{"gene":"RARRES2","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1997,"finding":"TIG2 (RARRES2) expression is transcriptionally induced by RAR-selective retinoids (but not RXR-selective retinoids or 1,25-dihydroxyvitamin D3) and requires a 3D tissue-like structure of keratinocytes and fibroblasts for induction; tazarotene (RAR beta/gamma-selective) upregulates TIG2 mRNA in skin raft cultures but not in primary keratinocyte or fibroblast monocultures.","method":"Subtraction hybridization, Northern blot analysis, skin raft cultures treated with RAR- and RXR-selective retinoids","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Northern blot with multiple ligand controls in 3D culture system, single lab but two orthogonal methods","pmids":["9204961"],"is_preprint":false},{"year":2003,"finding":"TIG2 (RARRES2/chemerin) was identified as the natural endogenous ligand of the orphan GPCR ChemR23 (CMKLR1); the bioactive circulating form corresponds to amino acid residues 21–154 of the 163 amino acid prepropeptide, isolated from human hemofiltrate by reverse pharmacology peptide library screening.","method":"Reverse pharmacology screening of a peptide library generated from human hemofiltrate; biochemical isolation and characterization","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical isolation from endogenous source, functional receptor binding demonstrated, replicated by subsequent studies","pmids":["14675762"],"is_preprint":false},{"year":2004,"finding":"Two processed bioactive forms of TIG2 (hamster ortholog) were isolated and characterized: residues T20–F156 and T20–A155 of the 163 amino acid propeptide, establishing that C-terminal proteolytic processing produces the bioactive chemerin forms.","method":"Heparin-affinity chromatography, reversed-phase HPLC, Edman sequencing, MALDI-TOF mass spectrometry","journal":"Journal of chromatography. B","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct protein sequencing and MS characterization, single lab, ortholog (hamster)","pmids":["15522723"],"is_preprint":false},{"year":2014,"finding":"In cultured bovine granulosa cells, recombinant CHEMERIN (RARRES2) reduced progesterone and estradiol production, decreased cholesterol content, reduced STAR, CYP19A1 and HMGCR protein levels, and inhibited MAPK3/MAPK1 phosphorylation; all effects were abolished by anti-CMKLR1 antibody, demonstrating that the inhibitory signaling is mediated through CMKLR1. Additionally, chemerin arrested bovine oocytes at the germinal vesicle stage and inhibited MAPK3/1 phosphorylation in cumulus-oocyte complexes.","method":"In vitro granulosa cell cultures with recombinant human CHEMERIN, anti-CMKLR1 antibody blockade, Western blotting for signaling proteins, in vitro oocyte maturation assay","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (steroidogenesis assay, Western blot, receptor blockade), defined molecular pathway, consistent results across two cell systems","pmids":["24671882"],"is_preprint":false},{"year":2015,"finding":"RARRES2 knockdown by siRNA in RSV-susceptible cell lines (HEp-2 and A549) reduced RSV replication, and expression of RARRES2 in low-susceptibility MDCK cells increased RSV replication 10- to 100-fold, establishing RARRES2 as a host cell factor that positively supports respiratory syncytial virus replication.","method":"cDNA library transfection into MDCK cells, microarray analysis, siRNA knockdown in HEp-2 and A549 cells, viral replication assay","journal":"Virus research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function and loss-of-function both performed, single lab, clear phenotypic readout","pmids":["26277777"],"is_preprint":false},{"year":2017,"finding":"RARRES2 overexpression in adrenocortical carcinoma (ACC) cell lines promoted β-catenin phosphorylation and degradation (inhibiting Wnt/β-catenin pathway) and inhibited p38 MAPK phosphorylation, reducing cell proliferation, invasion, and tumor growth in vivo in immunodeficient mouse xenograft models; this tumor-suppressive effect was immune-independent, as minimal CMKLR1 expression was detected and exogenous RARRES2 treatment had no phenotypic effect.","method":"RARRES2 overexpression in ACC cell lines, Western blotting for β-catenin phosphorylation/degradation and p38 phosphorylation, in vitro proliferation/invasion assays, in vivo xenograft models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (in vitro and in vivo), defined molecular mechanism, single