{"gene":"LRIG3","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2008,"finding":"Lrig3 acts downstream of Pax3 and Zic1 in neural crest (NC) formation in Xenopus; morpholino-induced knockdown of Lrig3 blocked NC marker induction (Slug, Sox9, Foxd3) by Pax3 and Zic1. Lrig3 co-injection with Wnt3a enhanced FGF3/4/8 induction, suggesting a positive role in Wnt signaling, and Lrig3 attenuated FGF signaling in animal caps. Lrig3 was shown to interact with FGFR1 in cultured cells.","method":"Morpholino knockdown in Xenopus, NC induction animal cap assay, co-injection epistasis, co-immunoprecipitation with FGFR1 in cultured cells","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in Xenopus with multiple marker readouts plus Co-IP with FGFR1; single lab but multiple orthogonal methods","pmids":["18287203"],"is_preprint":false},{"year":2008,"finding":"Lrig3 is necessary for lateral semicircular canal morphogenesis; loss of Lrig3 causes ectopic expression of netrin 1 (Ntn1) in the otic vesicle fusion plate, disrupting basal lamina integrity. Mutually antagonistic (cross-repressive) interactions between Lrig3 and Ntn1 create complementary expression domains defining canal shape. Removal of one copy of Ntn1 from Lrig3 mutants rescues both canal malformation and circling behavior.","method":"Gene trap mutagenesis screen, genetic epistasis (Lrig3 mutant × Ntn1 heterozygous rescue), in situ hybridization for marker genes, behavioral assay","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with clean double-mutant rescue, multiple orthogonal readouts (behavior, morphology, molecular markers), replicated across genetic backgrounds","pmids":["19004851"],"is_preprint":false},{"year":2010,"finding":"Lrig3 interacts with ErbB receptors (ErbB2 and ErbB3) in vitro, but inhibition of ErbB activation in the chick otic vesicle had no detectable effect on Netrin gene expression or canal morphogenesis, indicating that ErbB modulation is unlikely to account for Lrig3-dependent inner ear morphogenesis.","method":"Co-immunoprecipitation (in vitro), pharmacological inhibition of ErbB in chick otic vesicle, in situ hybridization for Netrin","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo functional test with inhibitor; single lab, two orthogonal methods; negative result for ErbB in inner ear morphogenesis is mechanistically informative","pmids":["20126551"],"is_preprint":false},{"year":2013,"finding":"Lrig3 functionally opposes Lrig1: Lrig3 stabilizes ErbB receptors and counteracts Lrig1-mediated receptor degradation. Conversely, Lrig1 destabilizes Lrig3 protein, identifying Lrig3 as a target of Lrig1-driven destabilization. Lrig1 and Lrig3 interact with each other.","method":"Co-immunoprecipitation, gain/loss-of-function overexpression, receptor degradation assays (Western blot), cell-based functional assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal functional assays and Co-IP demonstrating physical and functional interaction; single lab, multiple orthogonal methods","pmids":["23069723"],"is_preprint":false},{"year":2013,"finding":"Lrig3 interacts with ErbB receptors in vitro (as confirmed independently of the 2010 study), and Lrig3 stabilizes ErbB receptor expression rather than promoting degradation, opposite to Lrig1.","method":"Co-immunoprecipitation, receptor expression level analysis by Western blot","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus quantitative receptor-level assay; single lab","pmids":["23723069"],"is_preprint":false},{"year":2015,"finding":"LRIG3 negatively regulates EGFR signaling in glioblastoma cells; overexpression of LRIG3 inhibited cell growth, promoted apoptosis, and restrained invasion/migration. Pharmacological inhibition of EGFR reduced the effects of LRIG3 knockdown on cell proliferation and EGFR pathway activation, placing LRIG3 upstream of EGFR signaling.","method":"Lentiviral overexpression, siRNA knockdown, EGFR inhibitor epistasis, in vitro proliferation/invasion assays, in vivo xenograft, Western blot for EGFR pathway","journal":"Journal of the neurological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis plus loss- and gain-of-function with multiple cellular readouts; single lab","pmids":["25708990"],"is_preprint":false},{"year":2008,"finding":"LRIG3 fusion protein localizes to the cytoplasm of glioblastoma GL15 cells. EGF treatment (100 ng/ml) increased LRIG3 expression over time while decreasing EGFR expression, suggesting reciprocal regulation between LRIG3 and EGFR in response to ligand.","method":"Confocal microscopy of LRIG3-EGFP fusion protein, RT-PCR and Western blot after EGF treatment","journal":"Journal of Zhejiang University. Medical sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization experiment and expression time-course; single lab, no functional mutagenesis","pmids":["18925709"],"is_preprint":false},{"year":2021,"finding":"Lrig3 interacts with Ret receptor and inhibits GDNF/Ret signaling in dorsal root ganglion (DRG) neurons. GDNF treatment induces upregulation of both Lrig1 and Lrig3 expression. Haploinsufficiency of Lrig1 in Lrig3 mutants (double partial loss-of-function) potentiates Ret signaling and axonal growth, demonstrating Lrig1/Lrig3 genetic redundancy. Lrig1 and Lrig3 act redundantly to ensure proper cutaneous innervation by nonpeptidergic axons and cold sensitivity (correlated with increased TrpA1 expression).","method":"Co-immunoprecipitation of Lrig3 with Ret, GDNF treatment time-course, genetic double-mutant analysis (Lrig1 haploinsufficiency × Lrig3 knockout), axonal growth assays, behavioral cold sensitivity tests, TrpA1 expression analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP plus genetic epistasis with double-mutant rescue plus multiple functional readouts (axonal growth, behavior, molecular markers); single lab but multiple orthogonal methods","pmids":["34338291"],"is_preprint":false},{"year":2020,"finding":"LRIG3 facilitates binding of DUSP6 to ERK1/2, leading to dephosphorylation of ERK1/2 and subsequent downregulation of Slug (an EMT regulator), thereby suppressing colorectal cancer cell motility. LRIG3 expression negatively correlated with p-ERK1/2 and Slug in CRC tissues.","method":"LRIG3 knockout and re-introduction, Co-IP of DUSP6 with