{"gene":"LRIG3","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2008,"finding":"Xenopus Lrig3 acts downstream of Pax3 and Zic1 in neural crest formation, modulates Wnt signaling positively (co-injection with Wnt3a induces NC markers and Fgf3/4/8), and attenuates Fgf signaling; Lrig3 directly interacts with Fgf receptor 1 in cultured cells.","method":"Morpholino knockdown in Xenopus, NC induction animal cap assay, co-injection epistasis experiments, co-immunoprecipitation with FGFR1","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (MO knockdown, epistasis assay, Co-IP) in a single study with clear pathway placement","pmids":["18287203"],"is_preprint":false},{"year":2008,"finding":"Lrig3 is required for lateral semicircular canal morphogenesis in mice; loss of Lrig3 causes ectopic Netrin1 (Ntn1) expression, and mutually antagonistic interactions between Lrig3 and Ntn1 define complementary expression domains that control basement membrane breakdown during canal fusion. Genetic removal of one Ntn1 copy rescues both canal malformation and circling behavior in Lrig3 mutants.","method":"Gene trap mutagenesis, genetic epistasis (Lrig3 mutant × Ntn1 heterozygote cross), behavioral assay, in situ hybridization for marker genes","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 — clean genetic epistasis with rescue experiment and behavioral readout, replicated across multiple genetic combinations","pmids":["19004851"],"is_preprint":false},{"year":2010,"finding":"Lrig3 interacts with ErbB receptors (ErbB2 and ErbB3) in vitro; however, inhibition of ErbB activation in the chick otic vesicle has no effect on Netrin gene expression or canal morphogenesis, indicating ErbB modulation is not the in vivo mechanism for Lrig3-dependent inner ear development.","method":"Co-immunoprecipitation (in vitro), pharmacological ErbB inhibition in chick otic vesicle, in situ hybridization","journal":"PLoS ONE","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus functional in vivo dissociation, but single lab","pmids":["20126551"],"is_preprint":false},{"year":2013,"finding":"Lrig3 opposes Lrig1's negative regulation of ErbB receptors: Lrig3 stabilizes ErbB receptors and counteracts Lrig1-induced receptor degradation, while Lrig1 in turn destabilizes Lrig3 protein, identifying Lrig3 as a target of Lrig1.","method":"Co-immunoprecipitation, receptor stability assays, gain- and loss-of-function in cell lines","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal functional interaction with Co-IP and protein stability assays, single lab","pmids":["23723069"],"is_preprint":false},{"year":2015,"finding":"LRIG3 overexpression in glioblastoma cells inhibits proliferation, promotes apoptosis, and restrains invasion; mechanistically, LRIG3 negatively regulates the EGFR signaling pathway, and EGFR inhibition reduces the proliferative effects of LRIG3 knockdown.","method":"Lentiviral overexpression and siRNA knockdown in glioma cells, EGFR inhibitor epistasis, in vitro and in vivo tumor assays, Western blot for pathway components","journal":"Journal of the Neurological Sciences","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological epistasis with EGFR inhibitor supports pathway placement, single lab","pmids":["25708990"],"is_preprint":false},{"year":2020,"finding":"LRIG3 suppresses colorectal cancer cell motility by facilitating binding of DUSP6 to ERK1/2, leading to dephosphorylation of ERK1/2 and subsequent downregulation of Slug (an EMT driver), thereby constraining cell migration and invasion.","method":"LRIG3 knockout and re-expression, Co-immunoprecipitation (LRIG3-DUSP6-ERK1/2 complex), Western blot for p-ERK1/2 and Slug, Transwell migration/invasion assay","journal":"IUBMB Life","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP identifies complex plus functional rescue, single lab","pmids":["32107843"],"is_preprint":false},{"year":2021,"finding":"LRIG3 suppresses glioma angiogenesis by inhibiting activation of the PI3K/AKT signaling pathway, leading to downregulation of VEGFA in glioma