lab","pmids":["28114280"],"is_preprint":false},{"year":2023,"finding":"Reduced RARRES2 expression in brain-metastatic TNBC cells increased glycerophospholipid levels and decreased triacylglycerols via regulation of the PTEN-mTOR-SREBP1 signaling pathway, promoting survival in the brain microenvironment; RARRES2 deficiency thus promotes breast cancer brain metastasis through lipid metabolic reprogramming.","method":"In vitro and in vivo studies with RARRES2 manipulation, multi-omics approaches, lipidomics, pathway analysis of PTEN-mTOR-SREBP1","journal":"Military Medical Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics and lipidomics combined with in vivo models, single lab","pmids":["37491281"],"is_preprint":false},{"year":2026,"finding":"RARRES2 promotes HSPG2 expression in keloid fibroblasts by phosphorylating STAT3, which binds to the HSPG2 promoter; the RARRES2-STAT3-HSPG2 axis drives pro-scarring effects in primary fibroblasts and animal models.","method":"Mendelian randomization and multiomics, ChIP or promoter binding assay (p-STAT3 on HSPG2 promoter), RARRES2 manipulation in primary fibroblasts and animal models","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter binding and functional rescue in primary cells and animal model, single lab, not yet widely replicated","pmids":["42170108"],"is_preprint":false},{"year":2024,"finding":"In osteosarcoma, macrophage-secreted IGF-1 promotes RARRES2-mediated stemness maintenance in osteosarcoma stem cells (OSCs), establishing an IGF-RARRES2 axis in intercellular communication between OSCs and tumor-associated macrophages.","method":"Single-cell transcriptomics, cell communication analysis, in vitro validation with IGF-1 treatment and RARRES2 manipulation","journal":"Scientific reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, mechanistic follow-up limited in abstract, primarily computational with limited in vitro validation described","pmids":["38280909"],"is_preprint":false},{"year":2025,"finding":"During liver fibrosis regression in a TAA-induced mouse model, pericentral hepatocytes secrete Rarres2 to modulate hepatic stellate cell (HSC) function, suggesting a paracrine role for RARRES2 in fibrosis resolution.","method":"Single-cell fixed RNA profiling (FLEX) of TAA-induced mouse liver cirrhosis model with and without recovery phase; NicheNet intercellular communication analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single-cell transcriptomics and computational inference, limited direct functional validation of RARRES2 specifically","pmids":[],"is_preprint":true}],"current_model":"RARRES2 encodes chemerin, a secreted protein that undergoes C-terminal proteolytic processing from a 163 amino acid prepropeptide to generate bioactive forms that act as the endogenous ligand for the GPCR ChemR23/CMKLR1; its transcription is induced by RAR-selective retinoids in 3D skin tissue; signaling through CMKLR1 inhibits granulosa cell steroidogenesis and MAPK1/3 phosphorylation; in cancer cells, RARRES2 can act cell-autonomously (independent of CMKLR1) to suppress Wnt/β-catenin and p38 MAPK signaling, regulate PTEN-mTOR-SREBP1-dependent lipid metabolism, and activate a STAT3-HSPG2 pro-fibrotic axis in fibroblasts."},"narrative":{"mechanistic_narrative":"RARRES2 encodes chemerin, a secreted protein originally identified as a retinoid-responsive transcript whose induction requires the 3D tissue architecture of keratinocytes and fibroblasts and is driven specifically by RAR-selective retinoids [PMID:9204961]. The prepropeptide undergoes C-terminal proteolytic processing to generate bioactive forms — circulating species corresponding to residues ~21–154/155/156 of the 163-residue precursor — that serve as the endogenous ligand for the orphan GPCR ChemR23/CMKLR1 [PMID:14675762, PMID:15522723]. Through CMKLR1, chemerin acts as a negative regulator of ovarian steroidogenesis, suppressing progesterone and estradiol output, lowering STAR, CYP19A1 and HMGCR levels, inhibiting MAPK3/MAPK1 phosphorylation, and arresting oocyte maturation, with all effects blocked by CMKLR1 antagonism [PMID:24671882]. Beyond classical ligand–receptor signaling, RARRES2 also exerts cell-autonomous, CMKLR1-independent functions in cancer: it promotes β-catenin phosphorylation/degradation and inhibits p38 MAPK to suppress adrenocortical carcinoma growth [PMID:28114280], and its loss reprograms lipid metabolism through the PTEN-mTOR-SREBP1 axis to favor breast cancer brain metastasis [PMID:37491281]. In fibroblasts, RARRES2 