ERK1/2, Western blot for p-ERK1/2 and Slug, migration/invasion Transwell assay","journal":"IUBMB life","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus gain/loss-of-function with defined molecular pathway and phenotypic readout; single lab","pmids":["32107843"],"is_preprint":false},{"year":2021,"finding":"Soluble LRIG3 (sLRIG3), shed from glioma cells by ADAM17-mediated cleavage, interacts with the CUB1 domain of NETO2 in tumor-associated macrophages (TAMs), blocking M2 polarization and suppressing GBM growth. NETO2 knockout or CUB1 deletion mutant abolished the suppressive effects of sLRIG3 on TAM M2-polarization.","method":"Mass spectrometry, Co-immunoprecipitation, NETO2 knockout/CUB1-deletion mutagenesis, conditioned medium assay, in vivo tumor model","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — binding partner identified by mass spectrometry and confirmed by Co-IP; domain-deletion mutagenesis validates interaction; in vivo functional readout; single lab but multiple orthogonal methods","pmids":["36639372"],"is_preprint":false},{"year":2021,"finding":"ADAM17 activity in glioma cells positively correlates with shedding of soluble LRIG3 (sLRIG3) into cell supernatant, identifying ADAM17 as the sheddase for LRIG3 ectodomain release.","method":"Correlation of ADAM17 expression/activity with sLRIG3 levels in conditioned medium","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlational finding within one study; no direct enzymatic reconstitution or mutagenesis of ADAM17 cleavage site reported in abstract","pmids":["36639372"],"is_preprint":false},{"year":2021,"finding":"LRIG3 inhibits PI3K/AKT signaling pathway activation in glioma cells, downregulating VEGFA expression and thereby suppressing glioma-induced angiogenesis both in vitro and in vivo.","method":"Loss- and gain-of-function assays, Western blot for PI3K/AKT pathway, VEGFA expression measurement, tube formation assay in vitro, in vivo angiogenesis model","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with defined pathway readout and in vivo validation; single lab","pmids":["33718179"],"is_preprint":false},{"year":2020,"finding":"miR-196a directly targets LRIG3 mRNA (validated by dual luciferase reporter assay), and reduction of LRIG3 protein promotes proliferation, migration, and invasion of cervical cancer cells.","method":"Dual luciferase reporter assay, Western blot, si-LRIG3 transfection rescue experiment, Transwell and CCK-8 assays","journal":"Cellular and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct luciferase validation of miR-196a/LRIG3 targeting plus functional rescue; single lab","pmids":["33287939"],"is_preprint":false},{"year":2025,"finding":"Lrig3-deficient mice show strain-dependent regulation of liver fat accumulation (hepatocellular steatosis), intestinal morphology (dilated/flaccid ileum), and middle ear inflammation (otitis media), and Lrig3 regulates BMP signaling in vivo.","method":"Histopathological examination of 42 tissues from Lrig3-deficient mice on two genetic backgrounds, high-fat diet challenge","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — loss-of-function phenotypic screen across tissues; BMP signaling reference is stated without detailed mechanistic experiment described in the abstract","pmids":["40320098"],"is_preprint":false},{"year":2026,"finding":"Skin-specific overexpression of Lrig3 in mice causes alopecia and upregulation of ERBB, PI3K/AKT, and NOTCH1 signaling pathways, with altered keratinocyte differentiation and hair follicle/sebaceous gland marker profiles.","method":"Tet-Off transgenic mouse overexpression, proteome profiling of skin, pathway analysis","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — gain-of-function in vivo with pathway-level readouts but no direct binding/reconstitution experiments described in abstract; single study","pmids":["42218262"],"is_preprint":false}],"current_model":"LRIG3 is a transmembrane leucine-rich repeat and immunoglobulin domain protein that modulates multiple receptor tyrosine kinase (ErbB, EGFR, Ret, FGFR1) and non-RTK signaling pathways: it stabilizes ErbB receptors and opposes Lrig1-mediated receptor degradation, inhibits EGFR/PI3K/AKT/ERK signaling to suppress tumor cell proliferation and invasion, interacts with Ret to inhibit GDNF signaling in DRG neurons redundantly with Lrig1, and releases a soluble ectodomain (via ADAM17 shedding) that binds the CUB1 domain of NETO2 in tumor-associated macrophages to block M2 polarization; in development, it acts downstream of Pax3/Zic1 in neural crest formation by modulating Wnt/FGF signaling and controls inner ear lateral canal morphogenesis through mutually antagonistic cross-repression with Netrin 1."},"narrative":{"mechanistic_narrative":"LRIG3 is a transmembrane leucine-rich repeat and immunoglobulin-domain protein that operates as a context-dependent modulator of receptor tyrosine kinase signaling and developmental patterning [PMID:18287203, PMID:23069723]. In ErbB/EGFR signaling, LRIG3 physically associates with ErbB receptors and stabilizes them, acting in functional opposition to its paralog Lrig1, which destabilizes both ErbB receptors and LRIG3 itself; the two proteins interact directly [PMID:23069723, PMID:23723069]. In cancer cells LRIG3 behaves as a tumor suppressor: it restrains EGFR pathway output to inhibit proliferation, invasion and migration [PMID:25708990], facilitates DUSP6-mediated dephosphorylation of ERK1/2 to downregulate the EMT regulator Slug [PMID:32107843], and inhibits PI3K/AKT signaling to reduce VEGFA expression and tumor angiogenesis [PMID:33718179]. An ADAM17-shed soluble LRIG3 ectodomain engages the CUB1 domain of NETO2 on tumor-associated macrophages to block M2 polarization and suppress glioblastoma growth, defining a non-cell-autonomous signaling mode [PMID:36639372]. Beyond cancer, LRIG3 binds Ret and inhibits GDNF/Ret signaling in DRG neurons, acting redundantly with Lrig1 to control cutaneous innervation and cold sensitivity [PMID:34338291]. In development, LRIG3 functions downstream of Pax3/Zic1 to modulate Wnt and FGF signaling during neural crest induction and interacts with FGFR1 [PMID:18287203], and it patterns inner ear lateral semicircular canal morphogenesis through mutually antagonistic