cells.","method":"Loss- and gain-of-function assays in glioma cells, in vitro angiogenesis assay, in vivo xenograft, Western blot for PI3K/AKT pathway components","journal":"Frontiers in Oncology","confidence":"Medium","confidence_rationale":"Tier 3 — pathway inferred by Western blot of downstream components without direct enzymatic or binding evidence; functional phenotype is clear","pmids":["33718179"],"is_preprint":false},{"year":2021,"finding":"Lrig3 interacts with Ret receptor and inhibits GDNF/Ret signaling in mouse dorsal root ganglion neurons; GDNF treatment induces Lrig3 expression (negative feedback); Lrig1 and Lrig3 act redundantly to control cutaneous innervation of nonpeptidergic axons and behavioral sensitivity to cold via regulation of TrpA1 expression.","method":"Co-immunoprecipitation (Lrig3-Ret), DRG neuron culture, Lrig1/Lrig3 single and double mutant genetic epistasis, behavioral assay, immunostaining of skin innervation","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 — Co-IP plus clean genetic epistasis with compound mutants and behavioral/cellular readouts","pmids":["34338291"],"is_preprint":false},{"year":2023,"finding":"Soluble LRIG3 (sLRIG3) shed from glioma cells by ADAM17 blocks M2 polarization of tumor-associated macrophages (TAMs) by interacting with the CUB1 domain of NETO2 on TAMs; deletion of the CUB1 domain of NETO2 abolishes the suppressive effect of sLRIG3 on M2 polarization.","method":"Mass spectrometry, Co-immunoprecipitation, NETO2 silencing/knockout, domain-deletion mutant (NETO2 ΔCUB1), conditioned medium transfer assays, in vivo tumor growth assay","journal":"Cell Death & Disease","confidence":"High","confidence_rationale":"Tier 2 — MS-identified interaction confirmed by Co-IP plus domain-deletion rescue, multiple orthogonal approaches","pmids":["36639372"],"is_preprint":false},{"year":2020,"finding":"Circ-LRIG3 (hsa_circ_0027345) forms a ternary complex with EZH2 and STAT3, facilitating EZH2-mediated methylation of STAT3 and subsequent STAT3 phosphorylation/activation; activated STAT3 in turn binds the circ-LRIG3 promoter to increase its transcription, forming a positive feedback loop.","method":"Co-immunoprecipitation, RNA immunoprecipitation (RIP), ChIP assay, STAT3 inhibitor (C188-9), in vivo xenograft","journal":"Journal of Experimental & Clinical Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP/RIP/ChIP for complex; note this is for the circular RNA derived from the LRIG3 locus, not the LRIG3 protein itself","pmids":["33222697"],"is_preprint":false},{"year":2008,"finding":"LRIG3 protein localizes to the cytoplasm of glioblastoma GL15 cells (observed by confocal microscopy of LRIG3-EGFP fusion); EGFR expression decreases while LRIG3 expression increases upon EGF treatment in a time-dependent manner, suggesting reciprocal regulation.","method":"Confocal microscopy of LRIG3-EGFP fusion protein, RT-PCR and Western blot with EGF time-course","journal":"Zhejiang University Medical Sciences","confidence":"Low","confidence_rationale":"Tier 3 — localization by overexpressed fusion protein; reciprocal expression is correlative, not mechanistic","pmids":["18925709"],"is_preprint":false},{"year":2025,"finding":"Lrig3 regulates liver fat accumulation (hepatocellular steatosis) and intestinal morphology in mice in a strain-dependent manner; Lrig3-deficient mice also exhibit middle ear inflammation, and the paper notes Lrig3 regulates BMP signaling based on prior work.","method":"Histopathological examination of 42 tissues from Lrig3 knockout mice on two genetic backgrounds, high-fat diet challenge","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 — phenotypic description in KO mice without direct mechanistic dissection of BMP pathway","pmids":["40320098"],"is_preprint":false}],"current_model":"LRIG3 is a transmembrane leucine-rich repeat and immunoglobulin domain protein that functions as a context-dependent modulator of multiple receptor tyrosine kinase pathways: it interacts directly with FGFR1, ErbB receptors, and Ret to regulate their signaling (often inhibitory), opposes the negative regulatory activity of Lrig1 on ErbB receptors by stabilizing them, facilitates DUSP6-mediated ERK1/2 dephosphorylation to suppress EMT-driven cell motility, and in the inner ear controls lateral canal morphogenesis by creating mutually antagonistic expression domains with Netrin1 to regulate basement membrane breakdown; additionally, soluble shed LRIG3 interacts with NETO2 on tumor-associated macrophages to inhibit M2 polarization."