{"gene":"PITPNM3","run_date":"2026-04-28T19:45:44","timeline":{"discoveries":[{"year":2011,"finding":"PITPNM3 was identified as a functional receptor for CCL18 (produced by tumor-associated macrophages) that mediates CCL18-induced integrin clustering, enhanced adherence to extracellular matrix, intracellular calcium signaling activation, and breast cancer cell invasion and metastasis.","method":"Receptor identification by functional assay, siRNA knockdown, calcium signaling assay, integrin clustering assay, xenograft mouse model","journal":"Cancer Cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (functional receptor identification, knockdown, in vivo xenograft, signaling assays), high citation count, foundational study","pmids":["21481794"],"is_preprint":false},{"year":2007,"finding":"A missense mutation Q626H in PITPNM3 located in the C-terminal PYK2-binding domain causes autosomal dominant cone dystrophy (CORD5), indicating that PITPNM3 interacts with PYK2 (a nonreceptor protein tyrosine kinase) and plays a role in mammalian phototransduction.","method":"Genetic mapping, direct sequencing, mutation identification in patient families","journal":"European Journal of Human Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — disease-causing mutation identified in PYK2-binding domain, but functional interaction with PYK2 inferred from domain mapping rather than direct biochemical assay","pmids":["17377520"],"is_preprint":false},{"year":2013,"finding":"CCL18 binding to PITPNM3 (Nir1) promotes phosphorylation of Akt, LIMK, and cofilin, facilitating cofilin recycling and actin polymerization, and stabilizes Snail via the Akt/GSK3β signaling pathway to induce epithelial-mesenchymal transition (EMT) in breast cancer cells.","method":"Phosphorylation assays (western blot), siRNA knockdown, in vivo lung metastasis model, PI3K inhibitor (LY294002) treatment","journal":"European Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 — multiple signaling readouts with pathway inhibitors and in vivo validation, single lab","pmids":["24001613"],"is_preprint":false},{"year":2015,"finding":"CCL18 binding to PITPNM3 in hepatocellular carcinoma cells activates NF-κB signaling (phosphorylation of IKK and IκBα, p65 nuclear translocation), driving cell migration, invasion, and EMT; this signaling is abolished when PITPNM3 is silenced by siRNA.","method":"siRNA knockdown of PITPNM3, phosphorylation assays, nuclear translocation assays, migration and invasion assays","journal":"Tumour Biology","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA knockdown with defined pathway readouts, single lab","pmids":["26449829"],"is_preprint":false},{"year":2016,"finding":"CCL18 binding to PITPNM3 (Nir1) in lung cancer cells modulates RAC1 activation and ELMO1-dependent cytoskeleton reorganization, as well as ELMO1-integrin β1 signaling to enhance cell adhesion, migration, and invasion.","method":"siRNA knockdown, RAC1 activation assay, ELMO1 pathway analysis, adhesion and invasion assays","journal":"Molecular Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — defined signaling pathway with knockdown, single lab","pmids":["26756176"],"is_preprint":false},{"year":2020,"finding":"CCL18 binding to PITPNM3 (NIR1) in oral squamous cell carcinoma activates the JAK2/STAT3 signaling pathway to promote cancer cell growth, metastasis, and EMT; these effects are blocked by JAK inhibitor AG490 or siRNA knockdown of NIR1.","method":"siRNA knockdown, JAK inhibitor treatment (AG490), western blot for JAK2/STAT3 activation, proliferation and invasion assays","journal":"BMC Cancer","confidence":"Medium","confidence_rationale":"Tier 2 — pathway inhibitor and siRNA knockdown with defined phenotypic readouts, single lab","pmids":["32641093"],"is_preprint":false},{"year":2020,"finding":"Mitofusin-2 (Mfn-2) interacts with transcription factor SP1 (via Co-IP) and reduces SP1 binding to the PITPNM3 promoter (via ChIP assay), thereby suppressing PITPNM3 expression and inhibiting tumor growth in hepatic carcinoma cells.","method":"Co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), promoter analysis, transfection, in vivo tumorigenicity assay","journal":"Medical Science Monitor","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus ChIP plus in vivo validation identifying upstream transcriptional regulator of PITPNM3, single lab","pmids":["31955176"],"is_preprint":false},{"year":2022,"finding":"Nir1 (PITPNM3) constitutively localizes at endoplasmic reticulum-plasma membrane (ER-PM) junctions, interacts with Nir2 via a region between the FFAT motif and the DDHD domain, and promotes Nir2 recruitment to ER-PM junctions to facilitate replenishment of plasma membrane PIP2 during receptor-mediated signaling.","method":"Live-cell imaging (fluorescent localization), biochemical fractionation, Co-immunoprecipitation, domain mapping, PIP2 replenishment assays","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 1-2 — direct localization with functional consequence, Co-IP with domain mapping, multiple orthogonal methods","pmids":["35020418"],"is_preprint":false},{"year":2022,"finding":"CCL18 promotes phagocytosis in human microglial cells via CCR8 rather than PITPNM3, as selective siRNA knockdown of each receptor demonstrated that only CCR8 knockdown impaired CCL18-induced phagocytosis through NF-κB/Src signaling, establishing that PITPNM3 is not the dominant CCL18 receptor in microglia.","method":"siRNA