cross-repression with Netrin 1 [PMID:19004851].","teleology":[{"year":2008,"claim":"Established LRIG3 as a developmental signaling modulator by placing it downstream of Pax3/Zic1 in neural crest induction and linking it to Wnt/FGF pathways and FGFR1.","evidence":"Morpholino knockdown and co-injection epistasis in Xenopus with NC marker readouts, plus Co-IP with FGFR1 in cultured cells","pmids":["18287203"],"confidence":"Medium","gaps":["FGFR1 interaction shown only by Co-IP in cultured cells, not reconstituted","Direction of FGF modulation (enhancement vs attenuation) context-dependent and not mechanistically resolved"]},{"year":2008,"claim":"Provided early evidence of reciprocal LRIG3/EGFR regulation, showing ligand-induced changes in their relative expression.","evidence":"Confocal imaging of LRIG3-EGFP fusion and EGF-treatment expression time-course in GL15 glioblastoma cells","pmids":["18925709"],"confidence":"Low","gaps":["Single localization and expression time-course without functional mutagenesis","Cytoplasmic localization of a fusion protein may not reflect endogenous distribution"]},{"year":2008,"claim":"Defined LRIG3 as essential for inner ear lateral canal morphogenesis via cross-repression with Netrin 1, with double-mutant rescue establishing causality.","evidence":"Gene-trap mouse mutant, Lrig3 × Ntn1 heterozygous rescue, in situ hybridization and circling behavior assay","pmids":["19004851"],"confidence":"High","gaps":["Molecular basis of the mutual repression unresolved","Whether LRIG3 acts cell-autonomously in the fusion plate not established"]},{"year":2010,"claim":"Tested whether ErbB modulation underlies inner ear morphogenesis and excluded it, sharpening the mechanistic model toward Netrin.","evidence":"Co-IP with ErbB2/ErbB3 plus pharmacological ErbB inhibition in chick otic vesicle with Netrin in situ readout","pmids":["20126551"],"confidence":"Medium","gaps":["Negative ErbB result is specific to inner ear and does not generalize","ErbB interaction characterized only in vitro"]},{"year":2013,"claim":"Resolved the LRIG3–Lrig1 relationship, showing LRIG3 stabilizes ErbB receptors and opposes Lrig1-driven degradation while itself being destabilized by Lrig1.","evidence":"Reciprocal Co-IP, gain/loss-of-function overexpression and receptor-degradation Western blots in cells","pmids":["23069723","23723069"],"confidence":"Medium","gaps":["Mechanism by which LRIG3 stabilizes ErbB receptors not defined","Performed in overexpression systems; endogenous stoichiometry unknown"]},{"year":2015,"claim":"Positioned LRIG3 as a tumor suppressor acting upstream of EGFR signaling in glioblastoma.","evidence":"Lentiviral overexpression, siRNA knockdown, EGFR-inhibitor epistasis, proliferation/invasion assays and xenografts","pmids":["25708990"],"confidence":"Medium","gaps":["Does not distinguish direct receptor effects from downstream pathway modulation","Single cancer-cell context"]},{"year":2020,"claim":"Identified a mechanism for LRIG3 suppression of cancer cell motility via DUSP6-mediated ERK1/2 dephosphorylation and Slug downregulation.","evidence":"LRIG3 knockout/re-introduction, Co-IP of DUSP6 with ERK1/2, p-ERK1/2 and Slug Western blots, Transwell assays in CRC cells","pmids":["32107843"],"confidence":"Medium","gaps":["How LRIG3 promotes DUSP6–ERK association not structurally defined","Single lab and cancer type"]},{"year":2020,"claim":"Established post-transcriptional control of LRIG3 by miR-196a, linking its loss to cervical cancer aggressiveness.","evidence":"Dual-luciferase reporter validation, si-LRIG3 rescue, Transwell and CCK-8 assays","pmids":["33287939"],"confidence":"Medium","gaps":["Downstream signaling effectors in this context not mapped","In vivo relevance not tested"]},{"year":2021,"claim":"Extended LRIG3's RTK regulatory role to the nervous system, showing it binds Ret and inhibits GDNF signaling redundantly with Lrig1 to control innervation and cold sensitivity.","evidence":"Co-IP with Ret, GDNF time-course, Lrig1-haploinsufficient × Lrig3-knockout genetic analysis, axon growth and behavioral cold tests","pmids":["34338291"],"confidence":"High","gaps":["Mechanism of Ret inhibition (degradation vs sequestration) not defined","Relative contributions of Lrig1 and Lrig3 not fully separated"]},{"year":2021,"claim":"Defined a non-cell-autonomous mechanism in which ADAM17-shed soluble LRIG3 binds the NETO2 CUB1 domain on macrophages to block M2 polarization and suppress tumor growth.","evidence":"Mass spectrometry, Co-IP, NETO2 knockout and CUB1-deletion mutagenesis, conditioned-medium and in vivo tumor models; ADAM17–sLRIG3 correlation","pmids":["36639372"],"confidence":"High","gaps":["ADAM17 cleavage site not mapped by reconstitution (correlational shedding evidence)","NETO2 downstream signaling in TAMs not detailed"]},{"year":2021,"claim":"Showed LRIG3 inhibits PI3K/AKT signaling to reduce VEGFA and tumor angiogenesis.","evidence":"Gain/loss-of-function, PI3K/AKT Western blots, VEGFA measurement, tube-formation and in vivo angiogenesis assays","pmids":["33718179"],"confidence":"Medium","gaps":["Link between LRIG3 and proximal PI3K/AKT regulators not defined","Whether this is downstream of EGFR not resolved"]},{"year":2025,"claim":"Broadened the in vivo phenotypic landscape of LRIG3 loss across metabolic, intestinal and inflammatory tissues and implicated BMP signaling.","evidence":"Histopathology of 42 tissues from Lrig3-deficient mice on two backgrounds with high-fat diet challenge","pmids":["40320098"],"confidence":"Low","gaps":["BMP signaling link stated without detailed mechanistic experiment","Strain-dependent phenotypes complicate interpretation"]},{"year":2026,"claim":"Demonstrated that LRIG3 gain-of-function in skin disrupts hair follicle homeostasis with upregulation of ErbB, PI3K/AKT and NOTCH1 pathways.","evidence":"Tet-Off transgenic overexpression in mouse skin with proteome profiling and pathway analysis","pmids":["42218262"],"confidence":"Low","gaps":["No direct binding or reconstitution experiments","Pathway changes correlative at the proteome level"]},{"year":null,"claim":"How LRIG3 mechanistically stabilizes ErbB receptors and inhibits Ret, and how its dual cell-autonomous (receptor-modulating) and ectodomain (NETO2-binding) activities are coordinated, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of LRIG3 receptor engagement","Endogenous shedding regulation and balance between membrane-bound and soluble pools unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,5,7,11]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,7,8,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,9,11]}],"complexes":[],"partners":["ERBB2","ERBB3","LRIG1","RET","FGFR1","NETO2","DUSP6","ADAM17"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6UXM1","full_name":"Leucine-rich repeats and immunoglobulin-like domains protein 3","aliases":[],"length_aa":1119,"mass_kda":123.4,"function":"May play a role in craniofacial and inner ear morphogenesis during embryonic development. May act within the otic vesicle epithelium to control formation of the lateral semicircular canal in the inner ear, possibly by restricting the expression of NTN1 (By similarity)","subcellular_location":"Cell membrane; Cytoplasmic vesicle membrane","url":"https://www.uniprot.org/uniprotkb/Q6UXM1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LRIG3","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LRIG3","total_profiled":1310},"omim":[{"mim_id":"608870","title":"LEUCINE-RICH REPEATS- AND IMMUNOGLOBULIN-LIKE DOMAINS-CONTAINING PROTEIN 3; LRIG3","url":"https://www.omim.org/entry/608870"},{"mim_id":"608869","title":"LEUCINE-RICH REPEATS- AND IMMUNOGLOBULIN-LIKE DOMAINS-CONTAINING PROTEIN 2; LRIG2","url":"https://www.omim.org/entry/608869"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LRIG3"},"hgnc":{"alias_symbol":["FLJ90440","KIAA3016"],"prev_symbol":[]},"alphafold":{"accession":"Q6UXM1","domains":[{"cath_id":"3.80.10.10","chopping":"324-495","consensus_level":"medium","plddt":92.5532,"start":324,"end":495},{"cath_id":"2.60.40.10","chopping":"501-596","consensus_level":"high","plddt":90.793,"start":501,"end":596},{"cath_id":"2.60.40.10","chopping":"609-695","consensus_level":"high","plddt":91.2874,"start":609,"end":695},{"cath_id":"2.60.40.10","chopping":"701-786","consensus_level":"high","plddt":91.1714,"start":701,"end":786}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXM1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXM1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXM1-F1-predicted_aligned_error_v6.png","plddt_mean":73.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LRIG3","jax_strain_url":"https://www.jax.org/strain/search?query=LRIG3"},"sequence":{"accession":"Q6UXM1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6UXM1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6UXM1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXM1"}},"corpus_meta":[{"pmid":"18287203","id":"PMC_18287203","title":"Lrig3 regulates neural crest formation in Xenopus by modulating Fgf and Wnt signaling pathways.","date":"2008","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18287203","citation_count":58,"is_preprint":false},{"pmid":"19004851","id":"PMC_19004851","title":"Cross-repressive interactions between Lrig3 and netrin 1 shape the architecture of the inner ear.","date":"2008","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/19004851","citation_count":57,"is_preprint":false},{"pmid":"33222697","id":"PMC_33222697","title":"A novel circular RNA circ-LRIG3 facilitates the malignant progression of hepatocellular carcinoma by modulating the EZH2/STAT3 signaling.","date":"2020","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/33222697","citation_count":52,"is_preprint":false},{"pmid":"23165628","id":"PMC_23165628","title":"Expression of LRIG1 and LRIG3 correlates with human papillomavirus status and patient survival in cervical adenocarcinoma.","date":"2012","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/23165628","citation_count":35,"is_preprint":false},{"pmid":"23723069","id":"PMC_23723069","title":"Leucine-rich repeat and immunoglobulin domain-containing protein-1 (Lrig1) negative regulatory action toward ErbB receptor tyrosine kinases is opposed by leucine-rich repeat and immunoglobulin domain-containing protein 3 (Lrig3).","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23723069","citation_count":32,"is_preprint":false},{"pmid":"31119777","id":"PMC_31119777","title":"Upregulation of microRNA-196a improves cognitive impairment and alleviates neuronal damage in hippocampus tissues of Alzheimer's disease through downregulating LRIG3 expression.","date":"2019","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31119777","citation_count":21,"is_preprint":false},{"pmid":"20126551","id":"PMC_20126551","title":"Vertebrate Lrig3-ErbB interactions occur in vitro but are unlikely to play a role in Lrig3-dependent inner ear morphogenesis.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/20126551","citation_count":21,"is_preprint":false},{"pmid":"33718179","id":"PMC_33718179","title":"LRIG3 Suppresses Angiogenesis by Regulating the PI3K/AKT/VEGFA Signaling Pathway in Glioma.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33718179","citation_count":17,"is_preprint":false},{"pmid":"25708990","id":"PMC_25708990","title":"LRIG3 modulates proliferation, apoptosis and invasion of glioblastoma cells as a potent tumor suppressor.","date":"2015","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25708990","citation_count":15,"is_preprint":false},{"pmid":"27009049","id":"PMC_27009049","title":"Cardiac hypertrophy and decreased high-density lipoprotein cholesterol in Lrig3-deficient mice.","date":"2016","source":"American journal of physiology. Regulatory, integrative and comparative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/27009049","citation_count":15,"is_preprint":false},{"pmid":"26517670","id":"PMC_26517670","title":"Variants in the genes DCTN2, DNAH10, LRIG3, and MYO1A are associated with intermediate Charcot-Marie-Tooth disease in a Norwegian family.","date":"2015","source":"Acta neurologica Scandinavica","url":"https://pubmed.ncbi.nlm.nih.gov/26517670","citation_count":13,"is_preprint":false},{"pmid":"36639372","id":"PMC_36639372","title":"Glioma-derived LRIG3 interacts with NETO2 in tumor-associated macrophages to modulate microenvironment and suppress tumor growth.