{"gene":"TACR2","run_date":"2026-04-28T21:42:58","timeline":{"discoveries":[{"year":2007,"finding":"NK2R (TACR2) can be stabilized in at least two distinct active conformations (A1L and A2L) by its endogenous agonist neurokinin A (NKA): A1L exhibits fast NKA dissociation kinetics and triggers intracellular calcium elevation via Gq, while A2L exhibits slow NKA dissociation kinetics and triggers cAMP production. The allosteric compound LPI805 selectively stabilizes the A1L conformation and acts as a conformation-specific allosteric inhibitor, demonstrating functional selectivity at a GPCR.","method":"Radioligand binding kinetics (NKA dissociation assays), calcium signaling assay, cAMP assay, allosteric modulator pharmacology","journal":"FASEB Journal","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal assays (binding kinetics, Ca2+ signaling, cAMP) in a single rigorous study establishing receptor conformational states and functional selectivity","pmids":["17371796"],"is_preprint":false},{"year":2000,"finding":"In murine keratinocytes (PAM 212), substance P (SP) signals through NK-2R (not NK-1R) to elevate intracellular Ca2+ and induce IL-1α mRNA expression and secretion; both responses were specifically blocked by an NK-2R antagonist, establishing NK-2R as the mediator of SP-induced cytokine production in keratinocytes.","method":"RT-PCR (receptor expression), intracellular Ca2+ measurement, NK-2R antagonist pharmacology, dose-response IL-1α mRNA and bioactivity assays","journal":"Experimental Dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods in one study; single lab","pmids":["10688374"],"is_preprint":false},{"year":2017,"finding":"Genetic ablation of Tacr2 (NK2R knockout mice) causes gastric emptying disturbance associated with upregulation of nNOS and VIP, enhanced nitric oxide signaling, thinner gastric muscularis externa, reduced myenteric neurons, prolonged EFS-induced inhibition in gastric fundus, and decreased MMC frequency. NK2R was shown to negatively regulate nNOS and VIP expression both in vivo and in vitro, with CREB and NF-κB signaling pathways involved.","method":"Homologous recombination knockout mice, gastric emptying assay, EFS, MMC measurement, Western blot, immunohistochemistry, NOS inhibitor rescue (7-NI)","journal":"Neurogastroenterology and Motility","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular/molecular phenotype plus pharmacological rescue, multiple orthogonal readouts","pmids":["28585346"],"is_preprint":false},{"year":2019,"finding":"A chimeric human NK2R incorporating the rat NK2R C-terminus shows greater than 4-fold improved ligand-binding-competent and signaling-competent yields in yeast and mammalian cells, establishing that the C-terminal domain is a key determinant of proper NK2R folding and G protein-coupled signaling competence.","method":"Protein engineering (chimera construction), radioligand binding assay, downstream signaling assay in yeast and mammalian expression systems","journal":"Protein Engineering, Design & Selection","confidence":"Medium","confidence_rationale":"Tier 2 — functional reconstitution in two expression systems; single lab","pmids":["32400863"],"is_preprint":false},{"year":2021,"finding":"Congenital ablation of Tacr2 in mice partially suppresses basal LH levels and LH responses to NK2R agonist, but residual LH responses were abrogated by NK3R blockade in Tacr2-null males, establishing that NK2R contributes to tachykinin-mediated LH secretion with redundant/overlapping roles with NK3R in the gonadotropic axis.","method":"Tacr2 knockout mouse (congenital ablation), LH pulsatility measurement, pharmacological NK2R agonist challenge, NK3R antagonist epistasis","journal":"American Journal of Physiology - Endocrinology and Metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO plus pharmacological epistasis; single lab, moderate phenotype","pmids":["33427049"],"is_preprint":false},{"year":2024,"finding":"NK2R activation is sufficient to suppress appetite centrally and increase energy expenditure peripherally. In mice, selective long-acting NK2R agonists elicit weight loss by inducing energy expenditure and non-aversive appetite suppression that circumvents canonical leptin signaling. NK2R agonism acutely enhances insulin sensitization as demonstrated by hyperinsulinaemic-euglycaemic clamp, and in obese diabetic macaques reduces body weight, blood glucose, triglycerides, and cholesterol.","method":"Pharmacological agonism with selective long-acting NK2R agonists, metabolic phenotyping, hyperinsulinaemic-euglycaemic clamp, diet-induced obesity model mice, non-human primate (macaque) metabolic studies","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal approaches (clamp studies, genetic links, cross-species pharmacology) in a high-impact peer-reviewed study","pmids":["39537932"],"is_preprint":false},{"year":2022,"finding":"IFN-α/β stimulation significantly enhances NK2R gene expression in colon cancer cells via JAK1/2-dependent signaling. NKA stimulation of IFN-α/β-treated colon cancer cells augments proliferation and ERK1/2 phosphorylation, and NK2R blockade reduces proliferation in vitro and suppresses tumorigenesis in vivo.","method":"IFN-α/β stimulation with JAK inhibitor, NK2R antagonist pharmacology, ERK1/2 phosphorylation assay, in vitro proliferation assay, syngeneic mouse tumor model","journal":"Cancer Science","confidence":"Medium","confidence_rationale":"Tier 2 — multiple methods (molecular signaling + in