{"gene":"NISCH","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2000,"finding":"IRAS (imidazoline receptor antisera-selected) cDNA was cloned from a human hippocampal library; the 1504-amino acid protein contains signaling motifs found in cytokine receptors. Transfection of IRAS cDNA into Chinese hamster ovary cells produced high-affinity I1 imidazoline binding sites (nanomolar affinity for moxonidine and rilmenidine), establishing IRAS as the first protein with characteristics of an imidazoline I1 receptor.","method":"cDNA cloning, heterologous expression in CHO cells, radioligand binding assay, Western blot with epitope-selective antisera, ruthenium red staining","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — heterologous expression with radioligand binding and multiple biochemical methods in a single lab; foundational cloning paper","pmids":["10882231"],"is_preprint":false},{"year":2002,"finding":"IRAS associates directly with insulin receptor substrate-4 (IRS-4), and also associates with IRS-1, IRS-2, and IRS-3. Overexpression of IRAS enhanced IRS-4-dependent insulin stimulation of extracellularly regulated kinase (ERK), without altering insulin-stimulated tyrosine phosphorylation of IRS-4 or its association with PI3-kinase or Grb2. The domains of IRAS and IRS-4 responsible for their association were identified by co-immunoprecipitation and mass spectrometry.","method":"Co-immunoprecipitation, mass spectrometry, overexpression in HEK293 cells, Western blot for ERK activation and IRS-4 tyrosine phosphorylation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, MS identification, domain mapping, multiple orthogonal functional readouts in a single rigorous study","pmids":["11912194"],"is_preprint":false},{"year":2003,"finding":"IRAS is a cytosolic protein anchored to the intracellular side of plasma membranes via a PX domain. Stable transfection of IRAS into PC12 cells resulted in lower basal and NGF-stimulated levels of activated ERK compared to vector-only controls, indicating IRAS intrinsically mediates receptor signaling and modulates ERK activity.","method":"Stable transfection in PC12 cells, Western blot for phospho-ERK, subcellular localization analysis","journal":"Annals of the New York Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — stable transfection with functional readout, localization described, single lab with limited mechanistic depth","pmids":["15028618"],"is_preprint":false},{"year":2003,"finding":"Human IRAS stably transfected into PC12 cells localizes to the cytosol as a 167 kDa immunoreactive protein. IRAS expression conferred protection against apoptosis induced by serum starvation, thapsigargin, or staurosporine, reducing caspase-3 activity, phosphatidylserine translocation, and nuclear fragmentation. A partial activation of the PI3 kinase pathway was implicated in the anti-apoptotic effect.","method":"Stable transfection in PC12 cells, transient transfection in COS7 cells, caspase-3 activity assay, annexin V staining, nuclear fragmentation analysis, immunocytochemistry","journal":"Annals of the New York Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal apoptosis assays in two cell lines, single lab","pmids":["15028619"],"is_preprint":false},{"year":2007,"finding":"Antisense knockdown of IRAS in PC12 cells significantly reduced I1 imidazoline receptor binding site density (Bmax reduced from 691 to 400 fmol/mg protein) without affecting binding affinity, and attenuated moxonidine-induced ERK activation dose-dependently. Insulin-stimulated ERK activation was unchanged, indicating IRAS is specifically required for I1 receptor signaling.","method":"Antisense oligonucleotide transfection in PC12 cells, radioligand binding assay, Western blot for phospho-ERK","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function via antisense with quantitative binding and signaling readouts, replicates and extends earlier findings from a different lab","pmids":["17254010"],"is_preprint":false},{"year":2005,"finding":"IRAS, stably co-expressed with mu opioid receptor (MOR) in CHO cells (CHO-mu/IRAS), was necessary for low concentrations of agmatine (0.1–2.5 µM) to attenuate naloxone-precipitated cAMP overshoot indicative of cellular morphine dependence. This effect was blocked by efaroxan (I1R antagonist) and was absent in CHO-mu cells lacking IRAS, demonstrating IRAS mediates agmatine's high-affinity I1 receptor effects on opioid dependence signaling.","method":"Stable co-transfection in CHO cells, cAMP assay, pharmacological antagonism with efaroxan","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined cell-line comparison with loss-of-function (absent IRAS) and pharmacological validation, single lab","pmids":["16112088"],"is_preprint":false},{"year":2006,"finding":"In CHO cells co-expressing MOR and IRAS (CHO-mu/IRAS), agmatine (0.01–3 µM) concentration-dependently inhibited naloxone-precipitated elevation of intracellular calcium concentration; this effect required IRAS and was blocked by efaroxan. Agmatine also attenuated naloxone-precipitated increases in CREB and ERK1/2 phosphorylation and c-Fos expression in CHO-mu/IRAS but not in CHO-mu cells, with all effects blocked by efaroxan.","method":"Stable co-transfection in CHO cells, intracellular calcium measurement, Western blot for p-CREB, p-ERK1/2, c-Fos","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling endpoints in paired cell lines with pharmacological controls, single lab","pmids":["16962578"],"is_preprint":false},{"year":2015,"finding":"IRAS interacts with mu opioid receptor (MOR) through its PX domain (demonstrated in CHO and HEK293 cells co-expressing MOR and IRAS). This interaction facilitated recycling of internalized MOR, prevented DAMGO-induced MOR downregulation, accelerated MOR resensitization, and attenuated MOR desensitization. IRAS knockout mice showed exacerbated analgesic tolerance and physical dependence to opioids.","method":"Co-immunoprecipitation, domain deletion/mutation (PX domain), receptor recycling assay, receptor resensitization assay, IRAS knockout mice with behavioral opioid tolerance/dependence assessment","journal":"Molecular neurobiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with domain mapping, in vitro trafficking assays, and in vivo knockout validation in a single study","pmids":["26363797"],"is_preprint":false},{"year":2015,"finding":"NISCH (Nischarin) overexpression in ovarian cancer cells suppressed cell proliferation and colony formation by hindering cell-cycle progression, and attenuated cell invasion by inhibiting phosphorylation of FAK and ERK. In vivo, NISCH-expressing xenografts showed reduced growth, while NISCH knockdown xenografts showed increased peritoneal/pelvic metastases that were blocked by a FAK/Pyk2 inhibitor (PF-562271), placing NISCH upstream of FAK-ERK signaling in invasion suppression.","method":"Overexpression and knockdown in ovarian cancer cell lines, colony formation assay, cell cycle analysis, xenograft mouse model, Western blot for p-FAK and p-ERK, pharmacological rescue with FAK inhibitor","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional manipulation (OE and KD), in vitro and in vivo readouts, pathway placement via pharmacological epistasis, multiple orthogonal methods","pmids":["25724667"],"is_preprint":false},{"year":2013,"finding":"Tobacco smoke (mainstream and sidestream) induces promoter methylation of the NISCH gene in normal oral keratinocyte cell lines and in plasma of heavy smokers. Promoter methylation of NISCH was detected in 68% of heavy smokers without detectable tumors and in 69% of light smokers with lung cancer, suggesting smoke-induced epigenetic silencing of NISCH precedes detectable cancer.","method":"Quantitative fluorogenic real-time methylation-specific PCR in cell lines exposed to cigarette smoke extract and in patient plasma samples","journal":"Epigenetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct experimental induction of methylation in cell lines with clinical plasma validation; single lab, single epigenetic method","pmids":["23503203"],"is_preprint":false},{"year":2021,"finding":"KLF15-mediated lncRNA TFAP2A-AS1 suppresses NISCH expression via miR-3657 in gastric cancer cells; NISCH was validated as a direct target of miR-3657 and independently suppresses gastric cancer cell proliferation and migration. (Note: this finding relates to regulation of NISCH expression and its functional role in cell proliferation/migration, not to a non-coding RNA product of the NISCH locus itself.)","method":"qPCR, Western blot, functional proliferation and migration assays, FISH, miRNA target validation","journal":"Biology direct","confidence":"Low","confidence_rationale":"Tier 3 / Weak — NISCH functional role in gastric cancer cells established by knockdown/overexpression but mechanistic placement is limited; single lab","pmids":["34727954"],"is_preprint":false}],"current_model":"NISCH (Nischarin/IRAS) is a PX domain-containing cytosolic protein anchored to the inner face of the plasma membrane that functions as a molecular scaffold: it directly associates with insulin receptor substrates (IRS-1 through -4) to potentiate ERK signaling downstream of insulin, interacts with the mu opioid receptor through its PX domain to sort internalized receptor into recycling pathways (thereby attenuating opioid tolerance and dependence), constitutes a functional component of the I1-imidazoline receptor to mediate agmatine/moxonidine signaling through cAMP and calcium pathways, and acts as a tumor suppressor by inhibiting FAK-ERK phosphorylation to restrain cell proliferation and invasion; its promoter is subject to epigenetic silencing by tobacco smoke-induced methylation."},"narrative":{"mechanistic_narrative":"NISCH (Nischarin/IRAS) is a cytosolic PX-domain scaffold anchored to the inner face of the plasma membrane that integrates receptor signaling and restrains proliferative and invasive programs [PMID:15028618]. It directly associates with insulin receptor substrates IRS-1 through IRS-4 and potentiates insulin-stimulated ERK activation downstream of IRS-4 without altering IRS-4 tyrosine phosphorylation or its coupling to PI3-kinase or Grb2 [PMID:11912194]; consistent with an intrinsic role in modulating receptor-driven ERK output, it also confers protection against apoptosis through partial PI3-kinase pathway activation [PMID:15028619]. NISCH was originally identified as IRAS, conferring high-affinity I1-imidazoline binding sites, and is specifically required for I1 imidazoline receptor density and moxonidine/agmatine-evoked signaling through ERK, cAMP, calcium, CREB, and c-Fos pathways [PMID:10882231, PMID:17254010, PMID:16962578]. Through its PX domain it engages the mu opioid receptor to sort internalized receptor