knockdown of PITPNM3 vs. CCR8, phagocytosis assays (amyloid-β and dextran uptake), NF-κB/Src pathway analysis","journal":"Journal of Interferon & Cytokine Research","confidence":"Medium","confidence_rationale":"Tier 2 — comparative siRNA knockdown with defined functional readout distinguishing receptor contributions, single lab","pmids":["35041514"],"is_preprint":false},{"year":2025,"finding":"The LNS2 domain of Nir1 (PITPNM3), designated PILS-Nir1, binds phosphatidic acid (PA) and PIP2 in vitro (liposome binding assays), but only PA is necessary and sufficient for membrane localization of PILS-Nir1 in cells, identifying this domain as a PA biosensor and establishing a PA-sensing function for this region of PITPNM3.","method":"Liposome binding assays, pharmacological manipulation, fluorescent reporter in HEK293A cells, genetic manipulation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro reconstitution with liposomes plus cell-based validation, preprint not yet peer-reviewed","pmids":["38464273"],"is_preprint":true},{"year":2025,"finding":"A PITPNM3 mouse model with the human-associated mutation shows reduced cone electrophysiological response (full-field ERG) without corresponding histological retinal structural changes, revealing a functional role of PITPNM3 in cone photoreceptor function and indicating discordance between functional impairment and morphological changes.","method":"Heterozygous/homozygous mouse model generation, full-field electroretinogram (ERG), histological examination","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo mouse model with electrophysiological and histological readouts, single study","pmids":["41148841"],"is_preprint":false}],"current_model":"PITPNM3 functions as a plasma membrane receptor for the chemokine CCL18 that activates intracellular calcium signaling, integrin clustering, and downstream pathways (PI3K/Akt/GSK3β/Snail, NF-κB, JAK2/STAT3, RAC1/ELMO1) to promote cancer cell invasion and metastasis; it also constitutively localizes at ER-PM junctions where it interacts with Nir2 via a region between its FFAT motif and DDHD domain to promote PIP2 homeostasis, and its LNS2 domain binds phosphatidic acid to mediate membrane association, while mutations in its PYK2-binding domain cause autosomal dominant cone dystrophy (CORD5)."},"narrative":{"teleology":[{"year":2007,"claim":"Identification of a disease-causing mutation in PITPNM3 established that this gene is required for normal cone photoreceptor function and linked its PYK2-binding domain to retinal physiology.","evidence":"Genetic mapping and direct sequencing in families with autosomal dominant cone dystrophy (CORD5) identified the Q626H missense mutation","pmids":["17377520"],"confidence":"Medium","gaps":["Functional interaction with PYK2 inferred from domain mapping rather than demonstrated by direct biochemical assay","Mechanism by which Q626H disrupts cone photoreceptor signaling was unknown","No animal model at the time to confirm causality"]},{"year":2011,"claim":"The discovery that PITPNM3 acts as a functional receptor for macrophage-derived CCL18 revealed a previously unknown mechanism by which the tumor microenvironment drives breast cancer invasion and metastasis.","evidence":"Functional receptor identification assay, siRNA knockdown, calcium signaling and integrin clustering assays, and xenograft mouse model in breast cancer cells","pmids":["21481794"],"confidence":"High","gaps":["Structural basis of CCL18–PITPNM3 binding not determined","Whether PITPNM3 signals as a classical GPCR or through a distinct mechanism was unclear","Relative contribution of PITPNM3 versus other potential CCL18 receptors (e.g., CCR8) was not resolved"]},{"year":2013,"claim":"Mapping the downstream signaling cascade showed that CCL18–PITPNM3 engagement activates PI3K/Akt/GSK3β to stabilize Snail and promote EMT, and phosphorylates LIMK/cofilin to drive actin remodeling, connecting receptor activation to specific pro-metastatic effector pathways.","evidence":"Phosphorylation assays, PI3K inhibitor (LY294002) treatment, siRNA knockdown, and in vivo lung metastasis model in breast cancer","pmids":["24001613"],"confidence":"Medium","gaps":["Direct physical interaction between PITPNM3 and PI3K not demonstrated","Whether PITPNM3's PITP domain contributes to lipid-mediated signaling downstream of CCL18 was not tested","Single-lab study without independent replication"]},{"year":2015,"claim":"Extension of CCL18–PITPNM3 signaling to NF-κB activation in hepatocellular carcinoma demonstrated that PITPNM3-mediated pro-invasive signaling operates across multiple cancer types through diverse downstream pathways.","evidence":"siRNA knockdown of PITPNM3, phosphorylation of IKK/IκBα, p65 nuclear translocation, and migration/invasion assays in hepatocellular carcinoma cells","pmids":["26449829"],"confidence":"Medium","gaps":["Mechanism linking PITPNM3 to IKK phosphorylation not identified","Whether NF-κB and Akt/GSK3β pathways are activated simultaneously or context-dependently was unclear"]},{"year":2016,"claim":"Identification of RAC1/ELMO1-dependent cytoskeletal reorganization downstream of CCL18–PITPNM3 in lung cancer cells added a Rho-GTPase signaling axis to the receptor's effector repertoire and linked it to integrin β1-mediated adhesion.","evidence":"RAC1 activation assay, ELMO1 pathway analysis, siRNA knockdown, adhesion and invasion assays in lung cancer