vitro + in vivo); single lab","pmids":["35561088"],"is_preprint":false},{"year":2023,"finding":"IFN-γ signals through a STAT1-dependent cascade to upregulate NK2R expression in CD8+ T cells; NKA-NK2R signaling in turn augments IFN-γ and granzyme B production, promotes ERK1/2 phosphorylation and IκBα degradation, and is required for antitumor effector CD8+ T cell function in vivo, as NK2R-deficient mice show increased tumor growth.","method":"IFN-γ stimulation of CD8+ T cells, STAT1-dependence assay, NK2R knockout mice, CD8+ T cell depletion, in vitro cytokine production assay (IFN-γ, granzyme B), ERK1/2 and IκBα phosphorylation/degradation assays, liver cancer syngeneic model","journal":"Cancer Science","confidence":"High","confidence_rationale":"Tier 2 — genetic KO plus pharmacological and molecular mechanistic evidence with multiple orthogonal assays across in vitro and in vivo systems","pmids":["36715504"],"is_preprint":false},{"year":2019,"finding":"Chronic unpredictable mild stress (CUMS) in rats increases Tacr2 (NK2R) protein and mRNA expression in the hypothalamus, and this upregulation correlates with decreased DNA methylation of specific CpG sites in the Tacr2 gene, establishing DNA methylation as an epigenetic mechanism regulating NK2R expression in response to stress.","method":"CUMS rat model, RT-PCR, Western blot, MeDIP-seq, bisulfite sequencing PCR (BSP)","journal":"Behavioural Brain Research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal epigenetic and expression methods; single lab correlational but mechanistically linked","pmids":["30711443"],"is_preprint":false},{"year":2024,"finding":"Tumonolide, a macrocyclic natural product from a marine cyanobacterium, acts as a selective antagonist of TACR2 (NK2R) with an IC50 of 7.0 μM in a GPCR functional screen. Molecular docking studies established its binding mode in the NK2R orthosteric/allosteric pocket and rationalized selectivity over TACR1 and TACR3.","method":"GPCR functional screening panel (168 GPCRs), binding affinity assay, molecular docking, NMR structure elucidation, RNA sequencing","journal":"Chemistry (Weinheim)","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional screening plus docking; novel natural product ligand but limited mutagenesis validation","pmids":["39023398"],"is_preprint":false},{"year":2025,"finding":"NK2R signaling controls intestinal lipid mobilization: loss or pharmacological blockade of NK2R increases postprandial triglyceridemia and expands intestinal lipid stores, while NK2R agonism suppresses chylomicron output, reduces adiposity, and improves glycemia in diet-induced obesity. NK2R also shapes mucosal immune pathways, secretory lineage composition in a sex-specific manner, and fecal microbiota.","method":"NK2R genetic knockout and pharmacological agonism/antagonism, postprandial triglyceride measurement, transcriptomic analysis, colitis model, microbiome sequencing, dietary challenge","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — complementary genetic and pharmacological perturbations with multiple orthogonal readouts; preprint, not yet peer-reviewed","pmids":["41332647"],"is_preprint":true},{"year":2021,"finding":"TACR2 overexpression in prostate cancer cells inhibits migration and proliferation by regulating the Wnt/β-catenin signaling pathway, positioning TACR2 as a negative regulator of Wnt signaling in this context.","method":"TACR2 overexpression in prostate cancer cell lines, migration and proliferation assays, Wnt/β-catenin pathway analysis","journal":"Cancer Cell International","confidence":"Low","confidence_rationale":"Tier 3 — single lab, limited mechanistic follow-up on pathway placement","pmids":["34364377"],"is_preprint":false}],"current_model":"TACR2 (NK2R) is a G protein-coupled receptor for neurokinin A that couples to multiple signaling cascades (Gq/Ca2+ and Gs/cAMP) through distinct receptor conformations (A1L and A2L), controls intestinal motility by negatively regulating nNOS/VIP-NO signaling, suppresses appetite centrally and increases energy expenditure peripherally via pathways that circumvent leptin signaling, regulates CD8+ T cell antitumor effector function downstream of IFN-γ-STAT1-induced NK2R upregulation (activating ERK1/2 and NF-κB), controls intestinal lipid mobilization and mucosal inflammation, and can be modulated by allosteric compounds that selectively stabilize specific receptor conformations to achieve functional selectivity."},"narrative":{"teleology":[{"year":2000,"claim":"Establishing that NK2R mediates substance P-induced Ca²⁺ signaling and IL-1α cytokine production in keratinocytes answered whether tachykinin receptors other than NK1R drive innate immune responses in epithelial cells.","evidence":"RT-PCR, Ca²⁺ measurement, and NK2R-selective antagonist blockade in murine PAM 212 keratinocytes","pmids":["10688374"],"confidence":"Medium","gaps":["Single cell line; relevance to primary human keratinocytes not shown","Downstream transcription factor pathway linking Ca²⁺ to IL-1α induction not identified"]},{"year":2007,"claim":"Demonstrating that NK2R exists in two pharmacologically and functionally distinct active conformations (A1L/Gq/Ca²⁺ and A2L/Gs/cAMP) established a mechanistic framework for biased agonism and allosteric modulation at this receptor.","evidence":"Radioligand dissociation kinetics, Ca²⁺ and cAMP assays, and conformation-selective allosteric inhibitor (LPI805) pharmacology","pmids":["17371796"],"confidence":"High","gaps":["Structural