into recycling pathways, accelerating resensitization and limiting desensitization and downregulation, such that its loss exacerbates opioid analgesic tolerance and dependence in vivo [PMID:26363797]. As a tumor suppressor, NISCH inhibits FAK and ERK phosphorylation to block cell-cycle progression and invasion, and its silencing—including tobacco-smoke-induced promoter methylation—promotes proliferation and metastasis [PMID:25724667, PMID:23503203].","teleology":[{"year":2000,"claim":"Establishing the molecular identity of the imidazoline I1 receptor was a long-standing pharmacological gap; cloning IRAS provided the first protein reconstituting I1 binding characteristics.","evidence":"cDNA cloning from human hippocampus and heterologous expression with radioligand binding in CHO cells","pmids":["10882231"],"confidence":"Medium","gaps":["Whether IRAS alone constitutes the I1 receptor or acts within a larger complex was not resolved","No structural basis for ligand binding established"]},{"year":2002,"claim":"It was unknown how NISCH influences receptor signaling; identifying direct association with IRS proteins placed it as a scaffold that selectively amplifies insulin-driven ERK.","evidence":"Reciprocal Co-IP, mass spectrometry, and domain mapping with ERK and IRS-4 phosphorylation readouts in HEK293 cells","pmids":["11912194"],"confidence":"High","gaps":["Mechanism by which the IRAS-IRS-4 association amplifies ERK without changing IRS-4 phosphorylation not defined","Physiological insulin contexts untested"]},{"year":2003,"claim":"The subcellular basis and signaling polarity of NISCH were unclear; localization studies defined it as a PX-domain-anchored cytosolic protein that modulates ERK and survival signaling.","evidence":"Stable/transient transfection in PC12 and COS7 cells with phospho-ERK, caspase-3, annexin V, and nuclear fragmentation assays","pmids":["15028618","15028619"],"confidence":"Medium","gaps":["Direction of ERK modulation differs by context and was not mechanistically reconciled","PI3-kinase involvement in survival only partially defined"]},{"year":2007,"claim":"Whether NISCH is genuinely required for I1 receptor function rather than merely correlated was open; antisense loss-of-function showed it is specifically needed for I1 binding density and moxonidine-evoked ERK.","evidence":"Antisense knockdown in PC12 cells with radioligand binding and phospho-ERK assays","pmids":["17254010"],"confidence":"High","gaps":["Whether NISCH binds imidazoline ligands directly or assembles a receptor complex unresolved","Insulin signaling shown unaffected, but cross-talk not mapped"]},{"year":2006,"claim":"The downstream effectors of agmatine acting through IRAS at the opioid-relevant I1 receptor were undefined; paired cell-line studies traced effects to cAMP, calcium, CREB, ERK, and c-Fos.","evidence":"Stable MOR/IRAS co-transfection in CHO cells with cAMP, intracellular calcium, and Western blot endpoints under efaroxan antagonism","pmids":["16112088","16962578"],"confidence":"Medium","gaps":["Direct coupling between IRAS and these second-messenger pathways not biochemically reconstituted","Endogenous neuronal relevance untested"]},{"year":2015,"claim":"How NISCH affects opioid receptor fate was unknown; PX-domain-mediated interaction with MOR was shown to route internalized receptor into recycling, with in vivo consequences for tolerance and dependence.","evidence":"Co-IP with PX-domain mutagenesis, receptor recycling/resensitization assays, and IRAS knockout mouse behavior","pmids":["26363797"],"confidence":"High","gaps":["Trafficking machinery linking NISCH-PX to recycling endosomes not identified","Lipid/cargo specificity of the PX domain not characterized"]},{"year":2015,"claim":"The mechanistic basis of NISCH tumor suppression was unclear; bidirectional manipulation placed it upstream of FAK-ERK to restrain proliferation and invasion.","evidence":"Overexpression/knockdown in ovarian cancer cells, xenografts, and pharmacological FAK-inhibitor epistasis","pmids":["25724667"],"confidence":"High","gaps":["Direct biochemical link between NISCH and FAK not defined","Whether scaffolding or enzymatic inhibition underlies FAK suppression unknown"]},{"year":2013,"claim":"Whether NISCH loss is an early oncogenic event was open; tobacco-smoke induction of promoter methylation in keratinocytes and smoker plasma indicated epigenetic silencing precedes detectable tumors.","evidence":"Quantitative methylation-specific PCR in smoke-exposed cell lines and patient plasma","pmids":["23503203"],"confidence":"Medium","gaps":["Causal link between methylation and reduced NISCH protein in vivo not demonstrated","Single epigenetic method"]},{"year":2021,"claim":"Additional regulatory inputs controlling NISCH levels in cancer were sought; a KLF15/lncRNA/miR-3657 axis was reported to suppress NISCH, which itself limits gastric cancer proliferation and migration.","evidence":"qPCR, Western blot, FISH, miRNA target validation, and proliferation/migration assays in gastric cancer cells","pmids":["34727954"],"confidence":"Low","gaps":["Mechanistic placement of the regulatory axis is limited and single-lab","Direct miR-3657 targeting of NISCH 3'UTR not independently confirmed"]},{"year":null,"claim":"It remains unknown whether NISCH binds imidazoline ligands directly or assembles a receptor complex, and how its PX domain mechanistically couples to both endosomal trafficking and FAK-ERK suppression.