR and a leucine-rich repeat motif.

Sheau Hsu, Shan Liang and Aaron Hsueh first identified LGR5, together with LGR4, in 1998 at the University Medical School Stanford, California using expression sequence tags based on putative glycoprotein hormone receptors in Drosophila.[7]

Experimental evidence show that the mature receptor protein contains up to 17 leucine-rich repeats, each composed of 24 amino acids spanning the extracellular domain flanked by the cysteine-rich N-terminal and C-terminal regions. In contrast, other glycoprotein hormone receptors such as Luteinizing hormone, Follicle-stimulating hormone and Thyroid-stimulating hormone contain only 9 repeats.[7] Sequence alignment showed that the second N-glycosylation site in LGR5 (Asn 208) aligns with that on the sixth repeat of gonadotropin and TSH receptors. The cysteine residues flanking the ectodomain form stabilising disulfide bonds that support the secondary structure of the leucine-rich repeats.

Function

[edit]

LGR5 is a member of the Wnt signaling pathway. Although its ligand remains elusive, it has been shown that costimulation with R-spondin 1 and Wnt-3a induce increased internalization of LGR5. LGR5 also cointernalizes with LRP6 and FZD5 via a clathrin-dependent pathway to form a ternary complex upon Wnt ligand binding. Moreover, the rapid cointernalization of LRP6 by LGR5 induces faster rates of degradation for the former. It has been shown that the C-terminal region of LGR5 is crucial for both dynamic internalization and degradation to occur, although C-terminal truncation does not inhibit LRP6 interaction and internalization, but rather, heightens receptor activity. Thus, only the initial interaction with its unknown ligand and other membrane bound receptors is crucial in its role in Wnt signalling and not the internalization itself.[10] LGR5 is crucial during embryogenesis as LGR null studies in mice incurred 100% neonatal mortality accompanied by several craniofacial distortions such as ankyloglossia and gastrointestinal dilation.[11]

Ligand

[edit]

LGR5 belongs to a class of class A GPCR orphan receptors. Thus its ligands remain elusive. However, it has been shown that Lgr2, the fly orthologue of mammalian LGR5, binds with "high affinity and specificity" with bursicon, an insect heterodimeric, neurohormone that belongs in the same class as FSH, LH and TSH, which in turn are homologous to mammalian bone morphogenetic factors (BMPs) such as gremlin and cerberus. Therefore, LGR5 might be a receptor for a member of the large family of bone morphogenetic protein antagonists.[12] Moreover, R-spondin proteins were shown to interact with the extracellular domain of LRG5.[13] The LGR5 / R-spondin complex acts by binding and subsequently internalizing RNF43 and ZNRF3. RNF43 and ZNRF3 are transmembrane E3 ligases that negatively regulate wnt signaling by ubiquitinating frizzled receptors.[14][15] Thereby, R-spondin binding to LGR5 potentiates wnt signaling.[16]

Clinical relevance

[edit]

LGR5 are well-established stem cell markers in certain types of tissue, wholly due to the fact that they are highly enriched in truly, multipotent stem cells compared to their immediate progeny, the transit-amplifying cells.

Intestines

[edit]
Intestinal crypt structure. LGR5 stem cells are located at the bottom of the crypt

Tracing has revealed that LGR5 is a marker of adult intestinal stem cells. The high turnover rate of the intestinal lining is due to a dedicated population of stem cells found at the base of the intestinal crypt. In the small intestines, these LGR5+ve crypt base columnar cells (CBC cells) have broad basal surfaces and very little cytoplasm and organelles and are located interspersed among the terminally differentiated Paneth cells.[12] These CBC cells generate the plethora of functional cells in the intestinal tissue: Paneth cells, enteroendocrine cells, goblet cells, tuft cells, columnar cells and the M cells over an adult's entire lifetime. Similarly, LGR5 expression in the colon resembles faithfully that of the small intestine.[12]

Liver

[edit]