},"narrative":{"teleology":[{"year":2008,"claim":"Establishing LRIG3 as a signaling modulator in neural crest development resolved the question of where in the FGF/Wnt hierarchy this LRR protein operates: it acts downstream of Pax3/Zic1, attenuates FGF signaling via direct FGFR1 interaction, and positively modulates Wnt signaling.","evidence":"Morpholino knockdown, animal cap epistasis assays, and co-immunoprecipitation with FGFR1 in Xenopus","pmids":["18287203"],"confidence":"High","gaps":["Mechanism by which LRIG3 attenuates FGFR1 signaling (degradation vs. inhibition of activation) not determined","Wnt modulation mechanism not defined at molecular level"]},{"year":2008,"claim":"Genetic epistasis in mice revealed that LRIG3 controls lateral semicircular canal morphogenesis by antagonizing Netrin1 expression, with Ntn1 haploinsufficiency rescuing the canal defect and circling behavior of Lrig3 mutants.","evidence":"Gene trap mutagenesis, Lrig3 × Ntn1 genetic crosses, behavioral assay, in situ hybridization in mouse inner ear","pmids":["19004851"],"confidence":"High","gaps":["Molecular mechanism by which LRIG3 represses Netrin1 transcription is unknown","Whether LRIG3 acts cell-autonomously in the otic epithelium was not resolved"]},{"year":2010,"claim":"Although LRIG3 binds ErbB2/ErbB3 in vitro, pharmacological ErbB inhibition in chick otic vesicle did not phenocopy Lrig3 loss, dissociating ErbB modulation from the inner ear morphogenesis function.","evidence":"Co-immunoprecipitation of LRIG3 with ErbB2/ErbB3; pharmacological ErbB inhibition in chick otic vesicle explants","pmids":["20126551"],"confidence":"Medium","gaps":["The relevant in vivo receptor target in the inner ear remains unidentified","Single-lab finding without genetic ErbB loss-of-function"]},{"year":2013,"claim":"Defining the LRIG3–LRIG1 functional antagonism showed that LRIG3 stabilizes ErbB receptors and counteracts LRIG1-mediated degradation, while LRIG1 reciprocally destabilizes LRIG3 protein—establishing a paralog-level regulatory circuit.","evidence":"Co-immunoprecipitation, receptor stability assays, gain- and loss-of-function in cell lines","pmids":["23723069"],"confidence":"Medium","gaps":["Whether LRIG3–LRIG1 antagonism occurs in vivo in specific tissues is untested","Whether LRIG1-induced LRIG3 destabilization is ubiquitin-dependent is unknown"]},{"year":2015,"claim":"Extending LRIG3's RTK-inhibitory role to cancer, LRIG3 overexpression in glioblastoma cells suppressed proliferation and invasion via EGFR pathway downregulation, confirmed by EGFR inhibitor epistasis.","evidence":"Lentiviral overexpression and siRNA knockdown in glioma cells, EGFR inhibitor rescue, xenograft assays","pmids":["25708990"],"confidence":"Medium","gaps":["Whether LRIG3 directly binds EGFR or acts indirectly through other ErbB family members not resolved","Mechanism of EGFR downregulation (degradation, internalization, or transcriptional) not defined"]},{"year":2020,"claim":"Identifying LRIG3 as a scaffold that bridges DUSP6 to ERK1/2 provided a mechanism for its anti-migratory function: LRIG3 facilitates ERK dephosphorylation and consequent Slug downregulation, suppressing EMT-driven motility in colorectal cancer cells.","evidence":"Co-immunoprecipitation of LRIG3–DUSP6–ERK1/2 ternary complex, knockout and re-expression rescue, Transwell assays","pmids":["32107843"],"confidence":"Medium","gaps":["Structural basis for LRIG3 scaffolding of DUSP6 and ERK1/2 is unknown","Whether this mechanism operates in non-cancer contexts not tested"]},{"year":2021,"claim":"Demonstration that LRIG3 