cells","pmids":["26756176"],"confidence":"Medium","gaps":["Direct interaction between PITPNM3 and RAC1 or ELMO1 not shown","Relative importance of RAC1/ELMO1 versus Akt and NF-κB axes not compared"]},{"year":2020,"claim":"Two studies expanded the CCL18–PITPNM3 axis: JAK2/STAT3 was identified as another downstream effector in oral cancer, and Mfn-2/SP1-dependent transcriptional suppression of PITPNM3 was identified as an upstream regulatory mechanism in hepatic carcinoma.","evidence":"JAK inhibitor AG490 and siRNA in oral squamous cell carcinoma; Co-IP of Mfn-2/SP1, ChIP on PITPNM3 promoter, and in vivo tumorigenicity assay in hepatic carcinoma","pmids":["32641093","31955176"],"confidence":"Medium","gaps":["Whether SP1-dependent transcription is the dominant regulator of PITPNM3 expression across tissues is unknown","Both studies from single labs without independent replication"]},{"year":2022,"claim":"The demonstration that PITPNM3 constitutively resides at ER–PM junctions and recruits Nir2 to maintain PIP2 pools established a receptor-independent lipid-transfer function, revealing a dual role for the protein in both chemokine signaling and phosphoinositide homeostasis.","evidence":"Live-cell imaging, Co-IP with domain mapping (FFAT-DDHD interregion), PIP2 replenishment assays in cultured cells","pmids":["35020418"],"confidence":"High","gaps":["Whether PITPNM3's PITP domain itself transfers lipids was not resolved","Relationship between ER-PM junction function and CCL18 receptor activity is unknown","Structural basis of Nir1–Nir2 interaction not determined"]},{"year":2022,"claim":"Comparative receptor analysis in microglia demonstrated that CCL18-induced phagocytosis depends on CCR8 rather than PITPNM3, establishing that PITPNM3 is not a universal CCL18 receptor and that cell-type context determines receptor usage.","evidence":"Parallel siRNA knockdown of PITPNM3 and CCR8 with phagocytosis assays and NF-κB/Src pathway analysis in human microglial cells","pmids":["35041514"],"confidence":"Medium","gaps":["Whether PITPNM3 and CCR8 form heteromeric complexes or compete for CCL18 binding was not tested","PITPNM3's role in microglia outside phagocytosis not explored"]},{"year":2025,"claim":"Characterization of the LNS2 domain as a phosphatidic acid sensor provided a molecular mechanism for PITPNM3 membrane targeting and introduced this domain as a potential PA biosensor tool, while a CORD5 knock-in mouse confirmed functional cone impairment in vivo.","evidence":"Liposome binding assays and fluorescent reporters in HEK293A cells (preprint); heterozygous/homozygous knock-in mouse model with ERG and histology","pmids":["38464273","41148841"],"confidence":"Medium","gaps":["LNS2/PA binding study is a preprint awaiting peer review","Whether PA binding is required for PITPNM3's CCL18 receptor or ER-PM junction functions is untested","Mouse CORD5 model shows functional deficit without structural change — mechanism of cone dysfunction remains unresolved"]},{"year":null,"claim":"The structural basis of CCL18 binding to PITPNM3, how PITPNM3's lipid-transfer and chemokine-receptor functions are coordinated, and whether the PITP domain is catalytically active remain major unresolved questions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structure of CCL18–PITPNM3 complex or of full-length PITPNM3","PITP domain lipid-transfer activity not directly demonstrated","Relationship between ER-PM junction lipid homeostasis role and chemokine receptor signaling role not addressed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,2,3,4,5]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[7,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,7]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,3,4,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,4,5]}],"complexes":[],"partners":["CCL18","NIR2","ELMO1","SP1"],"other_free_text":[]},"mechanistic_narrative":"PITPNM3 (Nir1) is a multifunctional membrane-associated protein that serves as a receptor for the chemokine CCL18 and participates in phosphoinositide homeostasis at endoplasmic reticulum–plasma membrane contact sites. As a CCL18 receptor, PITPNM3 activates intracellular calcium signaling, integrin clustering, and multiple downstream pathways including PI3K/Akt/GSK3β/Snail, NF-κB, JAK2/STAT3, and RAC1/ELMO1 to promote cancer cell invasion, epithelial–mesenchymal transition, and metastasis across breast, hepatocellular, lung, and oral cancers [PMID:21481794, PMID:24001613, PMID:26449829, PMID:26756176, PMID:32641093]. PITPNM3 constitutively localizes at ER–PM junctions, where it interacts with Nir2 via a region between its FFAT motif and DDHD domain to recruit Nir2 and facilitate PIP2 replenishment during receptor-mediated signaling, and its LNS2 domain binds phosphatidic acid to mediate membrane association [PMID:35020418, PMID:38464273]. Missense mutation Q626H in the PYK2-binding domain causes autosomal dominant cone dystrophy (CORD5), and a knock-in mouse model carrying this mutation shows reduced cone electrophysiological responses without structural retinal changes, confirming a role in cone photoreceptor function [PMID:17377520, PMID:41148841]."