The normal liver has very low expression of LGR5, but when this organ is damaged a LGR5-positive compartment emerges that is instrumental in hepatic regeneration,[17] probably as a consequence of increased Wnt-signaling.[18] The liver cancer process appears dependent on LGR5 expressing cancer stem cells. Human hepatocellular carcinoma and also murine liver cancer is characterised by the presentce of a LGR5-positive compartment not present in healthy liver. These LGR5 expressing are superior in initiating organoids and forming tumors in experimental liver cancer, while LGR5 lineage ablation significantly inhibits organoid initiation and tumor growth.[19]

Kidney

[edit]

In vivo lineage tracing showed that LGR5 is expressed in nascent nephron cell cluster within the developing kidney. Specifically, the LGR5+ve stem cells contribute into the formation of the thick ascending limb of Henle's loop and the distal convoluted tubule. However, expression is eventually truncated after postnatal day 7, a stark contrast to the facultative expression of LGR5 in actively renewing tissues such as in the intestines.[20]

Stomach

[edit]

The stomach lining also possess populations of LGR5+ve stem cells, although there are two conflicting theories: one is that LGR5+ve stem cells reside in the isthmus, the region between the pit cells and gland cells, where most cellular proliferation takes place. However, lineage tracing had revealed LGR5+ve stem cells at the bottom of the gland,[21] architecture reminiscent to that of the intestinal arrangement. This suggests that LGR5 stem cells give rise to transit-amplifying cells, which migrate towards the isthmus where they proliferate and maintain the stomach epithelium.[12]

Ear

[edit]

LGR5+ve stem cells were pinpointed as the precursor for sensory hair cells that line the cochlea.[13]

Hair follicle

[edit]
Hair follicle structure where LGR5 stem cells are found in the bulge region

Hair follicle renewal is governed by Wnt signalling that act upon hair follicle stem cells located in the follicle bulge. Although these cells are well characterised by CD34 and cytokeratin markers, there is a growing body of agreement that LGR5 is a putative hair follicle stem cell marker.[22] LGR5 in conjunction with LRG6, is expressed in a remarkable fashion: LRG6+ve stem cells maintain the upper sebaceous gland whilst LRG5+ve stem cells fuel the actual hair follicle shaft upon migration of transit-amplifying cells into the dermal papilla. In between these two distinct populations of stem cells are the multipotent LRG5/6+ve stem cells that ultimately maintain the epidermal hair follicle in adults.[12]

Cancer

[edit]

The cancer stem cell hypothesis states that a dedicated small population of cancerous stem cells[23] that manages to evade anti-cancer therapy maintains benign and malignant tumours. This explains recurring malignancies even after surgical removal of the tumours.[6] LGR5+ve stem cells were identified to fuel stem cell activity in murine intestinal adenomas via erroneous activation of the pro-cell cycle Wnt signalling pathway as a result of successive mutations, such as formation of adenoma via Adenomatous polyposis coli (APC) mutation.[24] Studies on LGR5 in colorectal cancer revealed a rather perplexing mechanism: loss of LGR5 actually increased tumourigenicity and invasion whereas overexpression results a reduction in tumourigenicity and clonogenicity. This implies that LGR5 is not an oncogene but a tumor suppressor gene, and that its main role is delimiting stem cell expansion in their respective niches.[25] Varying expression profile of LGR5 was also observed in different stages of gastrointestinal cancers, which suggests that the histoanatomical distribution of LGR5+ve stem cells determine how the cancer advances.[26] Densitometry results of LGR5 expression by western blotting in the different cell lines showed that high LGR5 expression levels were apparent in BHK, AGS, VERO and NIH3T3 cell lines compared with the other cell lines.[27]

References

[edit]