drives a pro-fibrotic program by phosphorylating STAT3, which binds the HSPG2 promoter to induce HSPG2 expression [PMID:42170108]. RARRES2 has additionally been characterized as a host factor supporting respiratory syncytial virus replication [PMID:26277777].","teleology":[{"year":1997,"claim":"Established RARRES2 (TIG2) as a retinoid-inducible gene and defined an unusual requirement for 3D tissue context, distinguishing it from simple monolayer-inducible retinoid targets.","evidence":"Subtraction hybridization and Northern blot in skin raft cultures with RAR- vs RXR-selective retinoid controls","pmids":["9204961"],"confidence":"Medium","gaps":["Did not identify the protein product's function or whether it is secreted","Mechanism of the 3D-dependence of induction not resolved","No receptor or downstream pathway identified"]},{"year":2003,"claim":"Resolved the function of the RARRES2 product by identifying chemerin as the endogenous ligand for the orphan GPCR ChemR23/CMKLR1 and defining the bioactive circulating species.","evidence":"Reverse pharmacology screening of a human hemofiltrate peptide library with receptor binding/activation","pmids":["14675762"],"confidence":"High","gaps":["Did not define the protease(s) generating the bioactive form","Downstream signaling consequences of CMKLR1 activation not characterized here"]},{"year":2004,"claim":"Confirmed that C-terminal proteolytic processing of the precursor generates the bioactive chemerin forms, defining the precise residue boundaries.","evidence":"Heparin-affinity chromatography, RP-HPLC, Edman sequencing and MALDI-TOF MS of the hamster ortholog","pmids":["15522723"],"confidence":"Medium","gaps":["Performed in hamster ortholog rather than human","Identity of the activating proteases not established"]},{"year":2014,"claim":"Demonstrated a receptor-dependent physiological role: chemerin signals through CMKLR1 to suppress ovarian steroidogenesis and MAPK1/3 activation.","evidence":"Recombinant chemerin on bovine granulosa cells and cumulus-oocyte complexes with anti-CMKLR1 blockade, steroid assays and Western blot","pmids":["24671882"],"confidence":"High","gaps":["G-protein coupling and proximal signaling steps downstream of CMKLR1 not dissected","Validated in bovine cells; human in vivo relevance not addressed"]},{"year":2015,"claim":"Identified an unexpected role for RARRES2 as a host factor supporting RSV replication, separate from its endocrine ligand function.","evidence":"cDNA gain-of-function in MDCK cells and siRNA knockdown in HEp-2/A549 with viral replication readout","pmids":["26277777"],"confidence":"Medium","gaps":["Molecular mechanism linking RARRES2 to viral replication unknown","Whether secreted or intracellular RARRES2 mediates the effect not determined"]},{"year":2017,"claim":"Revealed a cell-autonomous, CMKLR1-independent tumor-suppressive function of RARRES2 acting on Wnt/β-catenin and p38 MAPK.","evidence":"RARRES2 overexpression in adrenocortical carcinoma lines with Western blot, in vitro proliferation/invasion assays and xenografts","pmids":["28114280"],"confidence":"Medium","gaps":["How intracellular RARRES2 engages β-catenin and p38 pathways mechanistically is unresolved","Generalizability beyond adrenocortical carcinoma not tested"]},{"year":2023,"claim":"Linked RARRES2 loss to lipid metabolic reprogramming via PTEN-mTOR-SREBP1, promoting breast cancer brain metastasis.","evidence":"RARRES2 manipulation with multi-omics and lipidomics in TNBC models in vitro and in vivo","pmids":["37491281"],"confidence":"Medium","gaps":["Direct biochemical link between RARRES2 and PTEN-mTOR-SREBP1 not established","Single lab, single tumor type"]},{"year":2024,"claim":"Placed RARRES2 in an intercellular IGF-1 axis maintaining osteosarcoma stem cell stemness.","evidence":"Single-cell transcriptomics and cell communication analysis with IGF-1 treatment and RARRES2 manipulation","pmids":["38280909"],"confidence":"Low","gaps":["Primarily computational with limited in vitro validation","Mechanism by which RARRES2 maintains stemness undefined"]},{"year":2026,"claim":"Defined a RARRES2-STAT3-HSPG2 transcriptional axis driving fibroblast pro-scarring activity.","evidence":"Mendelian randomization, multiomics, p-STAT3 promoter binding on HSPG2, and RARRES2 manipulation in primary fibroblasts and animal models","pmids":["42170108"],"confidence":"Medium","gaps":["How RARRES2 triggers STAT3 phosphorylation is not resolved","Not yet independently replicated"]},{"year":2025,"claim":"Proposed a paracrine role for hepatocyte-secreted Rarres2 in modulating hepatic stellate cells during fibrosis regression.","evidence":"Single-cell RNA profiling of TAA-induced mouse liver cirrhosis with NicheNet inference (preprint)","pmids":[],"confidence":"Low","gaps":["Computational inference with limited direct functional validation","Receptor and signaling pathway on stellate cells not defined"]},{"year":null,"claim":"It remains unresolved how RARRES2 switches between extracellular CMKLR1-dependent ligand signaling and cell-autonomous intracellular functions, and what proteases and cell-context cues govern this dichotomy.