},"prefetch_data":{"uniprot":{"accession":"Q9BZ71","full_name":"Membrane-associated phosphatidylinositol transfer protein 3","aliases":["Phosphatidylinositol transfer protein, membrane-associated 3","PITPnm 3","Pyk2 N-terminal domain-interacting receptor 1","NIR-1"],"length_aa":974,"mass_kda":106.8,"function":"Catalyzes the transfer of phosphatidylinositol and phosphatidylcholine between membranes (in vitro) (By similarity). Binds calcium ions","subcellular_location":"Endomembrane system","url":"https://www.uniprot.org/uniprotkb/Q9BZ71/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PITPNM3","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/PITPNM3","total_profiled":1310},"omim":[{"mim_id":"608921","title":"PHOSPHATIDYLINOSITOL TRANSFER PROTEIN, MEMBRANE-ASSOCIATED, 3; PITPNM3","url":"https://www.omim.org/entry/608921"},{"mim_id":"608920","title":"PHOSPHATIDYLINOSITOL TRANSFER PROTEIN, MEMBRANE-ASSOCIATED, 2; PITPNM2","url":"https://www.omim.org/entry/608920"},{"mim_id":"600977","title":"CONE-ROD DYSTROPHY 5; CORD5","url":"https://www.omim.org/entry/600977"},{"mim_id":"120970","title":"CONE-ROD DYSTROPHY 2; CORD2","url":"https://www.omim.org/entry/120970"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":37.5},{"tissue":"lymphoid tissue","ntpm":57.5}],"url":"https://www.proteinatlas.org/search/PITPNM3"},"hgnc":{"alias_symbol":["NIR1","RDGBA3","ACKR6"],"prev_symbol":["CORD5"]},"alphafold":{"accession":"Q9BZ71","domains":[{"cath_id":"-","chopping":"130-201_212-282_388-483_546-602","consensus_level":"high","plddt":85.494,"start":130,"end":602},{"cath_id":"2.60.40.380","chopping":"621-733","consensus_level":"medium","plddt":87.2048,"start":621,"end":733},{"cath_id":"3.40.50.1000","chopping":"737-913","consensus_level":"medium","plddt":80.2303,"start":737,"end":913}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BZ71","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BZ71-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BZ71-F1-predicted_aligned_error_v6.png","plddt_mean":66.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PITPNM3","jax_strain_url":"https://www.jax.org/strain/search?query=PITPNM3"},"sequence":{"accession":"Q9BZ71","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BZ71.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BZ71/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BZ71"}},"corpus_meta":[{"pmid":"21481794","id":"PMC_21481794","title":"CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3.","date":"2011","source":"Cancer cell","url":"https://pubmed.ncbi.nlm.nih.gov/21481794","citation_count":531,"is_preprint":false},{"pmid":"20444232","id":"PMC_20444232","title":"Identification of a nitrate-responsive cis-element in the Arabidopsis NIR1 promoter defines the presence of multiple cis-regulatory elements for nitrogen response.","date":"2010","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20444232","citation_count":90,"is_preprint":false},{"pmid":"8586428","id":"PMC_8586428","title":"A gene for autosomal dominant progressive cone dystrophy (CORD5) maps to chromosome 17p12-p13.","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8586428","citation_count":71,"is_preprint":false},{"pmid":"24001613","id":"PMC_24001613","title":"Nir1 promotes invasion of breast cancer cells by binding to chemokine (C-C motif) ligand 18 through the PI3K/Akt/GSK3β/Snail signalling pathway.","date":"2013","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/24001613","citation_count":61,"is_preprint":false},{"pmid":"26449829","id":"PMC_26449829","title":"CCL18/PITPNM3 enhances migration, invasion, and EMT through the NF-κB signaling pathway in hepatocellular carcinoma.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26449829","citation_count":57,"is_preprint":false},{"pmid":"17377520","id":"PMC_17377520","title":"Mutation in the PYK2-binding domain of PITPNM3 causes autosomal dominant cone dystrophy (CORD5) in two Swedish families.","date":"2007","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/17377520","citation_count":50,"is_preprint":false},{"pmid":"26259199","id":"PMC_26259199","title":"HY5 regulates nitrite reductase 1 (NIR1) and ammonium transporter1;2 (AMT1;2) in Arabidopsis seedlings.","date":"2015","source":"Plant science : an international journal of experimental plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/26259199","citation_count":48,"is_preprint":false},{"pmid":"26756176","id":"PMC_26756176","title":"CC chemokine ligand 18(CCL18) promotes migration and invasion of lung cancer cells by binding to Nir1 through Nir1-ELMO1/DOC180 signaling pathway.","date":"2016","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/26756176","citation_count":45,"is_preprint":false},{"pmid":"12552567","id":"PMC_12552567","title":"Identification of GUCY2D gene mutations in CORD5 families and evidence of incomplete penetrance.","date":"2003","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/12552567","citation_count":31,"is_preprint":false},{"pmid":"32641093","id":"PMC_32641093","title":"CCL18-NIR1 promotes oral cancer cell growth and metastasis by activating the JAK2/STAT3 signaling pathway.","date":"2020","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32641093","citation_count":30,"is_preprint":false},{"pmid":"8437574","id":"PMC_8437574","title":"nir1, a conditional-lethal mutation in barley causing a defect in nitrite reduction.","date":"1993","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/8437574","citation_count":21,"is_preprint":false},{"pmid":"35020418","id":"PMC_35020418","title":"Nir1 constitutively localizes at ER-PM junctions and promotes Nir2 recruitment for PIP2 