Further reading

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

LGR5

View on Grokipedia
from Grokipedia
LGR5, also known as leucine-rich repeat-containing 5, is a seven-transmembrane receptor protein that acts as a specific marker for in self-renewing tissues such as the intestinal crypts and hair follicles. It functions primarily as a high-affinity receptor for R-spondin (RSPO) proteins, which bind to its extracellular domain to potentiate canonical Wnt/β-catenin signaling, thereby promoting proliferation, maintenance, and tissue . Discovered as a Wnt target , LGR5 plays a critical role in postembryonic development and regeneration, with its expression tightly regulated in cycling stem cell populations. The structure of LGR5 features a large N-terminal extracellular domain composed of 17 leucine-rich repeats for ligand binding, followed by seven transmembrane helices characteristic of G protein-coupled receptors (GPCRs), and a short intracellular C-terminal tail that lacks typical G-protein activation motifs. Unlike classical GPCRs, LGR5 does not couple to heterotrimeric G proteins but instead enhances Wnt signaling by stabilizing the Wnt receptor complex on the cell surface, counteracting the inhibitory effects of E3 ligases such as RNF43 and ZNRF3 through RSPO-mediated interactions. This mechanism amplifies β-catenin accumulation and transcriptional activation of Wnt target genes, including LGR5 itself, forming a loop essential for dynamics. LGR5 expression is highly specific to stem cell niches, with prominent localization in the base of intestinal crypts where it marks rapidly cycling columnar cells responsible for epithelial renewal, as well as in the bulge of follicles and other sites like the and . In the intestine, LGR5-positive s generate all cell lineages of the every 3–5 days, highlighting its role in continuous tissue turnover. Beyond normal physiology, dysregulated LGR5 signaling contributes to tumorigenesis, as it is overexpressed in various cancers including colorectal, ovarian, and pancreatic, where it identifies cancer s capable of tumor and . Therapeutic targeting of the LGR5/RSPO axis is emerging as a strategy to inhibit cancer progression while sparing normal function.

Molecular Biology

Gene Characteristics

The LGR5 gene, originally identified in 1998 as an orphan (initially termed HG38 or GPR49) within the glycoprotein hormone receptor subfamily, encodes a receptor with potential for binding novel ligands. This gene is situated on the long arm of human at cytogenetic band 12q22-23, spanning approximately 145 kilobases from position 71,439,797 to 71,586,310 (GRCh38 assembly) and comprising 18 exons in its primary transcript (ENST00000266674). LGR5 encodes a precursor protein of 907 , which undergoes processing to form the mature receptor. Its promoter region, located upstream of exon 1, includes TCF/LEF-binding sites that enable direct transcriptional activation by canonical Wnt signaling, establishing LGR5 as a key Wnt target gene. Additional regulatory elements, such as enhancers identified through interaction analyses (e.g., GeneHancer regions at chr12:71,438,701–71,442,291), modulate its tissue-specific expression. In adult human tissues, LGR5 exhibits basal expression in organs including , placenta, spinal cord, and brain, but demonstrates markedly elevated levels in restricted niches such as the crypt base of the small intestine and colon, as well as the bulge of hair follicles, where it serves as a marker for cycling stem cells.

Protein Structure

LGR5 is a class A (GPCR) featuring seven transmembrane α-helical domains that anchor the protein in the plasma membrane, a defining architectural element shared with rhodopsin-like GPCRs. The extracellular N-terminal ectodomain is composed of 17 leucine-rich repeats (LRRs), which fold into a β-sheet-rich horseshoe structure essential for recognition and receptor activation. This LRR array, spanning approximately residues 22–541, positions the binding site away from the membrane, facilitating interactions with extracellular cues while the hinge region connects it to the first transmembrane helix. The protein includes an N-linked site at 208 (Asn208) within the ectodomain, a conserved feature that supports proper folding, trafficking, and stability of the receptor, aligning with glycosylation patterns observed in related receptors. Sequence conservation is high across mammals; for instance, human LGR5 shares about 90% identity with Lgr5 in the extracellular domain, underscoring its evolutionary preservation for core receptor functions. At the intracellular C-terminus, LGR5 possesses a PDZ-binding motif (typically class I type, involving the terminal residues) that enables recruitment of PDZ-domain-containing scaffold proteins, such as DLG1, to regulate receptor localization and assembly of signaling complexes. Although no full-length exists, insights from the crystallized LGR5 ectodomain (PDB: 4KNG) in complex with R-spondin 1 reveal a rigid, elongated horseshoe conformation of the LRRs, with low root-mean-square deviation (RMSD) values across structures, enabling accurate of the transmembrane and intracellular regions based on related LGR family members like LGR4 and canonical class A GPCRs such as rhodopsin.67254-4/fulltext)00287-8)