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified mechanism reconciling secreted-ligand and cell-autonomous roles","Activating proteases not mapped across tissues","Structural basis of intracellular signaling functions unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,3]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,3]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,2,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5]}],"complexes":[],"partners":["CMKLR1","STAT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99969","full_name":"Retinoic acid receptor responder protein 2","aliases":["Chemerin","RAR-responsive protein TIG2","Tazarotene-induced gene 2 protein"],"length_aa":163,"mass_kda":18.6,"function":"Adipocyte-secreted protein (adipokine) that regulates adipogenesis, metabolism and inflammation through activation of the chemokine-like receptor 1 (CMKLR1). Also acts as a ligand for CMKLR2. Can also bind to C-C chemokine receptor-like 2 (CCRL2), but with a lower affinity than it does to CMKLR1 or CMKLR2 (PubMed:27716822). Positively regulates adipocyte differentiation, modulates the expression of adipocyte genes involved in lipid and glucose metabolism and might play a role in angiogenesis, a process essential for the expansion of white adipose tissue. Also acts as a pro-inflammatory adipokine, causing an increase in secretion of pro-inflammatory and prodiabetic adipokines, which further impair adipose tissue metabolic function and have negative systemic effects including impaired insulin sensitivity, altered glucose and lipid metabolism, and a decrease in vascular function in other tissues. Can have both pro- and anti-inflammatory properties depending on the modality of enzymatic cleavage by different classes of proteases. Acts as a chemotactic factor for leukocyte populations expressing CMKLR1, particularly immature plasmacytoid dendritic cells, but also immature myeloid DCs, macrophages and natural killer cells. Exerts an anti-inflammatory role by preventing TNF/TNFA-induced VCAM1 expression and monocytes adhesion in vascular endothelial cells. The effect is mediated via inhibiting activation of NF-kappa-B and CRK/p38 through stimulation of AKT1/NOS3 signaling and nitric oxide production. Its dual role in inflammation and metabolism might provide a link between chronic inflammation and obesity, as well as obesity-related disorders such as type 2 diabetes and cardiovascular disease. Exhibits an antimicrobial function in the skin","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q99969/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RARRES2","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/RARRES2","total_profiled":1310},"omim":[{"mim_id":"608379","title":"CHEMOKINE, CC MOTIF, RECEPTOR-LIKE PROTEIN 2; CCRL2","url":"https://www.omim.org/entry/608379"},{"mim_id":"602351","title":"CHEMERIN CHEMOKINE-LIKE RECEPTOR 1; CMKLR1","url":"https://www.omim.org/entry/602351"},{"mim_id":"601973","title":"RETINOIC ACID RECEPTOR RESPONDER 2; RARRES2","url":"https://www.omim.org/entry/601973"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adrenal gland","ntpm":2645.8},{"tissue":"liver","ntpm":2145.2}],"url":"https://www.proteinatlas.org/search/RARRES2"},"hgnc":{"alias_symbol":["TIG2","HP10433"],"prev_symbol":[]},"alphafold":{"accession":"Q99969","domains":[{"cath_id":"3.10.450.10","chopping":"23-139","consensus_level":"high","plddt":91.8034,"start":23,"end":139}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99969","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99969-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99969-F1-predicted_aligned_error_v6.png","plddt_mean":86.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RARRES2","jax_strain_url":"https://www.jax.org/strain/search?query=RARRES2"},"sequence":{"accession":"Q99969","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99969.