directly interacts with the Ret receptor and inhibits GDNF/Ret signaling in DRG neurons, with LRIG1 and LRIG3 acting redundantly to control cutaneous innervation and cold sensitivity, extended the RTK-regulatory function to the peripheral nervous system.","evidence":"Co-immunoprecipitation of Lrig3–Ret, single and compound Lrig1/Lrig3 mutant mice, behavioral cold-sensitivity assay, skin innervation immunostaining","pmids":["34338291"],"confidence":"High","gaps":["Whether LRIG3 promotes Ret degradation or blocks ligand binding is not determined","Relative contributions of LRIG1 vs. LRIG3 to Ret regulation in different DRG neuron subtypes are unclear"]},{"year":2023,"claim":"Discovery that ADAM17-shed soluble LRIG3 interacts with the CUB1 domain of NETO2 on tumor-associated macrophages to suppress M2 polarization revealed a non-cell-autonomous, paracrine tumor-suppressive mechanism distinct from its RTK-modulatory roles.","evidence":"Mass spectrometry identification of sLRIG3–NETO2 interaction, Co-IP, NETO2 ΔCUB1 domain-deletion abolishes effect, in vivo tumor assay","pmids":["36639372"],"confidence":"High","gaps":["Signaling pathway downstream of NETO2 that mediates M2 suppression is not identified","Physiological relevance of sLRIG3-NETO2 interaction outside the tumor microenvironment is unknown"]},{"year":null,"claim":"The structural basis for LRIG3's receptor selectivity, the mechanism by which it simultaneously scaffolds phosphatases and modulates RTKs, and whether its paracrine (sLRIG3–NETO2) and cell-autonomous (RTK-inhibitory) functions are coordinated remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or cryo-EM model of LRIG3 in complex with any partner","In vivo relevance of LRIG3–DUSP6–ERK scaffolding outside colorectal cancer not tested","Whether ADAM17-mediated shedding is regulated and how it partitions LRIG3 between cell-autonomous and paracrine functions is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,4,5,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2,7,8]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,3,4,5,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8]}],"complexes":[],"partners":["FGFR1","ERBB2","ERBB3","RET","LRIG1","DUSP6","NETO2","ADAM17"],"other_free_text":[]},"mechanistic_narrative":"LRIG3 is a transmembrane leucine-rich repeat and immunoglobulin-like domain protein that functions as a context-dependent modulator of receptor tyrosine kinase signaling and intercellular communication during development and in cancer. It directly interacts with FGFR1, ErbB receptors, and the Ret receptor to attenuate their downstream signaling, and opposes the action of its paralog LRIG1 by stabilizing ErbB receptors against LRIG1-induced degradation [PMID:18287203, PMID:23723069, PMID:34338291]. In the inner ear, LRIG3 establishes mutually antagonistic expression domains with Netrin1 to control basement membrane breakdown during lateral semicircular canal morphogenesis [PMID:19004851]. LRIG3 also suppresses cancer cell motility by scaffolding a DUSP6–ERK1/2 complex that promotes ERK dephosphorylation and EMT inhibition, and its ADAM17-shed soluble ectodomain interacts with the CUB1 domain of NETO2 on tumor-associated macrophages to block M2 polarization [PMID:32107843, PMID:36639372]."},"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":49,"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":"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":"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":14,"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":"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":"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":"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}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14112,"output_tokens":2961,"usd":0.043375},"stage2":{"model":"claude-opus-4-6","input_tokens":6312,"output_tokens":2586,"usd":0.144315},"total_usd":0.18769,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"Xenopus Lrig3 acts downstream of Pax3 and Zic1 in neural crest formation, modulates Wnt signaling positively (co-injection with Wnt3a induces NC markers and Fgf3/4/8), and attenuates Fgf signaling; Lrig3 directly interacts with Fgf receptor 1 in cultured cells.