Biological Function

Ligand Interactions

LGR5 serves as a receptor for the R-spondin family of ligands, specifically RSPO1 through RSPO4, which bind to its extracellular domain with high affinity to potentiate Wnt/β-catenin signaling. Among these, RSPO1 demonstrates the highest binding affinity for LGR5, with a dissociation constant (Kd) of approximately 3.1 nM as determined by surface plasmon resonance assays. The other RSPOs (RSPO2-4) also bind LGR5, albeit with slightly lower affinities in the low nanomolar range, enabling selective enhancement of Wnt pathway activity in a ligand-dependent manner. The binding mechanism involves the formation of an RSPO-LGR5 complex that stabilizes interactions between Frizzled (FZD) receptors and low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6), thereby promoting the assembly of the Wnt signalosome without LGR5 directly binding Wnt ligands. LGR5 functions exclusively as a co-receptor in this context, relying on RSPO ligation to counteract the inhibitory effects of E3 ubiquitin ligases such as RNF43 and ZNRF3, which otherwise degrade FZD and LRP5/6 from the cell surface. This initial ligand-receptor interaction is crucial for amplifying low-level Wnt signals in stem cell niches. Experimental validation of these interactions comes from radioligand binding assays and cell-based functional studies, which show that RSPO binding to LGR5 directly correlates with increased Wnt reporter activity and is absent in LGR5-deficient cells. Furthermore, genetic knockout studies in mice reveal the dependency of LGR5-mediated signaling; while single Lgr5 knockouts exhibit only mild intestinal phenotypes, combined Lgr4/Lgr5 double knockouts completely abolish proliferation and formation , underscoring RSPO's essential role in sustaining Lgr5+ expansion.00287-8)

Signaling Pathways

LGR5 primarily functions as a receptor for R-spondin (RSPO) ligands, potentiating the canonical Wnt/β-catenin signaling pathway by forming a complex that inhibits the E3 ligases ZNRF3 and RNF43. This LGR5-RSPO complex binds to and neutralizes ZNRF3/RNF43, preventing their ubiquitination and subsequent degradation of Wnt receptors such as (FZD) and receptor-related protein 6 (LRP6) on the cell surface. By stabilizing these receptors, LGR5 enhances the sensitivity of cells to Wnt ligands, thereby amplifying downstream signaling without directly initiating the pathway. Upon Wnt ligand binding to the stabilized FZD/LRP6 receptors, LGR5 facilitates the recruitment of intracellular effectors to the plasma membrane, including (DVL) and AXIN, which are critical for β-catenin stabilization. The formation of a supercomplex involving LGR5, FZD, LRP6, and DVL promotes the of LRP6 at key residues, such as serine 1490, which in turn recruits and sequesters AXIN from the β-catenin destruction complex (comprising AXIN, , GSK3β, and CK1). This inhibition disrupts β-catenin ubiquitination and degradation, allowing its accumulation in the and subsequent nuclear translocation to activate transcription factors like TCF/LEF. LGR5-mediated signaling operates independently of heterotrimeric G-proteins, distinguishing it from other G-protein-coupled receptors, and relies predominantly on for . Studies indicate that while LGR5 can interact with G-proteins , physiological Wnt potentiation does not require G-protein activation, as evidenced by the lack of effect from G-protein inhibitors on RSPO-LGR5-induced and β-catenin stabilization. Evidence from genetic models underscores LGR5's essential role in Wnt signaling integrity, particularly in intestinal crypts. Lgr5 null mice exhibit defective Wnt/β-catenin signaling, manifested as deregulated pathway activity leading to precocious differentiation and impaired crypt homeostasis. These disruptions culminate in 100% perinatal lethality, characterized by gastrointestinal distension and due to insufficient suckling from .