homeostasis.","date":"2022","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/35020418","citation_count":18,"is_preprint":false},{"pmid":"27309477","id":"PMC_27309477","title":"Transforming Growth Factor Beta-Induced Factor 2-Linked X (TGIF2LX) Regulates Two Morphogenesis Genes, Nir1 and Nir2 in Human Colorectal.","date":"2016","source":"Acta medica Iranica","url":"https://pubmed.ncbi.nlm.nih.gov/27309477","citation_count":17,"is_preprint":false},{"pmid":"20507451","id":"PMC_20507451","title":"A defect in nir1, a nirA-like transcription factor, confers morphological abnormalities and loss of pathogenicity in Colletotrichum acutatum.","date":"2006","source":"Molecular plant pathology","url":"https://pubmed.ncbi.nlm.nih.gov/20507451","citation_count":14,"is_preprint":false},{"pmid":"20590364","id":"PMC_20590364","title":"PITPNM3 is an uncommon cause of cone and cone-rod dystrophies.","date":"2010","source":"Ophthalmic genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20590364","citation_count":13,"is_preprint":false},{"pmid":"36285700","id":"PMC_36285700","title":"Small Molecular Inhibitors Reverse Cancer Metastasis by Blockading Oncogenic PITPNM3.","date":"2022","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/36285700","citation_count":9,"is_preprint":false},{"pmid":"22405330","id":"PMC_22405330","title":"Ocular phenotype of CORD5, an autosomal dominant retinal dystrophy associated with PITPNM3 p.Q626H mutation.","date":"2012","source":"Acta ophthalmologica","url":"https://pubmed.ncbi.nlm.nih.gov/22405330","citation_count":8,"is_preprint":false},{"pmid":"31955176","id":"PMC_31955176","title":"Mitofusin-2 (Mfn-2) Might Have Anti-Cancer Effect through Interaction with Transcriptional Factor SP1 and Consequent Regulation on Phosphatidylinositol Transfer Protein 3 (PITPNM3) Expression.","date":"2020","source":"Medical science monitor : international medical journal of experimental and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/31955176","citation_count":6,"is_preprint":false},{"pmid":"29176531","id":"PMC_29176531","title":"AUTOIMMUNE RETINOPATHY IN A PATIENT WITH A MISSENSE MUTATION IN PITPNM3.","date":"2018","source":"Retinal cases & brief reports","url":"https://pubmed.ncbi.nlm.nih.gov/29176531","citation_count":5,"is_preprint":false},{"pmid":"35041514","id":"PMC_35041514","title":"Chemokine CCL18 Promotes Phagocytosis Through Its Receptor CCR8 Rather than PITPNM3 in Human Microglial Cells.","date":"2022","source":"Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/35041514","citation_count":4,"is_preprint":false},{"pmid":"7603437","id":"PMC_7603437","title":"The Nir1 locus in barley is tightly linked to the nitrite reductase apoprotein gene Nii.","date":"1995","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/7603437","citation_count":4,"is_preprint":false},{"pmid":"38312687","id":"PMC_38312687","title":"Long non-coding RNA MIR600HG as a ceRNA inhibits the pancreatic cancer progression through regulating the miR-1197/PITPNM3 axis.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/38312687","citation_count":2,"is_preprint":false},{"pmid":"40081235","id":"PMC_40081235","title":"Evidence of SUFBC2D directly deliver Fe-S cluster to apo- NITRITE REDUCTASE1 (NIR1).","date":"2025","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/40081235","citation_count":1,"is_preprint":false},{"pmid":"41148841","id":"PMC_41148841","title":"Generating a Preclinical Model for PITPNM3 and Evaluating Genotype-Phenotype Concordance: Insights from a Mouse Model.","date":"2025","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/41148841","citation_count":1,"is_preprint":false},{"pmid":"39132322","id":"PMC_39132322","title":"MIP-4 is Induced by Bleomycin and Stimulates Cell Migration Partially via Nir-1 Receptor.","date":"2024","source":"Biochemistry research international","url":"https://pubmed.ncbi.nlm.nih.gov/39132322","citation_count":1,"is_preprint":false},{"pmid":"38464273","id":"PMC_38464273","title":"PILS-Nir1 is a novel phosphatidic acid biosensor that reveals mechanisms of lipid production.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38464273","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.21.629891","title":"Spatial transcriptomics exploration of the primary neuroblastoma microenvironment unveils novel paracrine interactions","date":"2024-12-22","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.21.629891","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14077,"output_tokens":2649,"usd":0.040983},"stage2":{"model":"claude-opus-4-6","input_tokens":6012,"output_tokens":2953,"usd":0.155828},"total_usd":0.196811,"stage1_batch_id":"msgbatch_01SUR8NDzVrNmyszWyJeCct7","stage2_batch_id":"msgbatch_01G7Yfutko3cDWzejrwH5AMx","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"PITPNM3 was identified as a functional receptor for CCL18 (produced by tumor-associated macrophages) that mediates CCL18-induced integrin clustering, enhanced adherence to extracellular matrix, intracellular calcium signaling activation, and breast cancer cell invasion and metastasis.\",\n      \"method\": \"Receptor identification by functional assay, siRNA knockdown, calcium signaling assay, integrin clustering assay, xenograft mouse model\",\n      \"journal\": \"Cancer Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (functional receptor identification, knockdown, in vivo xenograft, signaling assays), high citation count, foundational study\",\n      \"pmids\": [\"21481794\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A missense mutation Q626H in PITPNM3 located in the C-terminal PYK2-binding domain causes autosomal dominant cone dystrophy (CORD5), indicating that PITPNM3 interacts with PYK2 (a nonreceptor protein tyrosine kinase) and plays a role in mammalian phototransduction.