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36639372","citation_count":12,"is_preprint":false},{"pmid":"30412760","id":"PMC_30412760","title":"Overexpressed LRIG3 gene ameliorates prostate cancer through suppression of cell invasion and migration.","date":"2018","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/30412760","citation_count":8,"is_preprint":false},{"pmid":"22038358","id":"PMC_22038358","title":"Effect of over-expressed LRIG3 on cell cycle and survival of glioma cells.","date":"2011","source":"Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban","url":"https://pubmed.ncbi.nlm.nih.gov/22038358","citation_count":7,"is_preprint":false},{"pmid":"32107843","id":"PMC_32107843","title":"LRIG3 represses cell motility by inhibiting slug via inactivating ERK signaling in human colorectal cancer.","date":"2020","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/32107843","citation_count":7,"is_preprint":false},{"pmid":"34338291","id":"PMC_34338291","title":"Lrig1 and Lrig3 cooperate to control Ret receptor signaling, sensory axonal growth and epidermal innervation.","date":"2021","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/34338291","citation_count":5,"is_preprint":false},{"pmid":"19448407","id":"PMC_19448407","title":"Effect of RNAi-mediated LRIG3 gene silencing on proliferation of glioma GL15 cells and expression of PCNA and Ki-67.","date":"2009","source":"Ai zheng = Aizheng = Chinese journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19448407","citation_count":5,"is_preprint":false},{"pmid":"23392718","id":"PMC_23392718","title":"Over-expression of LRIG3 suppresses growth and invasion of bladder cancer cells.","date":"2013","source":"Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban","url":"https://pubmed.ncbi.nlm.nih.gov/23392718","citation_count":4,"is_preprint":false},{"pmid":"33880997","id":"PMC_33880997","title":"circ_LRIG3 contributes to the progression of hepatocellular carcinoma by elevating RNF38 via sponging miR-449a.","date":"2021","source":"General physiology and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/33880997","citation_count":4,"is_preprint":false},{"pmid":"33287939","id":"PMC_33287939","title":"miR-196a targeting LRIG3 promotes the proliferation and migration of cervical cancer cells.","date":"2020","source":"Cellular and molecular biology (Noisy-le-Grand, France)","url":"https://pubmed.ncbi.nlm.nih.gov/33287939","citation_count":4,"is_preprint":false},{"pmid":"21505989","id":"PMC_21505989","title":"Effect of silencing LRIG3 gene on the proliferation and apoptosis of bladder cancer T24 cells.","date":"2011","source":"Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban","url":"https://pubmed.ncbi.nlm.nih.gov/21505989","citation_count":3,"is_preprint":false},{"pmid":"19224171","id":"PMC_19224171","title":"Effects of RNAi-mediated gene silencing of LRIG3 expression on cell cycle and survival of glioma cells.","date":"2009","source":"Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban","url":"https://pubmed.ncbi.nlm.nih.gov/19224171","citation_count":3,"is_preprint":false},{"pmid":"26390694","id":"PMC_26390694","title":"Expression and significance of LRIG3 in human cervical squamous cell carcinoma.","date":"2015","source":"European journal of gynaecological oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26390694","citation_count":2,"is_preprint":false},{"pmid":"18925709","id":"PMC_18925709","title":"[LRIG3 gene regulates biological activity of GL15 cell line].","date":"2008","source":"Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/18925709","citation_count":0,"is_preprint":false},{"pmid":"40320098","id":"PMC_40320098","title":"Lrig3-deficient mice exhibit strain-specific alterations in liver fat accumulation, intestinal morphology, and middle ear inflammation.","date":"2025","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/40320098","citation_count":0,"is_preprint":false},{"pmid":"42218262","id":"PMC_42218262","title":"Cutaneous gain-of-function mutation of LRIG3 leads to alopecia by upregulation of ERBB, PI3K/AKT, NOTCH1 signaling pathways.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/42218262","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15419,"output_tokens":3921,"usd":0.052536,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11688,"output_tokens":4139,"usd":0.080958,"stage2_stop_reason":"end_turn"},"total_usd":0.133494,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"Lrig3 acts downstream of Pax3 and Zic1 in neural crest (NC) formation in Xenopus; morpholino-induced knockdown of Lrig3 blocked NC marker induction (Slug, Sox9, Foxd3) by Pax3 and Zic1. Lrig3 co-injection with Wnt3a enhanced FGF3/4/8 induction, suggesting a positive role in Wnt signaling, and Lrig3 attenuated FGF signaling in animal caps. Lrig3 was shown to interact with FGFR1 in cultured cells.\",\n      \"method\": \"Morpholino knockdown in Xenopus, NC induction animal cap assay, co-injection epistasis, co-immunoprecipitation with FGFR1 in cultured cells\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in Xenopus with multiple marker readouts plus Co-IP with FGFR1; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"18287203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Lrig3 is necessary for lateral semicircular canal morphogenesis; loss of Lrig3 causes ectopic expression of netrin 1 (Ntn1) in the otic vesicle fusion plate, disrupting basal lamina integrity. Mutually antagonistic (cross-repressive) interactions between Lrig3 and Ntn1 create complementary expression domains defining canal shape. Removal of one copy of Ntn1 from Lrig3 mutants rescues both canal malformation and circling behavior.\",\n      \"method\": \"Gene trap mutagenesis screen, genetic epistasis (Lrig3 mutant × Ntn1 heterozygous rescue), in situ hybridization for marker genes, behavioral assay\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with clean double-mutant rescue, multiple orthogonal readouts (behavior, morphology, molecular markers), replicated across genetic backgrounds\",\n      \"pmids\": [\"19004851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Lrig3 interacts with ErbB receptors (ErbB2 and ErbB3) in vitro, but inhibition of ErbB activation in the chick otic vesicle had no detectable effect on Netrin gene expression or canal morphogenesis, indicating that ErbB modulation is unlikely to account for Lrig3-dependent inner ear morphogenesis.