\",\n      \"method\": \"Morpholino knockdown in Xenopus, NC induction animal cap assay, co-injection epistasis experiments, co-immunoprecipitation with FGFR1\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (MO knockdown, epistasis assay, Co-IP) in a single study with clear pathway placement\",\n      \"pmids\": [\"18287203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Lrig3 is required for lateral semicircular canal morphogenesis in mice; loss of Lrig3 causes ectopic Netrin1 (Ntn1) expression, and mutually antagonistic interactions between Lrig3 and Ntn1 define complementary expression domains that control basement membrane breakdown during canal fusion. Genetic removal of one Ntn1 copy rescues both canal malformation and circling behavior in Lrig3 mutants.\",\n      \"method\": \"Gene trap mutagenesis, genetic epistasis (Lrig3 mutant × Ntn1 heterozygote cross), behavioral assay, in situ hybridization for marker genes\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic epistasis with rescue experiment and behavioral readout, replicated across multiple genetic combinations\",\n      \"pmids\": [\"19004851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Lrig3 interacts with ErbB receptors (ErbB2 and ErbB3) in vitro; however, inhibition of ErbB activation in the chick otic vesicle has no effect on Netrin gene expression or canal morphogenesis, indicating ErbB modulation is not the in vivo mechanism for Lrig3-dependent inner ear development.\",\n      \"method\": \"Co-immunoprecipitation (in vitro), pharmacological ErbB inhibition in chick otic vesicle, in situ hybridization\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus functional in vivo dissociation, but single lab\",\n      \"pmids\": [\"20126551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Lrig3 opposes Lrig1's negative regulation of ErbB receptors: Lrig3 stabilizes ErbB receptors and counteracts Lrig1-induced receptor degradation, while Lrig1 in turn destabilizes Lrig3 protein, identifying Lrig3 as a target of Lrig1.\",\n      \"method\": \"Co-immunoprecipitation, receptor stability assays, gain- and loss-of-function in cell lines\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal functional interaction with Co-IP and protein stability assays, single lab\",\n      \"pmids\": [\"23723069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LRIG3 overexpression in glioblastoma cells inhibits proliferation, promotes apoptosis, and restrains invasion; mechanistically, LRIG3 negatively regulates the EGFR signaling pathway, and EGFR inhibition reduces the proliferative effects of LRIG3 knockdown.\",\n      \"method\": \"Lentiviral overexpression and siRNA knockdown in glioma cells, EGFR inhibitor epistasis, in vitro and in vivo tumor assays, Western blot for pathway components\",\n      \"journal\": \"Journal of the Neurological Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological epistasis with EGFR inhibitor supports pathway placement, single lab\",\n      \"pmids\": [\"25708990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LRIG3 suppresses colorectal cancer cell motility by facilitating binding of DUSP6 to ERK1/2, leading to dephosphorylation of ERK1/2 and subsequent downregulation of Slug (an EMT driver), thereby constraining cell migration and invasion.\",\n      \"method\": \"LRIG3 knockout and re-expression, Co-immunoprecipitation (LRIG3-DUSP6-ERK1/2 complex), Western blot for p-ERK1/2 and Slug, Transwell migration/invasion assay\",\n      \"journal\": \"IUBMB Life\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifies complex plus functional rescue, single lab\",\n      \"pmids\": [\"32107843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LRIG3 suppresses glioma angiogenesis by inhibiting activation of the PI3K/AKT signaling pathway, leading to downregulation of VEGFA in glioma cells.