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the PX domain or ligand-binding region","Direct biochemical effectors linking NISCH to FAK and to recycling endosomes unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,7]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[2,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,8]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,6,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,9]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[7]}],"complexes":[],"partners":["IRS4","IRS1","IRS2","IRS3","OPRM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y2I1","full_name":"Nischarin","aliases":["Imidazoline receptor 1","I-1","IR1","Imidazoline receptor antisera-selected protein","hIRAS","Imidazoline-1 receptor","I1R","Imidazoline-1 receptor candidate protein","I-1 receptor candidate protein","I1R candidate protein"],"length_aa":1504,"mass_kda":166.6,"function":"Acts either as the functional imidazoline-1 receptor (I1R) candidate or as a membrane-associated mediator of the I1R signaling. Binds numerous imidazoline ligands that induces initiation of cell-signaling cascades triggering to cell survival, growth and migration. Its activation by the agonist rilmenidine induces an increase in phosphorylation of mitogen-activated protein kinases MAPK1 and MAPK3 in rostral ventrolateral medulla (RVLM) neurons that exhibited rilmenidine-evoked hypotension (By similarity). Blocking its activation with efaroxan abolished rilmenidine-induced mitogen-activated protein kinase phosphorylation in RVLM neurons (By similarity). Acts as a modulator of Rac-regulated signal transduction pathways (By similarity). Suppresses Rac1-stimulated cell migration by interacting with PAK1 and inhibiting its kinase activity (By similarity). Also blocks Pak-independent Rac signaling by interacting with RAC1 and inhibiting Rac1-stimulated NF-kB response element and cyclin D1 promoter activation (By similarity). Also inhibits LIMK1 kinase activity by reducing LIMK1 'Tyr-508' phosphorylation (By similarity). Inhibits Rac-induced cell migration and invasion in breast and colon epithelial cells (By similarity). Inhibits lamellipodia formation, when overexpressed (By similarity). Plays a role in protection against apoptosis. Involved in association with IRS4 in the enhancement of insulin activation of MAPK1 and MAPK3. When overexpressed, induces a redistribution of cell surface ITGA5 integrin to intracellular endosomal structures","subcellular_location":"Cell membrane; Cytoplasm; Early endosome; Recycling endosome","url":"https://www.uniprot.org/uniprotkb/Q9Y2I1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NISCH","classification":"Not Classified","n_dependent_lines":331,"n_total_lines":1208,"dependency_fraction":0.2740066225165563},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PIK3R1","stoichiometry":0.2},{"gene":"PIK3R2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NISCH","total_profiled":1310},"omim":[{"mim_id":"615507","title":"NISCHARIN; NISCH","url":"https://www.omim.org/entry/615507"},{"mim_id":"607626","title":"ICHTHYOSIS, LEUKOCYTE VACUOLES, ALOPECIA, AND SCLEROSING CHOLANGITIS; ILVASC","url":"https://www.omim.org/entry/607626"},{"mim_id":"603718","title":"CLAUDIN 1; CLDN1","url":"https://www.omim.org/entry/603718"},{"mim_id":"602610","title":"PHOSPHATIDYLINOSITOL 3-KINASE, REGULATORY SUBUNIT 4; PIK3R4","url":"https://www.omim.org/entry/602610"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Microtubules","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":276.3}],"url":"https://www.proteinatlas.org/search/NISCH"},"hgnc":{"alias_symbol":["KIAA0975","I-1","IRAS"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y2I1","domains":[{"cath_id":"3.30.1520.10","chopping":"19-116","consensus_level":"high","plddt":89.1409,"start":19,"end":116},{"cath_id":"3.80.10.10","chopping":"347-458","consensus_level":"medium","plddt":91.256,"start":347,"end":458},{"cath_id":"2.30.29.30","chopping":"591-618_703-820","consensus_level":"medium","plddt":78.6294,"start":591,"end":820},{"cath_id":"2.30.29.30","chopping":"832-896_903-929_938-1006","consensus_level":"medium","plddt":63.4409,"start":832,"end":1006},{"cath_id":"2.30.29.30","chopping":"1110-1204_1215-1320","consensus_level":"high","plddt":81.0332,"start":1110,"end":1320},{"cath_id":"2.30.29.30","chopping":"1324-1444_1465-1503","consensus_level":"high","plddt":79.6556,"start":1324,"end":1503}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2I1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2I1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y2I1-F1-predicted_aligned_error_v6.png","plddt_mean":68.