basis for A1L vs A2L conformations not resolved","Physiological contexts in which one conformation predominates not determined"]},{"year":2017,"claim":"Genetic ablation of Tacr2 revealed that NK2R is required to suppress nNOS/VIP-NO signaling in the enteric nervous system and maintain normal gastric motility, answering how tachykinin signaling shapes inhibitory neurotransmission in the gut.","evidence":"Tacr2 knockout mice with gastric emptying assays, EFS, MMC recording, Western blot, immunohistochemistry, and NOS-inhibitor rescue","pmids":["28585346"],"confidence":"High","gaps":["Cell-type-specific contribution (smooth muscle vs enteric neuron) not dissected with conditional knockouts","Whether A1L or A2L conformation mediates nNOS suppression is unknown"]},{"year":2019,"claim":"Showing that the NK2R C-terminal domain is a key determinant of receptor folding and signaling competence addressed a longstanding difficulty in heterologous expression of this GPCR.","evidence":"Human–rat NK2R chimeras tested by radioligand binding and signaling in yeast and mammalian cells","pmids":["32400863"],"confidence":"Medium","gaps":["Structural mechanism by which the C-terminus facilitates folding not resolved","Single-lab finding without independent replication"]},{"year":2019,"claim":"Identifying stress-induced hypomethylation of Tacr2 CpG sites correlated with hypothalamic NK2R upregulation established epigenetic regulation as a mechanism modulating NK2R expression in stress-responsive brain circuits.","evidence":"CUMS rat model with RT-PCR, Western blot, MeDIP-seq, and bisulfite sequencing","pmids":["30711443"],"confidence":"Medium","gaps":["Correlational design; causal role of methylation changes not confirmed by targeted demethylation or CRISPRi","Functional consequences of hypothalamic NK2R upregulation on behavior not directly tested"]},{"year":2021,"claim":"Showing that NK2R contributes to tachykinin-mediated LH secretion with functional redundancy with NK3R clarified why isolated TACR2 loss may not cause overt hypogonadism.","evidence":"Tacr2 knockout mice with LH pulsatility measurement, NK2R agonist challenge, and NK3R antagonist epistasis","pmids":["33427049"],"confidence":"Medium","gaps":["Whether NK2R acts on GnRH neurons or KNDy neurons directly not resolved","Female reproductive phenotype not fully characterized"]},{"year":2022,"claim":"Discovering that IFN-α/β–JAK1/2 signaling upregulates NK2R in colon cancer cells, where NKA stimulation drives proliferation via ERK1/2, revealed a tumor-intrinsic pro-proliferative role for NK2R in the inflammatory microenvironment.","evidence":"IFN-α/β stimulation with JAK inhibitor, ERK1/2 phosphorylation, proliferation assays, and NK2R antagonist treatment in a syngeneic mouse tumor model","pmids":["35561088"],"confidence":"Medium","gaps":["Relative contribution of tumor-cell-intrinsic vs immune-cell NK2R signaling to net tumor outcome not dissected","Downstream ERK1/2 targets mediating proliferation not identified"]},{"year":2023,"claim":"Establishing that IFN-γ–STAT1 induces NK2R on CD8⁺ T cells and that NKA–NK2R signaling augments granzyme B and IFN-γ production via ERK1/2 and NF-κB resolved how tachykinin signaling enhances antitumor T cell effector function.","evidence":"IFN-γ stimulation, STAT1-dependence assay, NK2R knockout mice with increased tumor growth, ERK1/2/IκBα assays, syngeneic liver cancer model","pmids":["36715504"],"confidence":"High","gaps":["Source of NKA in the tumor microenvironment not identified","Whether NK2R signaling affects T cell exhaustion or memory differentiation is unknown"]},{"year":2024,"claim":"Demonstrating that selective NK2R agonism suppresses appetite centrally, increases energy expenditure peripherally, and improves insulin sensitivity—through leptin-independent pathways—positioned NK2R as a therapeutic target for obesity and metabolic disease.","evidence":"Long-acting NK2R agonists in diet-induced obese mice and diabetic macaques, hyperinsulinemic-euglycemic clamp, metabolic phenotyping","pmids":["39537932"],"confidence":"High","gaps":["Central neuronal populations mediating appetite suppression not identified","Mechanism by which NK2R agonism enhances peripheral energy expenditure is unknown","Long-term safety and efficacy data beyond the study period not available"]},{"year":null,"claim":"Key unresolved questions include the structural basis for A1L/A2L conformational selectivity, the identity of the central circuits mediating NK2R-driven appetite suppression, and how tumor-cell-intrinsic versus immune-cell NK2R signaling integrates to determine net tumor outcomes.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of NK2R in either active conformation","Central neuronal targets of NK2R for appetite and energy expenditure not mapped","Conditional knockout studies needed to separate cell-type-specific roles in cancer"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,5,7]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,5,6,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2]}],"complexes":[],"partners":["NKA","STAT1","CREB1","NOS1"],"other_free_text":[]},"mechanistic_narrative":"TACR2 (NK2R) is a G protein-coupled receptor for neurokinin A that functions as a pleiotropic regulator of gastrointestinal motility, energy homeostasis, immune cell effector function, and neuroendocrine signaling. The receptor adopts at least two distinct active conformations—A1L (Gq/Ca²⁺) and A2L (Gs/cAMP)—that are differentially stabilized by allosteric modulators, providing a molecular basis for functional selectivity [PMID:17371796]. In the gut, NK2R negatively regulates nNOS/VIP-NO signaling via CREB and NF-κB pathways to maintain gastric motility, and controls intestinal lipid mobilization by suppressing chylomicron output [PMID:28585346, PMID:39537932]. In the immune system, IFN-γ–STAT1 signaling induces NK2R expression on CD8⁺ T cells, where NKA–NK2R activation drives ERK1/2 phosphorylation, IκBα degradation, and enhanced IFN-γ and granzyme B production required for antitumor effector function [PMID:36715504]."