\",\n      \"method\": \"Loss- and gain-of-function assays in glioma cells, in vitro angiogenesis assay, in vivo xenograft, Western blot for PI3K/AKT pathway components\",\n      \"journal\": \"Frontiers in Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pathway inferred by Western blot of downstream components without direct enzymatic or binding evidence; functional phenotype is clear\",\n      \"pmids\": [\"33718179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Lrig3 interacts with Ret receptor and inhibits GDNF/Ret signaling in mouse dorsal root ganglion neurons; GDNF treatment induces Lrig3 expression (negative feedback); Lrig1 and Lrig3 act redundantly to control cutaneous innervation of nonpeptidergic axons and behavioral sensitivity to cold via regulation of TrpA1 expression.\",\n      \"method\": \"Co-immunoprecipitation (Lrig3-Ret), DRG neuron culture, Lrig1/Lrig3 single and double mutant genetic epistasis, behavioral assay, immunostaining of skin innervation\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus clean genetic epistasis with compound mutants and behavioral/cellular readouts\",\n      \"pmids\": [\"34338291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Soluble LRIG3 (sLRIG3) shed from glioma cells by ADAM17 blocks M2 polarization of tumor-associated macrophages (TAMs) by interacting with the CUB1 domain of NETO2 on TAMs; deletion of the CUB1 domain of NETO2 abolishes the suppressive effect of sLRIG3 on M2 polarization.\",\n      \"method\": \"Mass spectrometry, Co-immunoprecipitation, NETO2 silencing/knockout, domain-deletion mutant (NETO2 ΔCUB1), conditioned medium transfer assays, in vivo tumor growth assay\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS-identified interaction confirmed by Co-IP plus domain-deletion rescue, multiple orthogonal approaches\",\n      \"pmids\": [\"36639372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Circ-LRIG3 (hsa_circ_0027345) forms a ternary complex with EZH2 and STAT3, facilitating EZH2-mediated methylation of STAT3 and subsequent STAT3 phosphorylation/activation; activated STAT3 in turn binds the circ-LRIG3 promoter to increase its transcription, forming a positive feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, RNA immunoprecipitation (RIP), ChIP assay, STAT3 inhibitor (C188-9), in vivo xenograft\",\n      \"journal\": \"Journal of Experimental & Clinical Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP/RIP/ChIP for complex; note this is for the circular RNA derived from the LRIG3 locus, not the LRIG3 protein itself\",\n      \"pmids\": [\"33222697\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"LRIG3 protein localizes to the cytoplasm of glioblastoma GL15 cells (observed by confocal microscopy of LRIG3-EGFP fusion); EGFR expression decreases while LRIG3 expression increases upon EGF treatment in a time-dependent manner, suggesting reciprocal regulation.\",\n      \"method\": \"Confocal microscopy of LRIG3-EGFP fusion protein, RT-PCR and Western blot with EGF time-course\",\n      \"journal\": \"Zhejiang University Medical Sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — localization by overexpressed fusion protein; reciprocal expression is correlative, not mechanistic\",\n      \"pmids\": [\"18925709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Lrig3 regulates liver fat accumulation (hepatocellular steatosis) and intestinal morphology in mice in a strain-dependent manner; Lrig3-deficient mice also exhibit middle ear inflammation, and the paper notes Lrig3 regulates BMP signaling based on prior work.