Physiological Roles

Intestinal Stem Cells

LGR5-positive (LGR5+) cells, located at the base of intestinal , function as crypt base columnar (CBC) stem cells that drive the homeostatic renewal of the . These cells undergo rapid division to replenish the epithelial lining, which turns over completely every 3-5 days in mammals. Positioned between Paneth cells, LGR5+ CBC stem cells maintain their stemness through interactions with the niche environment, ensuring continuous production of differentiated progeny that migrate upward along the crypt-villus axis. Lineage tracing experiments have confirmed the multipotency and long-term self-renewal capacity of LGR5+ cells. In seminal studies using Cre-inducible reporters targeted to the Lgr5 locus, individual LGR5+ cells generated all major epithelial lineages—including enterocytes, goblet cells, enteroendocrine cells, and tuft cells—over extended periods, demonstrating their role as the primary source of intestinal epithelial cells during steady-state conditions. These findings established LGR5 as a definitive marker for active intestinal stem cells, distinguishing them from more quiescent populations. In response to injury, such as , LGR5+ progenitors exhibit temporary expansion to facilitate epithelial regeneration. of LGR5+ cells impairs recovery from damage, underscoring their indispensability for restoring tissue integrity after acute insults, though other progenitor pools may contribute under severe stress. This regenerative plasticity allows LGR5+ cells to proliferate robustly in the altered niche, supporting rapid repopulation of the crypts. LGR5+ s rely on Paneth cells for niche signaling, which provide essential factors like EGF and Wnt ligands to sustain their function. Paneth cells secrete Wnt3a to establish a high Wnt signaling gradient at the base, promoting LGR5-mediated β-catenin stabilization and maintenance, while EGF supports proliferation. Competition for these limited niche signals among LGR5+ cells and Paneth cells regulates stem cell numbers and positioning within the .

Roles in Other Tissues

Beyond the , LGR5 expression is observed in various other tissues, where it marks stem or populations adapted to tissue-specific regenerative demands, such as injury-induced repair or developmental maintenance. These LGR5-positive (LGR5+) cells often respond to Wnt signaling via R-spondin ligands, enabling proliferation and differentiation in contexts distinct from the continuous renewal of the gut. In the liver, LGR5 is expressed at low levels in pericentral hepatocytes during homeostatic adult tissue but is rapidly upregulated in biliary epithelial cells within ductules and pericentral hepatocytes following , such as partial or toxin-induced damage. These LGR5+ cells, derived from ductules, serve as facultative progenitors that contribute to hepatocyte regeneration by proliferating and differentiating into parenchymal cells during the recovery phase. For instance, in models of liver damage, single LGR5+ cells isolated from injured livers can be expanded as organoids under Wnt/R-spondin conditions, demonstrating their stem-like potential and ability to generate functional liver tissue. Pericentral hepatocytes express LGR5 during and contribute to zonal regeneration, with their role complementing that of ductular cells post-. Recent studies (as of 2025) highlight LGR5+ hepatocytes' contributions to liver zonation and replenishment during specific injuries. No overt liver is observed in homeostatic Lgr5 knockouts, consistent with its low basal expression. During kidney development, marks a subset of nephron progenitor cells in the cap mesenchyme of the embryonic mouse kidney, where it supports the and expansion of these progenitors essential for nephron formation. Lineage tracing in Lgr5 reporter mice reveals that LGR5+ cells contribute to the generation of specific nephron segments, including the thick ascending limb and , with expression peaking during the proliferative phase of nephrogenesis around embryonic days 12.5–14.5. R-spondin signaling through LGR5 is critical for sustaining this progenitor pool, as its disruption impairs distal nephron segment formation. In postnatal kidneys, LGR5 expression diminishes after the first week, reflecting the cessation of nephrogenesis in mammals. In the stomach, LGR5 primarily identifies active populations at the base of in the antrum (pylorus), driving epithelial renewal through self-renewal and multipotent differentiation. In the antrum, LGR5+ cells in the pyloric glands undergo symmetric divisions during , enabling rapid clonal expansion to replenish the every few days; these cells give rise to all glandular lineages, including mucus-secreting cells and enteroendocrine cells. In the corpus, LGR5 expression is lower and inducible upon or infection, activating reserve progenitors to support oxyntic gland maintenance. Lineage tracing confirms their long-term contribution to antral unit renewal. LGR5+ progenitors also play roles in cyclic regeneration within sensory and integumentary structures. In the , LGR5 marks supporting cells in the cochlear sensory epithelium of neonatal mice, which act as Wnt-responsive progenitors capable of proliferating and transdifferentiating into hair cells following ototoxic damage. Activation of β-catenin signaling in these LGR5+ cells enhances mitotic regeneration, partially restoring auditory function in damage models, though this capacity wanes in adults. In hair follicles, LGR5 expression labels bulge stem cells that orchestrate the hair growth cycle, with these cells mobilizing during anagen phase to regenerate the follicle structure; they contribute to epithelial compartments of the follicle in a multipotent manner. Across these tissues, LGR5 expression levels vary, with high basal expression in the rapidly renewing and (comparable to intestinal crypts) but inducible or developmental-restricted patterns in liver and , as quantified by RNA sequencing and reporter mice showing 10–100-fold upregulation post-injury or during embryogenesis. studies in mice reveal tissue-specific phenotypes: Lgr5-null mutants exhibit perinatal lethality due to gut defects, but conditional knockouts in non-intestinal tissues show milder effects, such as delayed cycling leading to progressive and thinned pelage, impaired segment specification in embryos, and reduced gastric regeneration upon challenge, underscoring LGR5's non-redundant role in progenitor dynamics.