},"prefetch_data":{"uniprot":{"accession":"P21452","full_name":"Substance-K receptor","aliases":["NK-2 receptor","NK-2R","Neurokinin A receptor","Tachykinin receptor 2"],"length_aa":398,"mass_kda":44.4,"function":"This is a receptor for the tachykinin neuropeptide substance K (neurokinin A) (PubMed:1659297, PubMed:1848773). Is also able to bind and respond to tachynins substance P and neurokinin B/neuromedin-K (By similarity). The rank order of affinity of this receptor to tachykinins is: substance K > neuromedin-K > substance P (By similarity). Substance K binding to its receptor triggers G protein-coupled receptor signaling via activation of G(q) and phosphatidylinositol hydrolysis by phospholipase C (PubMed:7957923, PubMed:35882833). Substance K binding also triggers signaling via activation of adenylate cyclase activity which results in increased intracellular levels of cyclic AMP (cAMP) (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P21452/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TACR2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TACR2","total_profiled":1310},"omim":[{"mim_id":"611129","title":"WW DOMAIN-BINDING PROTEIN 1-LIKE; WBP1L","url":"https://www.omim.org/entry/611129"},{"mim_id":"162321","title":"TACHYKININ RECEPTOR 2; TACR2","url":"https://www.omim.org/entry/162321"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":134.1}],"url":"https://www.proteinatlas.org/search/TACR2"},"hgnc":{"alias_symbol":["SKR","NK2R"],"prev_symbol":["TAC2R","NKNAR"]},"alphafold":{"accession":"P21452","domains":[{"cath_id":"1.20.1070.10","chopping":"35-230_239-311","consensus_level":"high","plddt":90.3626,"start":35,"end":311}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P21452","model_url":"https://alphafold.ebi.ac.uk/files/AF-P21452-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P21452-F1-predicted_aligned_error_v6.png","plddt_mean":79.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TACR2","jax_strain_url":"https://www.jax.org/strain/search?query=TACR2"},"sequence":{"accession":"P21452","fasta_url":"https://rest.uniprot.org/uniprotkb/P21452.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P21452/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P21452"}},"corpus_meta":[{"pmid":"17371796","id":"PMC_17371796","title":"A novel, conformation-specific allosteric inhibitor of the tachykinin NK2 receptor (NK2R) with functionally selective properties.","date":"2007","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/17371796","citation_count":65,"is_preprint":false},{"pmid":"27776126","id":"PMC_27776126","title":"The Skp1 Homologs SKR-1/2 Are Required for the Caenorhabditis elegans SKN-1 Antioxidant/Detoxification Response Independently of p38 MAPK.","date":"2016","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27776126","citation_count":51,"is_preprint":false},{"pmid":"8580956","id":"PMC_8580956","title":"The S locus receptor kinase gene encodes a soluble glycoprotein corresponding to the SKR extracellular domain in Brassica oleracea.","date":"1995","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8580956","citation_count":47,"is_preprint":false},{"pmid":"10688374","id":"PMC_10688374","title":"Substance P induction of murine keratinocyte PAM 212 interleukin 1 production is mediated by the neurokinin 2 receptor (NK-2R).","date":"2000","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/10688374","citation_count":46,"is_preprint":false},{"pmid":"39537932","id":"PMC_39537932","title":"NK2R control of energy expenditure and feeding to treat metabolic diseases.","date":"2024","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/39537932","citation_count":25,"is_preprint":false},{"pmid":"20175803","id":"PMC_20175803","title":"Pharmacogenetic study of the effects of NK2R G231E G>A and TBX21 H33Q C>G polymorphisms on asthma control with inhaled corticosteroid treatment.","date":"2009","source":"Journal of clinical pharmacy and therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/20175803","citation_count":23,"is_preprint":false},{"pmid":"18718460","id":"PMC_18718460","title":"SKR-1, a homolog of Skp1 and a member of the SCF(SEL-10) complex, regulates sex-determination and LIN-12/Notch signaling in C. elegans.","date":"2008","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/18718460","citation_count":20,"is_preprint":false},{"pmid":"19652174","id":"PMC_19652174","title":"Fine mapping and marker development for the crossability gene SKr on chromosome 5BS of hexaploid wheat (Triticum aestivum L.).","date":"2009","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19652174","citation_count":19,"is_preprint":false},{"pmid":"25437503","id":"PMC_25437503","title":"Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of pyrrolopiperidinone acetic acids as CRTh2 antagonists.","date":"2014","source":"Bioorganic & medicinal chemistry 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gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/12508374","citation_count":13,"is_preprint":false},{"pmid":"35561088","id":"PMC_35561088","title":"IFN-α/β-mediated NK2R expression is related to the malignancy of colon cancer cells.","date":"2022","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/35561088","citation_count":12,"is_preprint":false},{"pmid":"32749519","id":"PMC_32749519","title":"Identification of sulfakinin receptors (SKR) in Tenebrio molitor beetle and the influence of sulfakinins on carbohydrates metabolism.","date":"2020","source":"Journal of comparative physiology. 