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NISCH","jax_strain_url":"https://www.jax.org/strain/search?query=NISCH"},"sequence":{"accession":"Q9Y2I1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y2I1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y2I1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y2I1"}},"corpus_meta":[{"pmid":"10880413","id":"PMC_10880413","title":"Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS).","date":"2000","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/10880413","citation_count":1829,"is_preprint":false},{"pmid":"27912063","id":"PMC_27912063","title":"Structure of Mammalian Respiratory Supercomplex I1III2IV1.","date":"2016","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/27912063","citation_count":309,"is_preprint":false},{"pmid":"6193515","id":"PMC_6193515","title":"Ganglioside GM2 as a human tumor antigen (OFA-I-1).","date":"1983","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/6193515","citation_count":200,"is_preprint":false},{"pmid":"17015677","id":"PMC_17015677","title":"Cutting edge: hypoxia-inducible factor 1alpha and its activation-inducible short isoform I.1 negatively regulate functions of CD4+ and CD8+ T lymphocytes.","date":"2006","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/17015677","citation_count":176,"is_preprint":false},{"pmid":"12684185","id":"PMC_12684185","title":"Genetic epidemiology of insulin resistance and visceral adiposity. 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physiology","url":"https://pubmed.ncbi.nlm.nih.gov/9176240","citation_count":16,"is_preprint":false},{"pmid":"23208786","id":"PMC_23208786","title":"Genetic deletion of the HIF-1α isoform I.1 in T cells enhances antibacterial immunity and improves survival in a murine peritonitis model.","date":"2013","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23208786","citation_count":16,"is_preprint":false},{"pmid":"35581144","id":"PMC_35581144","title":"Terbium-Doped and Dual-Passivated γ-CsPb(I1- x Brx )3 Inorganic Perovskite Solar Cells with Improved Air Thermal Stability and High Efficiency.","date":"2022","source":"Advanced materials (Deerfield Beach, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/35581144","citation_count":16,"is_preprint":false},{"pmid":"15166304","id":"PMC_15166304","title":"Insulin sensitivity, body fat distribution, and family diabetes history: the IRAS Family Study.","date":"2004","source":"Obesity 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activation and induces MKP-2 phosphatase.","date":"2003","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/12865160","citation_count":15,"is_preprint":false},{"pmid":"18364473","id":"PMC_18364473","title":"Effects of spinal alpha(2)-adrenoceptor and I(1)-imidazoline receptor activation on hindlimb movement induction in spinal cord-injured mice.","date":"2008","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/18364473","citation_count":15,"is_preprint":false},{"pmid":"8483480","id":"PMC_8483480","title":"Follicle-stimulating hormone increases the turnover of G-protein alpha i-1- and alpha i-2-subunit messenger RNA in Sertoli cells by a mechanism that is independent of protein synthesis.","date":"1993","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/8483480","citation_count":15,"is_preprint":false},{"pmid":"32462866","id":"PMC_32462866","title":"Bioisosteric Replacement of Arylamide-Linked Spine Residues with N-Acylhydrazones and Selenophenes as a Design Strategy to Novel Dibenzosuberone Derivatives as Type I 1/2 p38α MAP Kinase Inhibitors.","date":"2020","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32462866","citation_count":15,"is_preprint":false},{"pmid":"23606885","id":"PMC_23606885","title":"Decrease of Obesity by Allantoin via Imidazoline I 1 -Receptor Activation in High Fat Diet-Fed Mice.","date":"2013","source":"Evidence-based complementary and alternative medicine : eCAM","url":"https://pubmed.ncbi.nlm.nih.gov/23606885","citation_count":15,"is_preprint":false},{"pmid":"26363797","id":"PMC_26363797","title":"IRAS Modulates Opioid Tolerance and Dependence by Regulating μ Opioid Receptor Trafficking.","date":"2015","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/26363797","citation_count":14,"is_preprint":false},{"pmid":"35006347","id":"PMC_35006347","title":"Copper(II) and silver(I)-1,10-phenanthroline-5,6-dione complexes interact with double-stranded DNA: further evidence of their apparent multi-modal activity towards Pseudomonas aeruginosa.","date":"2022","source":"Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35006347","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55024,"output_tokens":3125,"usd":0.105973,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10606,"output_tokens":3227,"usd":0.066852,"stage2_stop_reason":"end_turn"},"total_usd":0.172825,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"IRAS (imidazoline receptor antisera-selected) cDNA was cloned from a human hippocampal library; the 1504-amino acid protein contains signaling motifs found in cytokine receptors. Transfection of IRAS cDNA into Chinese hamster ovary cells produced high-affinity I1 imidazoline binding sites (nanomolar affinity for moxonidine and rilmenidine), establishing IRAS as the first protein with characteristics of an imidazoline I1 receptor.\",\n      \"method\": \"cDNA cloning, heterologous expression in CHO cells, radioligand binding assay, Western blot with epitope-selective antisera, ruthenium red staining\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — heterologous expression with radioligand binding and multiple biochemical methods in a single lab; foundational cloning paper\",\n      \"pmids\": [\"10882231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IRAS associates directly with insulin receptor substrate-4 (IRS-4), and also associates with IRS-1, IRS-2, and IRS-3. Overexpression of IRAS enhanced IRS-4-dependent insulin stimulation of extracellularly regulated kinase (ERK), without altering insulin-stimulated tyrosine phosphorylation of IRS-4 or its association with PI3-kinase or Grb2. The domains of IRAS and IRS-4 responsible for their association were identified by co-immunoprecipitation and mass spectrometry.