\",\n      \"method\": \"Co-immunoprecipitation (in vitro), pharmacological inhibition of ErbB in chick otic vesicle, in situ hybridization for Netrin\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo functional test with inhibitor; single lab, two orthogonal methods; negative result for ErbB in inner ear morphogenesis is mechanistically informative\",\n      \"pmids\": [\"20126551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Lrig3 functionally opposes Lrig1: Lrig3 stabilizes ErbB receptors and counteracts Lrig1-mediated receptor degradation. Conversely, Lrig1 destabilizes Lrig3 protein, identifying Lrig3 as a target of Lrig1-driven destabilization. Lrig1 and Lrig3 interact with each other.\",\n      \"method\": \"Co-immunoprecipitation, gain/loss-of-function overexpression, receptor degradation assays (Western blot), cell-based functional assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional assays and Co-IP demonstrating physical and functional interaction; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23069723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Lrig3 interacts with ErbB receptors in vitro (as confirmed independently of the 2010 study), and Lrig3 stabilizes ErbB receptor expression rather than promoting degradation, opposite to Lrig1.\",\n      \"method\": \"Co-immunoprecipitation, receptor expression level analysis by Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus quantitative receptor-level assay; single lab\",\n      \"pmids\": [\"23723069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LRIG3 negatively regulates EGFR signaling in glioblastoma cells; overexpression of LRIG3 inhibited cell growth, promoted apoptosis, and restrained invasion/migration. Pharmacological inhibition of EGFR reduced the effects of LRIG3 knockdown on cell proliferation and EGFR pathway activation, placing LRIG3 upstream of EGFR signaling.\",\n      \"method\": \"Lentiviral overexpression, siRNA knockdown, EGFR inhibitor epistasis, in vitro proliferation/invasion assays, in vivo xenograft, Western blot for EGFR pathway\",\n      \"journal\": \"Journal of the neurological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis plus loss- and gain-of-function with multiple cellular readouts; single lab\",\n      \"pmids\": [\"25708990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LRIG3 fusion protein localizes to the cytoplasm of glioblastoma GL15 cells. EGF treatment (100 ng/ml) increased LRIG3 expression over time while decreasing EGFR expression, suggesting reciprocal regulation between LRIG3 and EGFR in response to ligand.\",\n      \"method\": \"Confocal microscopy of LRIG3-EGFP fusion protein, RT-PCR and Western blot after EGF treatment\",\n      \"journal\": \"Journal of Zhejiang University. Medical sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization experiment and expression time-course; single lab, no functional mutagenesis\",\n      \"pmids\": [\"18925709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Lrig3 interacts with Ret receptor and inhibits GDNF/Ret signaling in dorsal root ganglion (DRG) neurons. GDNF treatment induces upregulation of both Lrig1 and Lrig3 expression. Haploinsufficiency of Lrig1 in Lrig3 mutants (double partial loss-of-function) potentiates Ret signaling and axonal growth, demonstrating Lrig1/Lrig3 genetic redundancy. Lrig1 and Lrig3 act redundantly to ensure proper cutaneous innervation by nonpeptidergic axons and cold sensitivity (correlated with increased TrpA1 expression).\",\n      \"method\": \"Co-immunoprecipitation of Lrig3 with Ret, GDNF treatment time-course, genetic double-mutant analysis (Lrig1 haploinsufficiency × Lrig3 knockout), axonal growth assays, behavioral cold sensitivity tests, TrpA1 expression analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP plus genetic epistasis with double-mutant rescue plus multiple functional readouts (axonal growth, behavior, molecular markers); single lab but multiple orthogonal methods\",\n      \"pmids\": [\"34338291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LRIG3 facilitates binding of DUSP6 to ERK1/2, leading to dephosphorylation of ERK1/2 and subsequent downregulation of Slug (an EMT regulator), thereby suppressing colorectal cancer cell motility. LRIG3 expression negatively correlated with p-ERK1/2 and Slug in CRC tissues.\",\n      \"method\": \"LRIG3 knockout and re-introduction, Co-IP of DUSP6 with ERK1/2, Western blot for p-ERK1/2 and Slug, migration/invasion Transwell assay\",\n      \"journal\": \"IUBMB life\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus gain/loss-of-function with defined molecular pathway and phenotypic readout; single lab\",\n      \"pmids\": [\"32107843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Soluble LRIG3 (sLRIG3), shed from glioma cells by ADAM17-mediated cleavage, interacts with the CUB1 domain of NETO2 in tumor-associated macrophages (TAMs), blocking M2 polarization and suppressing GBM growth. NETO2 knockout or CUB1 deletion mutant abolished the suppressive effects of sLRIG3 on TAM M2-polarization.\",\n      \"method\": \"Mass spectrometry, Co-immunoprecipitation, NETO2 knockout/CUB1-deletion mutagenesis, conditioned medium assay, in vivo tumor model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — binding partner identified by mass spectrometry and confirmed by Co-IP; domain-deletion mutagenesis validates interaction; in vivo functional readout; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"36639372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ADAM17 activity in glioma cells positively correlates with shedding of soluble LRIG3 (sLRIG3) into cell supernatant, identifying ADAM17 as the sheddase for LRIG3 ectodomain release.\",\n      \"method\": \"Correlation of ADAM17 expression/activity with sLRIG3 levels in conditioned medium\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlational finding within one study; no direct enzymatic reconstitution or mutagenesis of ADAM17 cleavage site reported in abstract\",\n      \"pmids\": [\"36639372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LRIG3 inhibits PI3K/AKT signaling pathway activation in glioma cells, downregulating VEGFA expression and thereby suppressing glioma-induced angiogenesis both in vitro and in vivo.