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99969/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99969"}},"corpus_meta":[{"pmid":"9204961","id":"PMC_9204961","title":"Tazarotene-induced gene 2 (TIG2), a novel retinoid-responsive gene in skin.","date":"1997","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/9204961","citation_count":241,"is_preprint":false},{"pmid":"14675762","id":"PMC_14675762","title":"Characterization of human circulating TIG2 as a ligand for the orphan receptor ChemR23.","date":"2003","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/14675762","citation_count":167,"is_preprint":false},{"pmid":"24671882","id":"PMC_24671882","title":"CHEMERIN (RARRES2) decreases in vitro granulosa cell steroidogenesis and blocks oocyte meiotic progression in bovine species.","date":"2014","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/24671882","citation_count":71,"is_preprint":false},{"pmid":"37491281","id":"PMC_37491281","title":"RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer.","date":"2023","source":"Military Medical Research","url":"https://pubmed.ncbi.nlm.nih.gov/37491281","citation_count":56,"is_preprint":false},{"pmid":"28114280","id":"PMC_28114280","title":"RARRES2 functions as a tumor suppressor by promoting β-catenin phosphorylation/degradation and inhibiting p38 phosphorylation in adrenocortical carcinoma.","date":"2017","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/28114280","citation_count":51,"is_preprint":false},{"pmid":"19303973","id":"PMC_19303973","title":"RARRES2, encoding the novel adipokine chemerin, is a genetic determinant of disproportionate regional body fat distribution: a comparative magnetic resonance imaging study.","date":"2009","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/19303973","citation_count":50,"is_preprint":false},{"pmid":"18955196","id":"PMC_18955196","title":"Downregulation of tazarotene induced gene-2 (TIG2) in skin squamous cell carcinoma.","date":"2008","source":"European journal of dermatology : EJD","url":"https://pubmed.ncbi.nlm.nih.gov/18955196","citation_count":33,"is_preprint":false},{"pmid":"25521368","id":"PMC_25521368","title":"Genome wide meta-analysis highlights the role of genetic variation in RARRES2 in the regulation of circulating serum chemerin.","date":"2014","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25521368","citation_count":31,"is_preprint":false},{"pmid":"29720894","id":"PMC_29720894","title":"Pleiotropic Associations of RARRES2 Gene Variants and Circulating Chemerin Levels: Potential Roles of Chemerin Involved in the Metabolic and Inflammation-Related Diseases.","date":"2018","source":"Mediators of inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/29720894","citation_count":22,"is_preprint":false},{"pmid":"29374087","id":"PMC_29374087","title":"Food restriction but not fish oil increases fertility in hens: role of RARRES2?","date":"2018","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29374087","citation_count":16,"is_preprint":false},{"pmid":"30866520","id":"PMC_30866520","title":"Circulating Chemerin Levels, but not the RARRES2 Polymorphisms, Predict the Long-Term Outcome of Angiographically Confirmed Coronary Artery Disease.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30866520","citation_count":16,"is_preprint":false},{"pmid":"33058983","id":"PMC_33058983","title":"Variants in the RARRES2 gene are associated with serum chemerin and increase the risk of diabetic kidney disease in type 2 diabetes.","date":"2020","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/33058983","citation_count":13,"is_preprint":false},{"pmid":"37246211","id":"PMC_37246211","title":"Targeting copper death genotyping associated gene RARRES2 suppresses glioblastoma progression and macrophages infiltration.","date":"2023","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/37246211","citation_count":11,"is_preprint":false},{"pmid":"27446956","id":"PMC_27446956","title":"Association of Polymorphisms in STRA6 and RARRES2 Genes with Type 2 Diabetes in Southern Han Chinese.","date":"2016","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/27446956","citation_count":11,"is_preprint":false},{"pmid":"30777067","id":"PMC_30777067","title":"Possible involvement of the RARRES2/CMKLR1-system in metabolic and reproductive parameters in Holstein dairy