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, overexpression in HEK293 cells, Western blot for ERK activation and IRS-4 tyrosine phosphorylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, MS identification, domain mapping, multiple orthogonal functional readouts in a single rigorous study\",\n      \"pmids\": [\"11912194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IRAS is a cytosolic protein anchored to the intracellular side of plasma membranes via a PX domain. Stable transfection of IRAS into PC12 cells resulted in lower basal and NGF-stimulated levels of activated ERK compared to vector-only controls, indicating IRAS intrinsically mediates receptor signaling and modulates ERK activity.\",\n      \"method\": \"Stable transfection in PC12 cells, Western blot for phospho-ERK, subcellular localization analysis\",\n      \"journal\": \"Annals of the New York Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — stable transfection with functional readout, localization described, single lab with limited mechanistic depth\",\n      \"pmids\": [\"15028618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human IRAS stably transfected into PC12 cells localizes to the cytosol as a 167 kDa immunoreactive protein. IRAS expression conferred protection against apoptosis induced by serum starvation, thapsigargin, or staurosporine, reducing caspase-3 activity, phosphatidylserine translocation, and nuclear fragmentation. A partial activation of the PI3 kinase pathway was implicated in the anti-apoptotic effect.\",\n      \"method\": \"Stable transfection in PC12 cells, transient transfection in COS7 cells, caspase-3 activity assay, annexin V staining, nuclear fragmentation analysis, immunocytochemistry\",\n      \"journal\": \"Annals of the New York Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal apoptosis assays in two cell lines, single lab\",\n      \"pmids\": [\"15028619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Antisense knockdown of IRAS in PC12 cells significantly reduced I1 imidazoline receptor binding site density (Bmax reduced from 691 to 400 fmol/mg protein) without affecting binding affinity, and attenuated moxonidine-induced ERK activation dose-dependently. Insulin-stimulated ERK activation was unchanged, indicating IRAS is specifically required for I1 receptor signaling.\",\n      \"method\": \"Antisense oligonucleotide transfection in PC12 cells, radioligand binding assay, Western blot for phospho-ERK\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function via antisense with quantitative binding and signaling readouts, replicates and extends earlier findings from a different lab\",\n      \"pmids\": [\"17254010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IRAS, stably co-expressed with mu opioid receptor (MOR) in CHO cells (CHO-mu/IRAS), was necessary for low concentrations of agmatine (0.1–2.5 µM) to attenuate naloxone-precipitated cAMP overshoot indicative of cellular morphine dependence. This effect was blocked by efaroxan (I1R antagonist) and was absent in CHO-mu cells lacking IRAS, demonstrating IRAS mediates agmatine's high-affinity I1 receptor effects on opioid dependence signaling.\",\n      \"method\": \"Stable co-transfection in CHO cells, cAMP assay, pharmacological antagonism with efaroxan\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined cell-line comparison with loss-of-function (absent IRAS) and pharmacological validation, single lab\",\n      \"pmids\": [\"16112088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In CHO cells co-expressing MOR and IRAS (CHO-mu/IRAS), agmatine (0.01–3 µM) concentration-dependently inhibited naloxone-precipitated elevation of intracellular calcium concentration; this effect required IRAS and was blocked by efaroxan. Agmatine also attenuated naloxone-precipitated increases in CREB and ERK1/2 phosphorylation and c-Fos expression in CHO-mu/IRAS but not in CHO-mu cells, with all effects blocked by efaroxan.\",\n      \"method\": \"Stable co-transfection in CHO cells, intracellular calcium measurement, Western blot for p-CREB, p-ERK1/2, c-Fos\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling endpoints in paired cell lines with pharmacological controls, single lab\",\n      \"pmids\": [\"16962578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IRAS interacts with mu opioid receptor (MOR) through its PX domain (demonstrated in CHO and HEK293 cells co-expressing MOR and IRAS). This interaction facilitated recycling of internalized MOR, prevented DAMGO-induced MOR downregulation, accelerated MOR resensitization, and attenuated MOR desensitization. IRAS knockout mice showed exacerbated analgesic tolerance and physical dependence to opioids.\",\n      \"method\": \"Co-immunoprecipitation, domain deletion/mutation (PX domain), receptor recycling assay, receptor resensitization assay, IRAS knockout mice with behavioral opioid tolerance/dependence assessment\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with domain mapping, in vitro trafficking assays, and in vivo knockout validation in a single study\",\n      \"pmids\": [\"26363797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"NISCH (Nischarin) overexpression in ovarian cancer cells suppressed cell proliferation and colony formation by hindering cell-cycle progression, and attenuated cell invasion by inhibiting phosphorylation of FAK and ERK. In vivo, NISCH-expressing xenografts showed reduced growth, while NISCH knockdown xenografts showed increased peritoneal/pelvic metastases that were blocked by a FAK/Pyk2 inhibitor (PF-562271), placing NISCH upstream of FAK-ERK signaling in invasion suppression.