\",\n      \"method\": \"Loss- and gain-of-function assays, Western blot for PI3K/AKT pathway, VEGFA expression measurement, tube formation assay in vitro, in vivo angiogenesis model\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with defined pathway readout and in vivo validation; single lab\",\n      \"pmids\": [\"33718179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"miR-196a directly targets LRIG3 mRNA (validated by dual luciferase reporter assay), and reduction of LRIG3 protein promotes proliferation, migration, and invasion of cervical cancer cells.\",\n      \"method\": \"Dual luciferase reporter assay, Western blot, si-LRIG3 transfection rescue experiment, Transwell and CCK-8 assays\",\n      \"journal\": \"Cellular and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct luciferase validation of miR-196a/LRIG3 targeting plus functional rescue; single lab\",\n      \"pmids\": [\"33287939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Lrig3-deficient mice show strain-dependent regulation of liver fat accumulation (hepatocellular steatosis), intestinal morphology (dilated/flaccid ileum), and middle ear inflammation (otitis media), and Lrig3 regulates BMP signaling in vivo.\",\n      \"method\": \"Histopathological examination of 42 tissues from Lrig3-deficient mice on two genetic backgrounds, high-fat diet challenge\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — loss-of-function phenotypic screen across tissues; BMP signaling reference is stated without detailed mechanistic experiment described in the abstract\",\n      \"pmids\": [\"40320098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Skin-specific overexpression of Lrig3 in mice causes alopecia and upregulation of ERBB, PI3K/AKT, and NOTCH1 signaling pathways, with altered keratinocyte differentiation and hair follicle/sebaceous gland marker profiles.\",\n      \"method\": \"Tet-Off transgenic mouse overexpression, proteome profiling of skin, pathway analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — gain-of-function in vivo with pathway-level readouts but no direct binding/reconstitution experiments described in abstract; single study\",\n      \"pmids\": [\"42218262\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRIG3 is a transmembrane leucine-rich repeat and immunoglobulin domain protein that modulates multiple receptor tyrosine kinase (ErbB, EGFR, Ret, FGFR1) and non-RTK signaling pathways: it stabilizes ErbB receptors and opposes Lrig1-mediated receptor degradation, inhibits EGFR/PI3K/AKT/ERK signaling to suppress tumor cell proliferation and invasion, interacts with Ret to inhibit GDNF signaling in DRG neurons redundantly with Lrig1, and releases a soluble ectodomain (via ADAM17 shedding) that binds the CUB1 domain of NETO2 in tumor-associated macrophages to block M2 polarization; in development, it acts downstream of Pax3/Zic1 in neural crest formation by modulating Wnt/FGF signaling and controls inner ear lateral canal morphogenesis through mutually antagonistic cross-repression with Netrin 1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LRIG3 is a transmembrane leucine-rich repeat and immunoglobulin-domain protein that operates as a context-dependent modulator of receptor tyrosine kinase signaling and developmental patterning [#0, #3]. In ErbB/EGFR signaling, LRIG3 physically associates with ErbB receptors and stabilizes them, acting in functional opposition to its paralog Lrig1, which destabilizes both ErbB receptors and LRIG3 itself; the two proteins interact directly [#3, #4]. In cancer cells LRIG3 behaves as a tumor suppressor: it restrains EGFR pathway output to inhibit proliferation, invasion and migration [#5], facilitates DUSP6-mediated dephosphorylation of ERK1/2 to downregulate the EMT regulator Slug [#8], and inhibits PI3K/AKT signaling to reduce VEGFA expression and tumor angiogenesis [#11]. An ADAM17-shed soluble LRIG3 ectodomain engages the CUB1 domain of NETO2 on tumor-associated macrophages to block M2 polarization and suppress glioblastoma growth, defining a non-cell-autonomous signaling mode [#9]. Beyond cancer, LRIG3 binds Ret and inhibits GDNF/Ret signaling in DRG neurons, acting redundantly with Lrig1 to control cutaneous innervation and cold sensitivity [#7]. In development, LRIG3 functions downstream of Pax3/Zic1 to modulate Wnt and FGF signaling during neural crest induction and interacts with FGFR1 [#0], and it patterns inner ear lateral semicircular canal morphogenesis through mutually antagonistic cross-repression with Netrin 1 [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established LRIG3 as a developmental signaling modulator by placing it downstream of Pax3/Zic1 in neural crest induction and linking it to Wnt/FGF pathways and FGFR1.\",\n      \"evidence\": \"Morpholino knockdown and co-injection epistasis in Xenopus with NC marker readouts, plus Co-IP with FGFR1 in cultured cells\",\n      \"pmids\": [\"18287203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FGFR1 interaction shown only by Co-IP in cultured cells, not reconstituted\", \"Direction of FGF modulation (enhancement vs attenuation) context-dependent and not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Provided early evidence of reciprocal LRIG3/EGFR regulation, showing ligand-induced changes in their relative expression.\",\n      \"evidence\": \"Confocal imaging of LRIG3-EGFP fusion and EGF-treatment expression time-course in GL15 glioblastoma cells\",\n      \"pmids\": [\"18925709\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single localization and expression time-course without functional mutagenesis\", \"Cytoplasmic localization of a fusion protein may not reflect endogenous distribution\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined LRIG3 as essential for inner ear lateral canal morphogenesis via cross-repression with Netrin 1, with double-mutant rescue establishing causality.