\",\n      \"method\": \"Histopathological examination of 42 tissues from Lrig3 knockout mice on two genetic backgrounds, high-fat diet challenge\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — phenotypic description in KO mice without direct mechanistic dissection of BMP pathway\",\n      \"pmids\": [\"40320098\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LRIG3 is a transmembrane leucine-rich repeat and immunoglobulin domain protein that functions as a context-dependent modulator of multiple receptor tyrosine kinase pathways: it interacts directly with FGFR1, ErbB receptors, and Ret to regulate their signaling (often inhibitory), opposes the negative regulatory activity of Lrig1 on ErbB receptors by stabilizing them, facilitates DUSP6-mediated ERK1/2 dephosphorylation to suppress EMT-driven cell motility, and in the inner ear controls lateral canal morphogenesis by creating mutually antagonistic expression domains with Netrin1 to regulate basement membrane breakdown; additionally, soluble shed LRIG3 interacts with NETO2 on tumor-associated macrophages to inhibit M2 polarization.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LRIG3 is a transmembrane leucine-rich repeat and immunoglobulin-like domain protein that functions as a context-dependent modulator of receptor tyrosine kinase signaling and intercellular communication during development and in cancer. It directly interacts with FGFR1, ErbB receptors, and the Ret receptor to attenuate their downstream signaling, and opposes the action of its paralog LRIG1 by stabilizing ErbB receptors against LRIG1-induced degradation [PMID:18287203, PMID:23723069, PMID:34338291]. In the inner ear, LRIG3 establishes mutually antagonistic expression domains with Netrin1 to control basement membrane breakdown during lateral semicircular canal morphogenesis [PMID:19004851]. LRIG3 also suppresses cancer cell motility by scaffolding a DUSP6–ERK1/2 complex that promotes ERK dephosphorylation and EMT inhibition, and its ADAM17-shed soluble ectodomain interacts with the CUB1 domain of NETO2 on tumor-associated macrophages to block M2 polarization [PMID:32107843, PMID:36639372].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing LRIG3 as a signaling modulator in neural crest development resolved the question of where in the FGF/Wnt hierarchy this LRR protein operates: it acts downstream of Pax3/Zic1, attenuates FGF signaling via direct FGFR1 interaction, and positively modulates Wnt signaling.\",\n      \"evidence\": \"Morpholino knockdown, animal cap epistasis assays, and co-immunoprecipitation with FGFR1 in Xenopus\",\n      \"pmids\": [\"18287203\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which LRIG3 attenuates FGFR1 signaling (degradation vs. inhibition of activation) not determined\",\n        \"Wnt modulation mechanism not defined at molecular level\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetic epistasis in mice revealed that LRIG3 controls lateral semicircular canal morphogenesis by antagonizing Netrin1 expression, with Ntn1 haploinsufficiency rescuing the canal defect and circling behavior of Lrig3 mutants.\",\n      \"evidence\": \"Gene trap mutagenesis, Lrig3 × Ntn1 genetic crosses, behavioral assay, in situ hybridization in mouse inner ear\",\n      \"pmids\": [\"19004851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular mechanism by which LRIG3 represses Netrin1 transcription is unknown\",\n        \"Whether LRIG3 acts cell-autonomously in the otic epithelium was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Although LRIG3 binds ErbB2/ErbB3 in vitro, pharmacological ErbB inhibition in chick otic vesicle did not phenocopy Lrig3 loss, dissociating ErbB modulation from the inner ear morphogenesis function.\",\n      \"evidence\": \"Co-immunoprecipitation of LRIG3 with ErbB2/ErbB3; pharmacological ErbB inhibition in chick otic vesicle explants\",\n      \"pmids\": [\"20126551\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"The relevant in vivo receptor target in the inner ear remains unidentified\",\n        \"Single-lab finding without genetic ErbB loss-of-function\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defining the LRIG3–LRIG1 functional antagonism showed that LRIG3 stabilizes ErbB receptors and counteracts LRIG1-mediated degradation, while LRIG1 reciprocally destabilizes LRIG3 protein—establishing a paralog-level regulatory circuit.