cows.","date":"2019","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/30777067","citation_count":9,"is_preprint":false},{"pmid":"26277777","id":"PMC_26277777","title":"Identification of CCL2, RARRES2 and EFNB2 as host cell factors that influence the multistep replication of respiratory syncytial virus.","date":"2015","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/26277777","citation_count":7,"is_preprint":false},{"pmid":"22479267","id":"PMC_22479267","title":"Evaluation of Bovine chemerin (RARRES2) Gene Variation on Beef Cattle Production Traits.","date":"2012","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22479267","citation_count":7,"is_preprint":false},{"pmid":"35531645","id":"PMC_35531645","title":"Common variants of RARRES2 and RETN contribute to susceptibility to hand osteoarthritis and related pain.","date":"2022","source":"Biomarkers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35531645","citation_count":6,"is_preprint":false},{"pmid":"38280909","id":"PMC_38280909","title":"RARRES2 is involved in the \"lock-and-key\" interactions between osteosarcoma stem cells and tumor-associated macrophages.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38280909","citation_count":6,"is_preprint":false},{"pmid":"15522723","id":"PMC_15522723","title":"A three-step purification strategy for isolation of hamster TIG2 from CHO cells: characterization of two processed endogenous forms.","date":"2004","source":"Journal of chromatography. B, Analytical technologies in the biomedical and life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/15522723","citation_count":6,"is_preprint":false},{"pmid":"36385772","id":"PMC_36385772","title":"The transforming growth factor beta ligand TIG-2 modulates the function of neuromuscular junction and muscle energy metabolism in Caenorhabditis elegans.","date":"2022","source":"Frontiers in molecular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/36385772","citation_count":5,"is_preprint":false},{"pmid":"21687971","id":"PMC_21687971","title":"Exploring polymorphisms of the bovine RARRES2 gene and their associations with growth traits.","date":"2011","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/21687971","citation_count":3,"is_preprint":false},{"pmid":"36531488","id":"PMC_36531488","title":"Association of serum levels of Visfatin, Intelectin-1, RARRES2 and their genetic variants with bone mineral density in postmenopausal females.","date":"2022","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/36531488","citation_count":3,"is_preprint":false},{"pmid":"34336137","id":"PMC_34336137","title":"Hypertension is associated with a variant in the RARRES2 gene in populations of Ouro Preto, Minas Gerais, Brazil: a cross-sectional study.","date":"2021","source":"International journal of molecular epidemiology and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34336137","citation_count":3,"is_preprint":false},{"pmid":"38000703","id":"PMC_38000703","title":"Association of RARRES2 rs17173608 gene polymorphism and serum Chemerin with acute myocardial infarction and its risk factors: A case-control study in an Iranian population.","date":"2023","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/38000703","citation_count":0,"is_preprint":false},{"pmid":"42170108","id":"PMC_42170108","title":"Integrative multiomics analysis identifies RARRES2 as a regulator of keloid pathogenesis through STAT3/HSPG2 signaling axis.","date":"2026","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/42170108","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.12.657772","title":"A single-cell fixed RNA profiling of liver fibrosis progression and regression reveals SEMA4D and LMCD1 as key mediators of fibrogenesis","date":"2025-06-12","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.12.657772","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.25.625246","title":"Sexual dimorphism of MASLD-driven bone loss","date":"2024-11-28","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.25.625246","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16868,"output_tokens":2639,"usd":0.045095,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9879,"output_tokens":3190,"usd":0.064573,"stage2_stop_reason":"end_turn"},"total_usd":0.109668,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"TIG2 (RARRES2) expression is transcriptionally induced by RAR-selective retinoids (but not RXR-selective retinoids or 1,25-dihydroxyvitamin D3) and requires a 3D tissue-like structure of keratinocytes and fibroblasts for induction; tazarotene (RAR beta/gamma-selective) upregulates TIG2 mRNA in skin raft cultures but not in primary keratinocyte or fibroblast monocultures.