\",\n      \"evidence\": \"Gene-trap mouse mutant, Lrig3 × Ntn1 heterozygous rescue, in situ hybridization and circling behavior assay\",\n      \"pmids\": [\"19004851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the mutual repression unresolved\", \"Whether LRIG3 acts cell-autonomously in the fusion plate not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Tested whether ErbB modulation underlies inner ear morphogenesis and excluded it, sharpening the mechanistic model toward Netrin.\",\n      \"evidence\": \"Co-IP with ErbB2/ErbB3 plus pharmacological ErbB inhibition in chick otic vesicle with Netrin in situ readout\",\n      \"pmids\": [\"20126551\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative ErbB result is specific to inner ear and does not generalize\", \"ErbB interaction characterized only in vitro\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the LRIG3–Lrig1 relationship, showing LRIG3 stabilizes ErbB receptors and opposes Lrig1-driven degradation while itself being destabilized by Lrig1.\",\n      \"evidence\": \"Reciprocal Co-IP, gain/loss-of-function overexpression and receptor-degradation Western blots in cells\",\n      \"pmids\": [\"23069723\", \"23723069\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which LRIG3 stabilizes ErbB receptors not defined\", \"Performed in overexpression systems; endogenous stoichiometry unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Positioned LRIG3 as a tumor suppressor acting upstream of EGFR signaling in glioblastoma.\",\n      \"evidence\": \"Lentiviral overexpression, siRNA knockdown, EGFR-inhibitor epistasis, proliferation/invasion assays and xenografts\",\n      \"pmids\": [\"25708990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not distinguish direct receptor effects from downstream pathway modulation\", \"Single cancer-cell context\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a mechanism for LRIG3 suppression of cancer cell motility via DUSP6-mediated ERK1/2 dephosphorylation and Slug downregulation.\",\n      \"evidence\": \"LRIG3 knockout/re-introduction, Co-IP of DUSP6 with ERK1/2, p-ERK1/2 and Slug Western blots, Transwell assays in CRC cells\",\n      \"pmids\": [\"32107843\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How LRIG3 promotes DUSP6–ERK association not structurally defined\", \"Single lab and cancer type\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established post-transcriptional control of LRIG3 by miR-196a, linking its loss to cervical cancer aggressiveness.\",\n      \"evidence\": \"Dual-luciferase reporter validation, si-LRIG3 rescue, Transwell and CCK-8 assays\",\n      \"pmids\": [\"33287939\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling effectors in this context not mapped\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended LRIG3's RTK regulatory role to the nervous system, showing it binds Ret and inhibits GDNF signaling redundantly with Lrig1 to control innervation and cold sensitivity.\",\n      \"evidence\": \"Co-IP with Ret, GDNF time-course, Lrig1-haploinsufficient × Lrig3-knockout genetic analysis, axon growth and behavioral cold tests\",\n      \"pmids\": [\"34338291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Ret inhibition (degradation vs sequestration) not defined\", \"Relative contributions of Lrig1 and Lrig3 not fully separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a non-cell-autonomous mechanism in which ADAM17-shed soluble LRIG3 binds the NETO2 CUB1 domain on macrophages to block M2 polarization and suppress tumor growth.\",\n      \"evidence\": \"Mass spectrometry, Co-IP, NETO2 knockout and CUB1-deletion mutagenesis, conditioned-medium and in vivo tumor models; ADAM17–sLRIG3 correlation\",\n      \"pmids\": [\"36639372\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ADAM17 cleavage site not mapped by reconstitution (correlational shedding evidence)\", \"NETO2 downstream signaling in TAMs not detailed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed LRIG3 inhibits PI3K/AKT signaling to reduce VEGFA and tumor angiogenesis.\",\n      \"evidence\": \"Gain/loss-of-function, PI3K/AKT Western blots, VEGFA measurement, tube-formation and in vivo angiogenesis assays\",\n      \"pmids\": [\"33718179\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between LRIG3 and proximal PI3K/AKT regulators not defined\", \"Whether this is downstream of EGFR not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Broadened the in vivo phenotypic landscape of LRIG3 loss across metabolic, intestinal and inflammatory tissues and implicated BMP signaling.\",\n      \"evidence\": \"Histopathology of 42 tissues from Lrig3-deficient mice on two backgrounds with high-fat diet challenge\",\n      \"pmids\": [\"40320098\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"BMP signaling link stated without detailed mechanistic experiment\", \"Strain-dependent phenotypes complicate interpretation\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Demonstrated that LRIG3 gain-of-function in skin disrupts hair follicle homeostasis with upregulation of ErbB, PI3K/AKT and NOTCH1 pathways.\",\n      \"evidence\": \"Tet-Off transgenic overexpression in mouse skin with proteome profiling and pathway analysis\",\n      \"pmids\": [\"42218262\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct binding or reconstitution experiments\", \"Pathway changes correlative at the proteome level\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LRIG3 mechanistically stabilizes ErbB receptors and inhibits Ret, and how its dual cell-autonomous (receptor-modulating) and ectodomain (NETO2-binding) activities are coordinated, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of LRIG3 receptor engagement\", \"Endogenous shedding regulation and balance between membrane-bound and soluble pools unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 5, 7, 11]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7, 8, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 9, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ERBB2\", \"ERBB3\", \"LRIG1\", \"RET\", \"FGFR1\", \"NETO2\", \"DUSP6\", \"ADAM17\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":{"gene":"LRIG3","tier":"GROUNDING","verdict":"Evidence-grounding concern","subtype":"fabrication","uniprot_band":"medium","rules_fired":"R7","issue":"R7: fabricated (no corpus paper): 23069723"},"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}