\",\n      \"method\": \"Genetic mapping, direct sequencing, mutation identification in patient families\",\n      \"journal\": \"European Journal of Human Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — disease-causing mutation identified in PYK2-binding domain, but functional interaction with PYK2 inferred from domain mapping rather than direct biochemical assay\",\n      \"pmids\": [\"17377520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CCL18 binding to PITPNM3 (Nir1) promotes phosphorylation of Akt, LIMK, and cofilin, facilitating cofilin recycling and actin polymerization, and stabilizes Snail via the Akt/GSK3β signaling pathway to induce epithelial-mesenchymal transition (EMT) in breast cancer cells.\",\n      \"method\": \"Phosphorylation assays (western blot), siRNA knockdown, in vivo lung metastasis model, PI3K inhibitor (LY294002) treatment\",\n      \"journal\": \"European Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple signaling readouts with pathway inhibitors and in vivo validation, single lab\",\n      \"pmids\": [\"24001613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CCL18 binding to PITPNM3 in hepatocellular carcinoma cells activates NF-κB signaling (phosphorylation of IKK and IκBα, p65 nuclear translocation), driving cell migration, invasion, and EMT; this signaling is abolished when PITPNM3 is silenced by siRNA.\",\n      \"method\": \"siRNA knockdown of PITPNM3, phosphorylation assays, nuclear translocation assays, migration and invasion assays\",\n      \"journal\": \"Tumour Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA knockdown with defined pathway readouts, single lab\",\n      \"pmids\": [\"26449829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CCL18 binding to PITPNM3 (Nir1) in lung cancer cells modulates RAC1 activation and ELMO1-dependent cytoskeleton reorganization, as well as ELMO1-integrin β1 signaling to enhance cell adhesion, migration, and invasion.\",\n      \"method\": \"siRNA knockdown, RAC1 activation assay, ELMO1 pathway analysis, adhesion and invasion assays\",\n      \"journal\": \"Molecular Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined signaling pathway with knockdown, single lab\",\n      \"pmids\": [\"26756176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCL18 binding to PITPNM3 (NIR1) in oral squamous cell carcinoma activates the JAK2/STAT3 signaling pathway to promote cancer cell growth, metastasis, and EMT; these effects are blocked by JAK inhibitor AG490 or siRNA knockdown of NIR1.\",\n      \"method\": \"siRNA knockdown, JAK inhibitor treatment (AG490), western blot for JAK2/STAT3 activation, proliferation and invasion assays\",\n      \"journal\": \"BMC Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway inhibitor and siRNA knockdown with defined phenotypic readouts, single lab\",\n      \"pmids\": [\"32641093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Mitofusin-2 (Mfn-2) interacts with transcription factor SP1 (via Co-IP) and reduces SP1 binding to the PITPNM3 promoter (via ChIP assay), thereby suppressing PITPNM3 expression and inhibiting tumor growth in hepatic carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP), promoter analysis, transfection, in vivo tumorigenicity assay\",\n      \"journal\": \"Medical Science Monitor\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus ChIP plus in vivo validation identifying upstream transcriptional regulator of PITPNM3, single lab\",\n      \"pmids\": [\"31955176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Nir1 (PITPNM3) constitutively localizes at endoplasmic reticulum-plasma membrane (ER-PM) junctions, interacts with Nir2 via a region between the FFAT motif and the DDHD domain, and promotes Nir2 recruitment to ER-PM junctions to facilitate replenishment of plasma membrane PIP2 during receptor-mediated signaling.\",\n      \"method\": \"Live-cell imaging (fluorescent localization), biochemical fractionation, Co-immunoprecipitation, domain mapping, PIP2 replenishment assays\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct localization with functional consequence, Co-IP with domain mapping, multiple orthogonal methods\",\n      \"pmids\": [\"35020418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CCL18 promotes phagocytosis in human microglial cells via CCR8 rather than PITPNM3, as selective siRNA knockdown of each receptor demonstrated that only CCR8 knockdown impaired CCL18-induced phagocytosis through NF-κB/Src signaling, establishing that PITPNM3 is not the dominant CCL18 receptor in microglia.\",\n      \"method\": \"siRNA knockdown of PITPNM3 vs. CCR8, phagocytosis assays (amyloid-β and dextran uptake), NF-κB/Src pathway analysis\",\n      \"journal\": \"Journal of Interferon & Cytokine Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — comparative siRNA knockdown with defined functional readout distinguishing receptor contributions, single lab\",\n      \"pmids\": [\"35041514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The LNS2 domain of Nir1 (PITPNM3), designated PILS-Nir1, binds phosphatidic acid (PA) and PIP2 in vitro (liposome binding assays), but only PA is necessary and sufficient for membrane localization of PILS-Nir1 in cells, identifying this domain as a PA biosensor and establishing a PA-sensing function for this region of PITPNM3.