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Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/33427049","citation_count":8,"is_preprint":false},{"pmid":"25437504","id":"PMC_25437504","title":"Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists I.","date":"2014","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/25437504","citation_count":7,"is_preprint":false},{"pmid":"39023398","id":"PMC_39023398","title":"Isolation, Structure Elucidation, and Biological Activity of the Selective TACR2 Antagonist Tumonolide and its Aldehyde from a Marine Cyanobacterium.","date":"2024","source":"Chemistry (Weinheim an der Bergstrasse, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39023398","citation_count":5,"is_preprint":false},{"pmid":"25437505","id":"PMC_25437505","title":"Structure-activity relationships (SAR) and structure-kinetic relationships (SKR) of bicyclic heteroaromatic acetic acids as potent CRTh2 antagonists II: lead optimization.","date":"2014","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/25437505","citation_count":5,"is_preprint":false},{"pmid":"28585346","id":"PMC_28585346","title":"Ablation of Tacr2 in mice leads to gastric emptying disturbance.","date":"2017","source":"Neurogastroenterology and motility","url":"https://pubmed.ncbi.nlm.nih.gov/28585346","citation_count":4,"is_preprint":false},{"pmid":"19375820","id":"PMC_19375820","title":"No association of Tachykinin receptor 2 (TACR2) polymorphisms with Alzheimer's disease.","date":"2009","source":"Neurobiology of aging","url":"https://pubmed.ncbi.nlm.nih.gov/19375820","citation_count":3,"is_preprint":false},{"pmid":"32400863","id":"PMC_32400863","title":"Improved ligand-binding- and signaling-competent human NK2R yields in yeast using a chimera with the rat NK2R C-terminus enable NK2R-G protein signaling platform.","date":"2019","source":"Protein engineering, design & selection : PEDS","url":"https://pubmed.ncbi.nlm.nih.gov/32400863","citation_count":3,"is_preprint":false},{"pmid":"37904319","id":"PMC_37904319","title":"Homology modeling, virtual screening, molecular docking, and ADME approaches to identify a potent agent targeting NK2R protein.","date":"2023","source":"Biotechnology and applied biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37904319","citation_count":2,"is_preprint":false},{"pmid":"39945496","id":"PMC_39945496","title":"Negative Effect of Gst-35 on the Health Span of Caenorhabditis elegans Through Lysosomal Dysfunction via the Pmk-1 and Skr Genes.","date":"2025","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/39945496","citation_count":1,"is_preprint":false},{"pmid":"41332647","id":"PMC_41332647","title":"NK2R signaling governs intestinal lipid mobilization and mucosal inflammation.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41332647","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.06.24.600447","title":"Skp1 is a conserved structural component of the meiotic synaptonemal complex","date":"2024-06-28","source":"bioRxiv","url":"https://doi.org/10.1101/2024.06.24.600447","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14831,"output_tokens":3200,"usd":0.046247},"stage2":{"model":"claude-opus-4-6","input_tokens":6630,"output_tokens":2556,"usd":0.145575},"total_usd":0.191822,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"NK2R (TACR2) can be stabilized in at least two distinct active conformations (A1L and A2L) by its endogenous agonist neurokinin A (NKA): A1L exhibits fast NKA dissociation kinetics and triggers intracellular calcium elevation via Gq, while A2L exhibits slow NKA dissociation kinetics and triggers cAMP production. The allosteric compound LPI805 selectively stabilizes the A1L conformation and acts as a conformation-specific allosteric inhibitor, demonstrating functional selectivity at a GPCR.\",\n      \"method\": \"Radioligand binding kinetics (NKA dissociation assays), calcium signaling assay, cAMP assay, allosteric modulator pharmacology\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal assays (binding kinetics, Ca2+ signaling, cAMP) in a single rigorous study establishing receptor conformational states and functional selectivity\",\n      \"pmids\": [\"17371796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"In murine keratinocytes (PAM 212), substance P (SP) signals through NK-2R (not NK-1R) to elevate intracellular Ca2+ and induce IL-1α mRNA expression and secretion; both responses were specifically blocked by an NK-2R antagonist, establishing NK-2R as the mediator of SP-induced cytokine production in keratinocytes.