\",\n      \"evidence\": \"Co-immunoprecipitation, receptor stability assays, gain- and loss-of-function in cell lines\",\n      \"pmids\": [\"23723069\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether LRIG3–LRIG1 antagonism occurs in vivo in specific tissues is untested\",\n        \"Whether LRIG1-induced LRIG3 destabilization is ubiquitin-dependent is unknown\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extending LRIG3's RTK-inhibitory role to cancer, LRIG3 overexpression in glioblastoma cells suppressed proliferation and invasion via EGFR pathway downregulation, confirmed by EGFR inhibitor epistasis.\",\n      \"evidence\": \"Lentiviral overexpression and siRNA knockdown in glioma cells, EGFR inhibitor rescue, xenograft assays\",\n      \"pmids\": [\"25708990\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether LRIG3 directly binds EGFR or acts indirectly through other ErbB family members not resolved\",\n        \"Mechanism of EGFR downregulation (degradation, internalization, or transcriptional) not defined\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying LRIG3 as a scaffold that bridges DUSP6 to ERK1/2 provided a mechanism for its anti-migratory function: LRIG3 facilitates ERK dephosphorylation and consequent Slug downregulation, suppressing EMT-driven motility in colorectal cancer cells.\",\n      \"evidence\": \"Co-immunoprecipitation of LRIG3–DUSP6–ERK1/2 ternary complex, knockout and re-expression rescue, Transwell assays\",\n      \"pmids\": [\"32107843\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis for LRIG3 scaffolding of DUSP6 and ERK1/2 is unknown\",\n        \"Whether this mechanism operates in non-cancer contexts not tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstration that LRIG3 directly interacts with the Ret receptor and inhibits GDNF/Ret signaling in DRG neurons, with LRIG1 and LRIG3 acting redundantly to control cutaneous innervation and cold sensitivity, extended the RTK-regulatory function to the peripheral nervous system.\",\n      \"evidence\": \"Co-immunoprecipitation of Lrig3–Ret, single and compound Lrig1/Lrig3 mutant mice, behavioral cold-sensitivity assay, skin innervation immunostaining\",\n      \"pmids\": [\"34338291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether LRIG3 promotes Ret degradation or blocks ligand binding is not determined\",\n        \"Relative contributions of LRIG1 vs. LRIG3 to Ret regulation in different DRG neuron subtypes are unclear\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery that ADAM17-shed soluble LRIG3 interacts with the CUB1 domain of NETO2 on tumor-associated macrophages to suppress M2 polarization revealed a non-cell-autonomous, paracrine tumor-suppressive mechanism distinct from its RTK-modulatory roles.\",\n      \"evidence\": \"Mass spectrometry identification of sLRIG3–NETO2 interaction, Co-IP, NETO2 ΔCUB1 domain-deletion abolishes effect, in vivo tumor assay\",\n      \"pmids\": [\"36639372\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Signaling pathway downstream of NETO2 that mediates M2 suppression is not identified\",\n        \"Physiological relevance of sLRIG3-NETO2 interaction outside the tumor microenvironment is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for LRIG3's receptor selectivity, the mechanism by which it simultaneously scaffolds phosphatases and modulates RTKs, and whether its paracrine (sLRIG3–NETO2) and cell-autonomous (RTK-inhibitory) functions are coordinated remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or cryo-EM model of LRIG3 in complex with any partner\",\n        \"In vivo relevance of LRIG3–DUSP6–ERK scaffolding outside colorectal cancer not tested\",\n        \"Whether ADAM17-mediated shedding is regulated and how it partitions LRIG3 between cell-autonomous and paracrine functions is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 4, 5, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2, 7, 8]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 3, 4, 5, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FGFR1\", \"ERBB2\", \"ERBB3\", \"RET\", \"LRIG1\", \"DUSP6\", \"NETO2\", \"ADAM17\"],\n    \"other_free_text\": []\n  }\n}\n```"}