\",\n      \"method\": \"Liposome binding assays, pharmacological manipulation, fluorescent reporter in HEK293A cells, genetic manipulation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with liposomes plus cell-based validation, preprint not yet peer-reviewed\",\n      \"pmids\": [\"38464273\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A PITPNM3 mouse model with the human-associated mutation shows reduced cone electrophysiological response (full-field ERG) without corresponding histological retinal structural changes, revealing a functional role of PITPNM3 in cone photoreceptor function and indicating discordance between functional impairment and morphological changes.\",\n      \"method\": \"Heterozygous/homozygous mouse model generation, full-field electroretinogram (ERG), histological examination\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse model with electrophysiological and histological readouts, single study\",\n      \"pmids\": [\"41148841\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PITPNM3 functions as a plasma membrane receptor for the chemokine CCL18 that activates intracellular calcium signaling, integrin clustering, and downstream pathways (PI3K/Akt/GSK3β/Snail, NF-κB, JAK2/STAT3, RAC1/ELMO1) to promote cancer cell invasion and metastasis; it also constitutively localizes at ER-PM junctions where it interacts with Nir2 via a region between its FFAT motif and DDHD domain to promote PIP2 homeostasis, and its LNS2 domain binds phosphatidic acid to mediate membrane association, while mutations in its PYK2-binding domain cause autosomal dominant cone dystrophy (CORD5).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PITPNM3 (Nir1) is a multifunctional membrane-associated protein that serves as a receptor for the chemokine CCL18 and participates in phosphoinositide homeostasis at endoplasmic reticulum–plasma membrane contact sites. As a CCL18 receptor, PITPNM3 activates intracellular calcium signaling, integrin clustering, and multiple downstream pathways including PI3K/Akt/GSK3β/Snail, NF-κB, JAK2/STAT3, and RAC1/ELMO1 to promote cancer cell invasion, epithelial–mesenchymal transition, and metastasis across breast, hepatocellular, lung, and oral cancers [PMID:21481794, PMID:24001613, PMID:26449829, PMID:26756176, PMID:32641093]. PITPNM3 constitutively localizes at ER–PM junctions, where it interacts with Nir2 via a region between its FFAT motif and DDHD domain to recruit Nir2 and facilitate PIP2 replenishment during receptor-mediated signaling, and its LNS2 domain binds phosphatidic acid to mediate membrane association [PMID:35020418, PMID:38464273]. Missense mutation Q626H in the PYK2-binding domain causes autosomal dominant cone dystrophy (CORD5), and a knock-in mouse model carrying this mutation shows reduced cone electrophysiological responses without structural retinal changes, confirming a role in cone photoreceptor function [PMID:17377520, PMID:41148841].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of a disease-causing mutation in PITPNM3 established that this gene is required for normal cone photoreceptor function and linked its PYK2-binding domain to retinal physiology.\",\n      \"evidence\": \"Genetic mapping and direct sequencing in families with autosomal dominant cone dystrophy (CORD5) identified the Q626H missense mutation\",\n      \"pmids\": [\"17377520\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional interaction with PYK2 inferred from domain mapping rather than demonstrated by direct biochemical assay\",\n        \"Mechanism by which Q626H disrupts cone photoreceptor signaling was unknown\",\n        \"No animal model at the time to confirm causality\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The discovery that PITPNM3 acts as a functional receptor for macrophage-derived CCL18 revealed a previously unknown mechanism by which the tumor microenvironment drives breast cancer invasion and metastasis.\",\n      \"evidence\": \"Functional receptor identification assay, siRNA knockdown, calcium signaling and integrin clustering assays, and xenograft mouse model in breast cancer cells\",\n      \"pmids\": [\"21481794\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of CCL18–PITPNM3 binding not determined\",\n        \"Whether PITPNM3 signals as a classical GPCR or through a distinct mechanism was unclear\",\n        \"Relative contribution of PITPNM3 versus other potential CCL18 receptors (e.g., CCR8) was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Mapping the downstream signaling cascade showed that CCL18–PITPNM3 engagement activates PI3K/Akt/GSK3β to stabilize Snail and promote EMT, and phosphorylates LIMK/cofilin to drive actin remodeling, connecting receptor activation to specific pro-metastatic effector pathways.\",\n      \"evidence\": \"Phosphorylation assays, PI3K inhibitor (LY294002) treatment, siRNA knockdown, and in vivo lung metastasis model in breast cancer\",\n      \"pmids\": [\"24001613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct physical interaction between PITPNM3 and PI3K not demonstrated\",\n        \"Whether PITPNM3's PITP domain contributes to lipid-mediated signaling downstream of CCL18 was not tested\",\n        \"Single-lab study without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extension of CCL18–PITPNM3 signaling to NF-κB activation in hepatocellular carcinoma demonstrated that PITPNM3-mediated pro-invasive signaling operates across multiple cancer types through diverse downstream pathways.