\",\n      \"method\": \"RT-PCR (receptor expression), intracellular Ca2+ measurement, NK-2R antagonist pharmacology, dose-response IL-1α mRNA and bioactivity assays\",\n      \"journal\": \"Experimental Dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in one study; single lab\",\n      \"pmids\": [\"10688374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Genetic ablation of Tacr2 (NK2R knockout mice) causes gastric emptying disturbance associated with upregulation of nNOS and VIP, enhanced nitric oxide signaling, thinner gastric muscularis externa, reduced myenteric neurons, prolonged EFS-induced inhibition in gastric fundus, and decreased MMC frequency. NK2R was shown to negatively regulate nNOS and VIP expression both in vivo and in vitro, with CREB and NF-κB signaling pathways involved.\",\n      \"method\": \"Homologous recombination knockout mice, gastric emptying assay, EFS, MMC measurement, Western blot, immunohistochemistry, NOS inhibitor rescue (7-NI)\",\n      \"journal\": \"Neurogastroenterology and Motility\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular/molecular phenotype plus pharmacological rescue, multiple orthogonal readouts\",\n      \"pmids\": [\"28585346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A chimeric human NK2R incorporating the rat NK2R C-terminus shows greater than 4-fold improved ligand-binding-competent and signaling-competent yields in yeast and mammalian cells, establishing that the C-terminal domain is a key determinant of proper NK2R folding and G protein-coupled signaling competence.\",\n      \"method\": \"Protein engineering (chimera construction), radioligand binding assay, downstream signaling assay in yeast and mammalian expression systems\",\n      \"journal\": \"Protein Engineering, Design & Selection\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reconstitution in two expression systems; single lab\",\n      \"pmids\": [\"32400863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Congenital ablation of Tacr2 in mice partially suppresses basal LH levels and LH responses to NK2R agonist, but residual LH responses were abrogated by NK3R blockade in Tacr2-null males, establishing that NK2R contributes to tachykinin-mediated LH secretion with redundant/overlapping roles with NK3R in the gonadotropic axis.\",\n      \"method\": \"Tacr2 knockout mouse (congenital ablation), LH pulsatility measurement, pharmacological NK2R agonist challenge, NK3R antagonist epistasis\",\n      \"journal\": \"American Journal of Physiology - Endocrinology and Metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO plus pharmacological epistasis; single lab, moderate phenotype\",\n      \"pmids\": [\"33427049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NK2R activation is sufficient to suppress appetite centrally and increase energy expenditure peripherally. In mice, selective long-acting NK2R agonists elicit weight loss by inducing energy expenditure and non-aversive appetite suppression that circumvents canonical leptin signaling. NK2R agonism acutely enhances insulin sensitization as demonstrated by hyperinsulinaemic-euglycaemic clamp, and in obese diabetic macaques reduces body weight, blood glucose, triglycerides, and cholesterol.\",\n      \"method\": \"Pharmacological agonism with selective long-acting NK2R agonists, metabolic phenotyping, hyperinsulinaemic-euglycaemic clamp, diet-induced obesity model mice, non-human primate (macaque) metabolic studies\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal approaches (clamp studies, genetic links, cross-species pharmacology) in a high-impact peer-reviewed study\",\n      \"pmids\": [\"39537932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IFN-α/β stimulation significantly enhances NK2R gene expression in colon cancer cells via JAK1/2-dependent signaling. NKA stimulation of IFN-α/β-treated colon cancer cells augments proliferation and ERK1/2 phosphorylation, and NK2R blockade reduces proliferation in vitro and suppresses tumorigenesis in vivo.\",\n      \"method\": \"IFN-α/β stimulation with JAK inhibitor, NK2R antagonist pharmacology, ERK1/2 phosphorylation assay, in vitro proliferation assay, syngeneic mouse tumor model\",\n      \"journal\": \"Cancer Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods (molecular signaling + in vitro + in vivo); single lab\",\n      \"pmids\": [\"35561088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IFN-γ signals through a STAT1-dependent cascade to upregulate NK2R expression in CD8+ T cells; NKA-NK2R signaling in turn augments IFN-γ and granzyme B production, promotes ERK1/2 phosphorylation and IκBα degradation, and is required for antitumor effector CD8+ T cell function in vivo, as NK2R-deficient mice show increased tumor growth.\",\n      \"method\": \"IFN-γ stimulation of CD8+ T cells, STAT1-dependence assay, NK2R knockout mice, CD8+ T cell depletion, in vitro cytokine production assay (IFN-γ, granzyme B), ERK1/2 and IκBα phosphorylation/degradation assays, liver cancer syngeneic model\",\n      \"journal\": \"Cancer Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO plus pharmacological and molecular mechanistic evidence with multiple orthogonal assays across in vitro and in vivo systems\",\n      \"pmids\": [\"36715504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Chronic unpredictable mild stress (CUMS) in rats increases Tacr2 (NK2R) protein and mRNA expression in the hypothalamus, and this upregulation correlates with decreased DNA methylation of specific CpG sites in the Tacr2 gene, establishing DNA methylation as an epigenetic mechanism regulating NK2R expression in response to stress.