\",\n      \"method\": \"Subtraction hybridization, Northern blot analysis, skin raft cultures treated with RAR- and RXR-selective retinoids\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Northern blot with multiple ligand controls in 3D culture system, single lab but two orthogonal methods\",\n      \"pmids\": [\"9204961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TIG2 (RARRES2/chemerin) was identified as the natural endogenous ligand of the orphan GPCR ChemR23 (CMKLR1); the bioactive circulating form corresponds to amino acid residues 21–154 of the 163 amino acid prepropeptide, isolated from human hemofiltrate by reverse pharmacology peptide library screening.\",\n      \"method\": \"Reverse pharmacology screening of a peptide library generated from human hemofiltrate; biochemical isolation and characterization\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical isolation from endogenous source, functional receptor binding demonstrated, replicated by subsequent studies\",\n      \"pmids\": [\"14675762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Two processed bioactive forms of TIG2 (hamster ortholog) were isolated and characterized: residues T20–F156 and T20–A155 of the 163 amino acid propeptide, establishing that C-terminal proteolytic processing produces the bioactive chemerin forms.\",\n      \"method\": \"Heparin-affinity chromatography, reversed-phase HPLC, Edman sequencing, MALDI-TOF mass spectrometry\",\n      \"journal\": \"Journal of chromatography. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct protein sequencing and MS characterization, single lab, ortholog (hamster)\",\n      \"pmids\": [\"15522723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In cultured bovine granulosa cells, recombinant CHEMERIN (RARRES2) reduced progesterone and estradiol production, decreased cholesterol content, reduced STAR, CYP19A1 and HMGCR protein levels, and inhibited MAPK3/MAPK1 phosphorylation; all effects were abolished by anti-CMKLR1 antibody, demonstrating that the inhibitory signaling is mediated through CMKLR1. Additionally, chemerin arrested bovine oocytes at the germinal vesicle stage and inhibited MAPK3/1 phosphorylation in cumulus-oocyte complexes.\",\n      \"method\": \"In vitro granulosa cell cultures with recombinant human CHEMERIN, anti-CMKLR1 antibody blockade, Western blotting for signaling proteins, in vitro oocyte maturation assay\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (steroidogenesis assay, Western blot, receptor blockade), defined molecular pathway, consistent results across two cell systems\",\n      \"pmids\": [\"24671882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RARRES2 knockdown by siRNA in RSV-susceptible cell lines (HEp-2 and A549) reduced RSV replication, and expression of RARRES2 in low-susceptibility MDCK cells increased RSV replication 10- to 100-fold, establishing RARRES2 as a host cell factor that positively supports respiratory syncytial virus replication.\",\n      \"method\": \"cDNA library transfection into MDCK cells, microarray analysis, siRNA knockdown in HEp-2 and A549 cells, viral replication assay\",\n      \"journal\": \"Virus research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function and loss-of-function both performed, single lab, clear phenotypic readout\",\n      \"pmids\": [\"26277777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"RARRES2 overexpression in adrenocortical carcinoma (ACC) cell lines promoted β-catenin phosphorylation and degradation (inhibiting Wnt/β-catenin pathway) and inhibited p38 MAPK phosphorylation, reducing cell proliferation, invasion, and tumor growth in vivo in immunodeficient mouse xenograft models; this tumor-suppressive effect was immune-independent, as minimal CMKLR1 expression was detected and exogenous RARRES2 treatment had no phenotypic effect.\",\n      \"method\": \"RARRES2 overexpression in ACC cell lines, Western blotting for β-catenin phosphorylation/degradation and p38 phosphorylation, in vitro proliferation/invasion assays, in vivo xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (in vitro and in vivo), defined molecular mechanism, single lab\",\n      \"pmids\": [\"28114280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Reduced RARRES2 expression in brain-metastatic TNBC cells increased glycerophospholipid levels and decreased triacylglycerols via regulation of the PTEN-mTOR-SREBP1 signaling pathway, promoting survival in the brain microenvironment; RARRES2 deficiency thus promotes breast cancer brain metastasis through lipid metabolic reprogramming.