\",\n      \"method\": \"Overexpression and knockdown in ovarian cancer cell lines, colony formation assay, cell cycle analysis, xenograft mouse model, Western blot for p-FAK and p-ERK, pharmacological rescue with FAK inhibitor\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional manipulation (OE and KD), in vitro and in vivo readouts, pathway placement via pharmacological epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"25724667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Tobacco smoke (mainstream and sidestream) induces promoter methylation of the NISCH gene in normal oral keratinocyte cell lines and in plasma of heavy smokers. Promoter methylation of NISCH was detected in 68% of heavy smokers without detectable tumors and in 69% of light smokers with lung cancer, suggesting smoke-induced epigenetic silencing of NISCH precedes detectable cancer.\",\n      \"method\": \"Quantitative fluorogenic real-time methylation-specific PCR in cell lines exposed to cigarette smoke extract and in patient plasma samples\",\n      \"journal\": \"Epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct experimental induction of methylation in cell lines with clinical plasma validation; single lab, single epigenetic method\",\n      \"pmids\": [\"23503203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KLF15-mediated lncRNA TFAP2A-AS1 suppresses NISCH expression via miR-3657 in gastric cancer cells; NISCH was validated as a direct target of miR-3657 and independently suppresses gastric cancer cell proliferation and migration. (Note: this finding relates to regulation of NISCH expression and its functional role in cell proliferation/migration, not to a non-coding RNA product of the NISCH locus itself.)\",\n      \"method\": \"qPCR, Western blot, functional proliferation and migration assays, FISH, miRNA target validation\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — NISCH functional role in gastric cancer cells established by knockdown/overexpression but mechanistic placement is limited; single lab\",\n      \"pmids\": [\"34727954\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NISCH (Nischarin/IRAS) is a PX domain-containing cytosolic protein anchored to the inner face of the plasma membrane that functions as a molecular scaffold: it directly associates with insulin receptor substrates (IRS-1 through -4) to potentiate ERK signaling downstream of insulin, interacts with the mu opioid receptor through its PX domain to sort internalized receptor into recycling pathways (thereby attenuating opioid tolerance and dependence), constitutes a functional component of the I1-imidazoline receptor to mediate agmatine/moxonidine signaling through cAMP and calcium pathways, and acts as a tumor suppressor by inhibiting FAK-ERK phosphorylation to restrain cell proliferation and invasion; its promoter is subject to epigenetic silencing by tobacco smoke-induced methylation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NISCH (Nischarin/IRAS) is a cytosolic PX-domain scaffold anchored to the inner face of the plasma membrane that integrates receptor signaling and restrains proliferative and invasive programs [#2]. It directly associates with insulin receptor substrates IRS-1 through IRS-4 and potentiates insulin-stimulated ERK activation downstream of IRS-4 without altering IRS-4 tyrosine phosphorylation or its coupling to PI3-kinase or Grb2 [#1]; consistent with an intrinsic role in modulating receptor-driven ERK output, it also confers protection against apoptosis through partial PI3-kinase pathway activation [#3]. NISCH was originally identified as IRAS, conferring high-affinity I1-imidazoline binding sites, and is specifically required for I1 imidazoline receptor density and moxonidine/agmatine-evoked signaling through ERK, cAMP, calcium, CREB, and c-Fos pathways [#0, #4, #6]. Through its PX domain it engages the mu opioid receptor to sort internalized receptor into recycling pathways, accelerating resensitization and limiting desensitization and downregulation, such that its loss exacerbates opioid analgesic tolerance and dependence in vivo [#7]. As a tumor suppressor, NISCH inhibits FAK and ERK phosphorylation to block cell-cycle progression and invasion, and its silencing—including tobacco-smoke-induced promoter methylation—promotes proliferation and metastasis [#8, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing the molecular identity of the imidazoline I1 receptor was a long-standing pharmacological gap; cloning IRAS provided the first protein reconstituting I1 binding characteristics.\",\n      \"evidence\": \"cDNA cloning from human hippocampus and heterologous expression with radioligand binding in CHO cells\",\n      \"pmids\": [\"10882231\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether IRAS alone constitutes the I1 receptor or acts within a larger complex was not resolved\", \"No structural basis for ligand binding established\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"It was unknown how NISCH influences receptor signaling; identifying direct association with IRS proteins placed it as a scaffold that selectively amplifies insulin-driven ERK.