\",\n      \"method\": \"CUMS rat model, RT-PCR, Western blot, MeDIP-seq, bisulfite sequencing PCR (BSP)\",\n      \"journal\": \"Behavioural Brain Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal epigenetic and expression methods; single lab correlational but mechanistically linked\",\n      \"pmids\": [\"30711443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Tumonolide, a macrocyclic natural product from a marine cyanobacterium, acts as a selective antagonist of TACR2 (NK2R) with an IC50 of 7.0 μM in a GPCR functional screen. Molecular docking studies established its binding mode in the NK2R orthosteric/allosteric pocket and rationalized selectivity over TACR1 and TACR3.\",\n      \"method\": \"GPCR functional screening panel (168 GPCRs), binding affinity assay, molecular docking, NMR structure elucidation, RNA sequencing\",\n      \"journal\": \"Chemistry (Weinheim)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional screening plus docking; novel natural product ligand but limited mutagenesis validation\",\n      \"pmids\": [\"39023398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NK2R signaling controls intestinal lipid mobilization: loss or pharmacological blockade of NK2R increases postprandial triglyceridemia and expands intestinal lipid stores, while NK2R agonism suppresses chylomicron output, reduces adiposity, and improves glycemia in diet-induced obesity. NK2R also shapes mucosal immune pathways, secretory lineage composition in a sex-specific manner, and fecal microbiota.\",\n      \"method\": \"NK2R genetic knockout and pharmacological agonism/antagonism, postprandial triglyceride measurement, transcriptomic analysis, colitis model, microbiome sequencing, dietary challenge\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — complementary genetic and pharmacological perturbations with multiple orthogonal readouts; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"41332647\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TACR2 overexpression in prostate cancer cells inhibits migration and proliferation by regulating the Wnt/β-catenin signaling pathway, positioning TACR2 as a negative regulator of Wnt signaling in this context.\",\n      \"method\": \"TACR2 overexpression in prostate cancer cell lines, migration and proliferation assays, Wnt/β-catenin pathway analysis\",\n      \"journal\": \"Cancer Cell International\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, limited mechanistic follow-up on pathway placement\",\n      \"pmids\": [\"34364377\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TACR2 (NK2R) is a G protein-coupled receptor for neurokinin A that couples to multiple signaling cascades (Gq/Ca2+ and Gs/cAMP) through distinct receptor conformations (A1L and A2L), controls intestinal motility by negatively regulating nNOS/VIP-NO signaling, suppresses appetite centrally and increases energy expenditure peripherally via pathways that circumvent leptin signaling, regulates CD8+ T cell antitumor effector function downstream of IFN-γ-STAT1-induced NK2R upregulation (activating ERK1/2 and NF-κB), controls intestinal lipid mobilization and mucosal inflammation, and can be modulated by allosteric compounds that selectively stabilize specific receptor conformations to achieve functional selectivity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TACR2 (NK2R) is a G protein-coupled receptor for neurokinin A that functions as a pleiotropic regulator of gastrointestinal motility, energy homeostasis, immune cell effector function, and neuroendocrine signaling. The receptor adopts at least two distinct active conformations—A1L (Gq/Ca²⁺) and A2L (Gs/cAMP)—that are differentially stabilized by allosteric modulators, providing a molecular basis for functional selectivity [PMID:17371796]. In the gut, NK2R negatively regulates nNOS/VIP-NO signaling via CREB and NF-κB pathways to maintain gastric motility, and controls intestinal lipid mobilization by suppressing chylomicron output [PMID:28585346, PMID:39537932]. In the immune system, IFN-γ–STAT1 signaling induces NK2R expression on CD8⁺ T cells, where NKA–NK2R activation drives ERK1/2 phosphorylation, IκBα degradation, and enhanced IFN-γ and granzyme B production required for antitumor effector function [PMID:36715504].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that NK2R mediates substance P-induced Ca²⁺ signaling and IL-1α cytokine production in keratinocytes answered whether tachykinin receptors other than NK1R drive innate immune responses in epithelial cells.\",\n      \"evidence\": \"RT-PCR, Ca²⁺ measurement, and NK2R-selective antagonist blockade in murine PAM 212 keratinocytes\",\n      \"pmids\": [\"10688374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single cell line; relevance to primary human keratinocytes not shown\",\n        \"Downstream transcription factor pathway linking Ca²⁺ to IL-1α induction not identified\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrating that NK2R exists in two pharmacologically and functionally distinct active conformations (A1L/Gq/Ca²⁺ and A2L/Gs/cAMP) established a mechanistic framework for biased agonism and allosteric modulation at this receptor.\",\n      \"evidence\": \"Radioligand dissociation kinetics, Ca²⁺ and cAMP assays, and conformation-selective allosteric inhibitor (LPI805) pharmacology\",\n      \"pmids\": [\"17371796\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for A1L vs A2L conformations not resolved\",\n        \"Physiological contexts in which one conformation predominates not determined\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Genetic ablation of Tacr2 revealed that NK2R is required to suppress nNOS/VIP-NO signaling in the enteric nervous system and maintain normal gastric motility, answering how tachykinin signaling shapes inhibitory neurotransmission in the gut.