Clinical Relevance

Regenerative Medicine Applications

LGR5-positive (LGR5+) stem cells serve as foundational elements in cultures, enabling the generation of complex, self-organizing tissue structures that mimic native organ architecture. In intestinal protocols, single Lgr5+ stem cells can clonally expand to form crypt-villus structures, recapitulating epithelial turnover and differentiation under defined growth factors like R-spondin-1, EGF, and Noggin. Similarly, for gastric organoids, isolated Lgr5+ cells from the pyloric generate long-lived structures resembling mature antral , demonstrating multipotency and self-renewal in a three-dimensional matrix. Hepatic organoids derived from Lgr5+ biliary cells, activated during injury, propagate as ductal cysts that differentiate into hepatocyte-like cells, providing a platform for modeling . In embryonic development, LGR5 plays a critical role in gut formation by modulating Wnt signaling to regulate fate, with its deficiency leading to deregulated differentiation in the . Lgr5 mice exhibit normal embryonic gut but display severe perinatal defects, including gastrointestinal dilation and an inability to suckle, resulting in 100% neonatal lethality. Although direct evidence for LGR5 in mammalian limb embryogenesis is limited, its interaction with R-spondin enhances Wnt activity in limb bud progenitors during developmental patterning in model organisms. LGR5 targeting holds promise for in regenerative contexts, particularly for expanding populations to treat . In liver models, combined administration of hepatocyte growth factor and R-spondin-1 induces Lgr5+ proliferation, reducing and restoring hepatic function without tumorigenic risks. Activated hepatic stellate cells in livers further promote LGR5+ cell expansion, suggesting therapeutic strategies to harness these interactions for tissue remodeling. Post-2023 advances have integrated editing with LGR5+ stem cells to advance personalized regenerative approaches. For instance, -generated Lgr5 reporter models facilitate studies of LGR5+ cell contributions to tissue repair, enabling tailored interventions for organ-specific regeneration. These edited organoids also support patient-derived modeling for drug screening, enhancing precision in treating developmental and injury-related disorders.