\",\n      \"evidence\": \"Reciprocal Co-IP, mass spectrometry, and domain mapping with ERK and IRS-4 phosphorylation readouts in HEK293 cells\",\n      \"pmids\": [\"11912194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which the IRAS-IRS-4 association amplifies ERK without changing IRS-4 phosphorylation not defined\", \"Physiological insulin contexts untested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The subcellular basis and signaling polarity of NISCH were unclear; localization studies defined it as a PX-domain-anchored cytosolic protein that modulates ERK and survival signaling.\",\n      \"evidence\": \"Stable/transient transfection in PC12 and COS7 cells with phospho-ERK, caspase-3, annexin V, and nuclear fragmentation assays\",\n      \"pmids\": [\"15028618\", \"15028619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direction of ERK modulation differs by context and was not mechanistically reconciled\", \"PI3-kinase involvement in survival only partially defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Whether NISCH is genuinely required for I1 receptor function rather than merely correlated was open; antisense loss-of-function showed it is specifically needed for I1 binding density and moxonidine-evoked ERK.\",\n      \"evidence\": \"Antisense knockdown in PC12 cells with radioligand binding and phospho-ERK assays\",\n      \"pmids\": [\"17254010\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NISCH binds imidazoline ligands directly or assembles a receptor complex unresolved\", \"Insulin signaling shown unaffected, but cross-talk not mapped\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The downstream effectors of agmatine acting through IRAS at the opioid-relevant I1 receptor were undefined; paired cell-line studies traced effects to cAMP, calcium, CREB, ERK, and c-Fos.\",\n      \"evidence\": \"Stable MOR/IRAS co-transfection in CHO cells with cAMP, intracellular calcium, and Western blot endpoints under efaroxan antagonism\",\n      \"pmids\": [\"16112088\", \"16962578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct coupling between IRAS and these second-messenger pathways not biochemically reconstituted\", \"Endogenous neuronal relevance untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"How NISCH affects opioid receptor fate was unknown; PX-domain-mediated interaction with MOR was shown to route internalized receptor into recycling, with in vivo consequences for tolerance and dependence.\",\n      \"evidence\": \"Co-IP with PX-domain mutagenesis, receptor recycling/resensitization assays, and IRAS knockout mouse behavior\",\n      \"pmids\": [\"26363797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking machinery linking NISCH-PX to recycling endosomes not identified\", \"Lipid/cargo specificity of the PX domain not characterized\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The mechanistic basis of NISCH tumor suppression was unclear; bidirectional manipulation placed it upstream of FAK-ERK to restrain proliferation and invasion.\",\n      \"evidence\": \"Overexpression/knockdown in ovarian cancer cells, xenografts, and pharmacological FAK-inhibitor epistasis\",\n      \"pmids\": [\"25724667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between NISCH and FAK not defined\", \"Whether scaffolding or enzymatic inhibition underlies FAK suppression unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Whether NISCH loss is an early oncogenic event was open; tobacco-smoke induction of promoter methylation in keratinocytes and smoker plasma indicated epigenetic silencing precedes detectable tumors.\",\n      \"evidence\": \"Quantitative methylation-specific PCR in smoke-exposed cell lines and patient plasma\",\n      \"pmids\": [\"23503203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal link between methylation and reduced NISCH protein in vivo not demonstrated\", \"Single epigenetic method\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Additional regulatory inputs controlling NISCH levels in cancer were sought; a KLF15/lncRNA/miR-3657 axis was reported to suppress NISCH, which itself limits gastric cancer proliferation and migration.\",\n      \"evidence\": \"qPCR, Western blot, FISH, miRNA target validation, and proliferation/migration assays in gastric cancer cells\",\n      \"pmids\": [\"34727954\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanistic placement of the regulatory axis is limited and single-lab\", \"Direct miR-3657 targeting of NISCH 3'UTR not independently confirmed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether NISCH binds imidazoline ligands directly or assembles a receptor complex, and how its PX domain mechanistically couples to both endosomal trafficking and FAK-ERK suppression.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the PX domain or ligand-binding region\", \"Direct biochemical effectors linking NISCH to FAK and to recycling endosomes unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 6, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"IRS4\", \"IRS1\", \"IRS2\", \"IRS3\", \"OPRM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}