\",\n      \"evidence\": \"siRNA knockdown of PITPNM3, phosphorylation of IKK/IκBα, p65 nuclear translocation, and migration/invasion assays in hepatocellular carcinoma cells\",\n      \"pmids\": [\"26449829\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism linking PITPNM3 to IKK phosphorylation not identified\",\n        \"Whether NF-κB and Akt/GSK3β pathways are activated simultaneously or context-dependently was unclear\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of RAC1/ELMO1-dependent cytoskeletal reorganization downstream of CCL18–PITPNM3 in lung cancer cells added a Rho-GTPase signaling axis to the receptor's effector repertoire and linked it to integrin β1-mediated adhesion.\",\n      \"evidence\": \"RAC1 activation assay, ELMO1 pathway analysis, siRNA knockdown, adhesion and invasion assays in lung cancer cells\",\n      \"pmids\": [\"26756176\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct interaction between PITPNM3 and RAC1 or ELMO1 not shown\",\n        \"Relative importance of RAC1/ELMO1 versus Akt and NF-κB axes not compared\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Two studies expanded the CCL18–PITPNM3 axis: JAK2/STAT3 was identified as another downstream effector in oral cancer, and Mfn-2/SP1-dependent transcriptional suppression of PITPNM3 was identified as an upstream regulatory mechanism in hepatic carcinoma.\",\n      \"evidence\": \"JAK inhibitor AG490 and siRNA in oral squamous cell carcinoma; Co-IP of Mfn-2/SP1, ChIP on PITPNM3 promoter, and in vivo tumorigenicity assay in hepatic carcinoma\",\n      \"pmids\": [\"32641093\", \"31955176\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SP1-dependent transcription is the dominant regulator of PITPNM3 expression across tissues is unknown\",\n        \"Both studies from single labs without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The demonstration that PITPNM3 constitutively resides at ER–PM junctions and recruits Nir2 to maintain PIP2 pools established a receptor-independent lipid-transfer function, revealing a dual role for the protein in both chemokine signaling and phosphoinositide homeostasis.\",\n      \"evidence\": \"Live-cell imaging, Co-IP with domain mapping (FFAT-DDHD interregion), PIP2 replenishment assays in cultured cells\",\n      \"pmids\": [\"35020418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether PITPNM3's PITP domain itself transfers lipids was not resolved\",\n        \"Relationship between ER-PM junction function and CCL18 receptor activity is unknown\",\n        \"Structural basis of Nir1–Nir2 interaction not determined\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Comparative receptor analysis in microglia demonstrated that CCL18-induced phagocytosis depends on CCR8 rather than PITPNM3, establishing that PITPNM3 is not a universal CCL18 receptor and that cell-type context determines receptor usage.\",\n      \"evidence\": \"Parallel siRNA knockdown of PITPNM3 and CCR8 with phagocytosis assays and NF-κB/Src pathway analysis in human microglial cells\",\n      \"pmids\": [\"35041514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether PITPNM3 and CCR8 form heteromeric complexes or compete for CCL18 binding was not tested\",\n        \"PITPNM3's role in microglia outside phagocytosis not explored\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Characterization of the LNS2 domain as a phosphatidic acid sensor provided a molecular mechanism for PITPNM3 membrane targeting and introduced this domain as a potential PA biosensor tool, while a CORD5 knock-in mouse confirmed functional cone impairment in vivo.\",\n      \"evidence\": \"Liposome binding assays and fluorescent reporters in HEK293A cells (preprint); heterozygous/homozygous knock-in mouse model with ERG and histology\",\n      \"pmids\": [\"38464273\", \"41148841\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"LNS2/PA binding study is a preprint awaiting peer review\",\n        \"Whether PA binding is required for PITPNM3's CCL18 receptor or ER-PM junction functions is untested\",\n        \"Mouse CORD5 model shows functional deficit without structural change — mechanism of cone dysfunction remains unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of CCL18 binding to PITPNM3, how PITPNM3's lipid-transfer and chemokine-receptor functions are coordinated, and whether the PITP domain is catalytically active remain major unresolved questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structure of CCL18–PITPNM3 complex or of full-length PITPNM3\",\n        \"PITP domain lipid-transfer activity not directly demonstrated\",\n        \"Relationship between ER-PM junction lipid homeostasis role and chemokine receptor signaling role not addressed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 2, 3, 4, 5]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [7, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0, 2, 3, 4, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 3, 4, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CCL18\", \"Nir2\", \"ELMO1\", \"SP1\"],\n    \"other_free_text\": []\n  }\n}\n```"}