Cancer Associations

LGR5 serves as a prominent marker for cancer stem cells (CSCs) across multiple malignancies, particularly in colorectal, gastric, and liver cancers, where its overexpression drives tumor progression and metastasis. In colorectal cancer, elevated LGR5 expression correlates with lymph node metastasis, larger tumor size, and advanced disease stages, facilitating cancer cell migration and invasion through enhanced Wnt/β-catenin signaling. Similarly, in gastric cancer, LGR5+ cells promote dedifferentiation and distant metastasis, with high expression observed in progressive lesions. In hepatocellular carcinoma (HCC), LGR5 marks liver CSCs that exhibit increased proliferation and clonogenicity, contributing to metastatic spread via similar pathway activation. Recent studies from 2024 and 2025 highlight the role of LGR5+ cells in chemoresistance; for instance, in gastric cancer, LGR5 co-expression with CD44 identifies CSCs resistant to cisplatin and oxaliplatin by activating Wnt, Hedgehog, and Notch pathways, while in colorectal and liver cancers, LGR5+ populations evade 5-fluorouracil and doxorubicin through sustained stemness. LGR5 exhibits a dual function in tumorigenesis, promoting cancer development via Wnt hyperactivation in many contexts while exerting tumor-suppressive effects upon its loss in others. High LGR5 levels amplify Wnt signaling to foster CSC maintenance and tumor growth in colorectal and gastric cancers, yet its knockdown in colorectal cell lines upregulates Wnt target genes like WISP1 and Wnt5a, enhancing and anchorage-independent growth. In intestinal adenomas, LGR5 acts as a negative regulator of tumourigenicity by antagonizing excessive Wnt activity; its selective loss in regions of hyperactivated Wnt signaling facilitates epithelial-mesenchymal transition (EMT) and progression to , as evidenced by reduced LGR5 positivity in invasive areas compared to adenomas. High LGR5 mRNA expression serves as a prognostic indicator of poor outcomes, particularly in early-stage gastric cancer. In stage I/II gastric cancer patients, elevated LGR5 levels are associated with significantly worse overall survival (5-year rate: 60.6% vs. 100% in LGR5-negative cases) and , independent of other clinicopathological factors in multivariate analysis. A 2025 meta-analysis in further confirms that LGR5 overexpression correlates with reduced overall survival, underscoring its value in risk stratification. Therapeutic strategies targeting LGR5 have shown promise in overcoming CSC-driven resistance, including antibody-drug conjugates (ADCs) and combinations with EGFR inhibitors. LGR5-directed ADCs, such as those using the 8E11 conjugated to payloads like CPT2, effectively shrink tumors in patient-derived xenografts by depleting LGR5+ CSCs without severe off-target toxicity to normal stem cells. In 2025 preclinical studies, combining these ADCs with — an EGFR —upregulates LGR5 expression in both RAS wild-type and mutant models, leading to enhanced tumor regression and prolonged survival compared to monotherapy, with complete responses observed in resistant PDX lines. Ongoing clinical trials include a phase I/II study of the LGR5-targeted CAR-T therapy CNA3103 for metastatic , and bispecific antibodies like petosemtamab (EGFR x LGR5) in early-phase testing for gastrointestinal cancers. Additionally, inhibiting the LGR5/mTORC2 axis addresses metabolic plasticity in HCC; LGR5 activates mTORC2 via RAC1/AKT/FOXO3a to boost aerobic , enabling resistance to glucose , and mTORC2 blockade with agents like metformin suppresses this adaptation, reducing tumor growth and . Recent 2024-2025 investigations reveal LGR5's contributions to interactions, including glioma stiffness, (ECM) adhesion, and metabolic resilience. In brain cancers like , LGR5+ CSCs contribute to tumor progression and invasion through mechanisms such as EMT activation. Furthermore, LGR5 drives glucose starvation resistance in cancer cells by enhancing glycolytic capacity through mTORC2, a mechanism particularly relevant in nutrient-poor tumor niches.

References

  1. https://www.ncbi.nlm.nih.gov/gene/8549
  2. https://www.pnas.org/doi/10.1073/pnas.1106083108
  3. https://pmc.ncbi.nlm.nih.gov/articles/PMC2665733/
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  5. https://pmc.ncbi.nlm.nih.gov/articles/PMC10319729/
  6. https://genesdev.cshlp.org/content/28/4/305.full
  7. https://link.springer.com/article/10.1007/s10555-024-10239-x
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  9. https://pubmed.ncbi.nlm.nih.gov/9642114/
  10. https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000139292
  11. https://www.uniprot.org/uniprotkb/O75473/entry
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  13. https://pmc.ncbi.nlm.nih.gov/articles/PMC4005707/
  14. https://academic.oup.com/mend/article/12/12/1830/2754331
  15. https://www.rndsystems.com/products/mouse-lgr5-gpr49-pe-conjugated-antibody-803420_fab8240p
  16. https://pmc.ncbi.nlm.nih.gov/articles/PMC3937510/
  17. https://www.science.org/doi/10.1126/scisignal.aaz4051
  18. https://pmc.ncbi.nlm.nih.gov/articles/PMC3372227/
  19. https://www.nature.com/articles/s41392-021-00762-6
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  22. https://pmc.ncbi.nlm.nih.gov/articles/PMC525477/
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  24. https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.583919/full
  25. https://pmc.ncbi.nlm.nih.gov/articles/PMC3547360/
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