\",\n      \"evidence\": \"Tacr2 knockout mice with gastric emptying assays, EFS, MMC recording, Western blot, immunohistochemistry, and NOS-inhibitor rescue\",\n      \"pmids\": [\"28585346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Cell-type-specific contribution (smooth muscle vs enteric neuron) not dissected with conditional knockouts\",\n        \"Whether A1L or A2L conformation mediates nNOS suppression is unknown\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that the NK2R C-terminal domain is a key determinant of receptor folding and signaling competence addressed a longstanding difficulty in heterologous expression of this GPCR.\",\n      \"evidence\": \"Human–rat NK2R chimeras tested by radioligand binding and signaling in yeast and mammalian cells\",\n      \"pmids\": [\"32400863\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural mechanism by which the C-terminus facilitates folding not resolved\",\n        \"Single-lab finding without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying stress-induced hypomethylation of Tacr2 CpG sites correlated with hypothalamic NK2R upregulation established epigenetic regulation as a mechanism modulating NK2R expression in stress-responsive brain circuits.\",\n      \"evidence\": \"CUMS rat model with RT-PCR, Western blot, MeDIP-seq, and bisulfite sequencing\",\n      \"pmids\": [\"30711443\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Correlational design; causal role of methylation changes not confirmed by targeted demethylation or CRISPRi\",\n        \"Functional consequences of hypothalamic NK2R upregulation on behavior not directly tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showing that NK2R contributes to tachykinin-mediated LH secretion with functional redundancy with NK3R clarified why isolated TACR2 loss may not cause overt hypogonadism.\",\n      \"evidence\": \"Tacr2 knockout mice with LH pulsatility measurement, NK2R agonist challenge, and NK3R antagonist epistasis\",\n      \"pmids\": [\"33427049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether NK2R acts on GnRH neurons or KNDy neurons directly not resolved\",\n        \"Female reproductive phenotype not fully characterized\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovering that IFN-α/β–JAK1/2 signaling upregulates NK2R in colon cancer cells, where NKA stimulation drives proliferation via ERK1/2, revealed a tumor-intrinsic pro-proliferative role for NK2R in the inflammatory microenvironment.\",\n      \"evidence\": \"IFN-α/β stimulation with JAK inhibitor, ERK1/2 phosphorylation, proliferation assays, and NK2R antagonist treatment in a syngeneic mouse tumor model\",\n      \"pmids\": [\"35561088\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Relative contribution of tumor-cell-intrinsic vs immune-cell NK2R signaling to net tumor outcome not dissected\",\n        \"Downstream ERK1/2 targets mediating proliferation not identified\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Establishing that IFN-γ–STAT1 induces NK2R on CD8⁺ T cells and that NKA–NK2R signaling augments granzyme B and IFN-γ production via ERK1/2 and NF-κB resolved how tachykinin signaling enhances antitumor T cell effector function.\",\n      \"evidence\": \"IFN-γ stimulation, STAT1-dependence assay, NK2R knockout mice with increased tumor growth, ERK1/2/IκBα assays, syngeneic liver cancer model\",\n      \"pmids\": [\"36715504\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Source of NKA in the tumor microenvironment not identified\",\n        \"Whether NK2R signaling affects T cell exhaustion or memory differentiation is unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that selective NK2R agonism suppresses appetite centrally, increases energy expenditure peripherally, and improves insulin sensitivity—through leptin-independent pathways—positioned NK2R as a therapeutic target for obesity and metabolic disease.\",\n      \"evidence\": \"Long-acting NK2R agonists in diet-induced obese mice and diabetic macaques, hyperinsulinemic-euglycemic clamp, metabolic phenotyping\",\n      \"pmids\": [\"39537932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Central neuronal populations mediating appetite suppression not identified\",\n        \"Mechanism by which NK2R agonism enhances peripheral energy expenditure is unknown\",\n        \"Long-term safety and efficacy data beyond the study period not available\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for A1L/A2L conformational selectivity, the identity of the central circuits mediating NK2R-driven appetite suppression, and how tumor-cell-intrinsic versus immune-cell NK2R signaling integrates to determine net tumor outcomes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of NK2R in either active conformation\",\n        \"Central neuronal targets of NK2R for appetite and energy expenditure not mapped\",\n        \"Conditional knockout studies needed to separate cell-type-specific roles in cancer\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 5, 6, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NKA\",\n      \"STAT1\",\n      \"CREB1\",\n      \"NOS1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}