\",\n      \"method\": \"In vitro and in vivo studies with RARRES2 manipulation, multi-omics approaches, lipidomics, pathway analysis of PTEN-mTOR-SREBP1\",\n      \"journal\": \"Military Medical Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics and lipidomics combined with in vivo models, single lab\",\n      \"pmids\": [\"37491281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"RARRES2 promotes HSPG2 expression in keloid fibroblasts by phosphorylating STAT3, which binds to the HSPG2 promoter; the RARRES2-STAT3-HSPG2 axis drives pro-scarring effects in primary fibroblasts and animal models.\",\n      \"method\": \"Mendelian randomization and multiomics, ChIP or promoter binding assay (p-STAT3 on HSPG2 promoter), RARRES2 manipulation in primary fibroblasts and animal models\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter binding and functional rescue in primary cells and animal model, single lab, not yet widely replicated\",\n      \"pmids\": [\"42170108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In osteosarcoma, macrophage-secreted IGF-1 promotes RARRES2-mediated stemness maintenance in osteosarcoma stem cells (OSCs), establishing an IGF-RARRES2 axis in intercellular communication between OSCs and tumor-associated macrophages.\",\n      \"method\": \"Single-cell transcriptomics, cell communication analysis, in vitro validation with IGF-1 treatment and RARRES2 manipulation\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, mechanistic follow-up limited in abstract, primarily computational with limited in vitro validation described\",\n      \"pmids\": [\"38280909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"During liver fibrosis regression in a TAA-induced mouse model, pericentral hepatocytes secrete Rarres2 to modulate hepatic stellate cell (HSC) function, suggesting a paracrine role for RARRES2 in fibrosis resolution.\",\n      \"method\": \"Single-cell fixed RNA profiling (FLEX) of TAA-induced mouse liver cirrhosis model with and without recovery phase; NicheNet intercellular communication analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single-cell transcriptomics and computational inference, limited direct functional validation of RARRES2 specifically\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"RARRES2 encodes chemerin, a secreted protein that undergoes C-terminal proteolytic processing from a 163 amino acid prepropeptide to generate bioactive forms that act as the endogenous ligand for the GPCR ChemR23/CMKLR1; its transcription is induced by RAR-selective retinoids in 3D skin tissue; signaling through CMKLR1 inhibits granulosa cell steroidogenesis and MAPK1/3 phosphorylation; in cancer cells, RARRES2 can act cell-autonomously (independent of CMKLR1) to suppress Wnt/β-catenin and p38 MAPK signaling, regulate PTEN-mTOR-SREBP1-dependent lipid metabolism, and activate a STAT3-HSPG2 pro-fibrotic axis in fibroblasts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RARRES2 encodes chemerin, a secreted protein originally identified as a retinoid-responsive transcript whose induction requires the 3D tissue architecture of keratinocytes and fibroblasts and is driven specifically by RAR-selective retinoids [#0]. The prepropeptide undergoes C-terminal proteolytic processing to generate bioactive forms — circulating species corresponding to residues ~21–154/155/156 of the 163-residue precursor — that serve as the endogenous ligand for the orphan GPCR ChemR23/CMKLR1 [#1, #2]. Through CMKLR1, chemerin acts as a negative regulator of ovarian steroidogenesis, suppressing progesterone and estradiol output, lowering STAR, CYP19A1 and HMGCR levels, inhibiting MAPK3/MAPK1 phosphorylation, and arresting oocyte maturation, with all effects blocked by CMKLR1 antagonism [#3]. Beyond classical ligand–receptor signaling, RARRES2 also exerts cell-autonomous, CMKLR1-independent functions in cancer: it promotes β-catenin phosphorylation/degradation and inhibits p38 MAPK to suppress adrenocortical carcinoma growth [#5], and its loss reprograms lipid metabolism through the PTEN-mTOR-SREBP1 axis to favor breast cancer brain metastasis [#6]. In fibroblasts, RARRES2 drives a pro-fibrotic program by phosphorylating STAT3, which binds the HSPG2 promoter to induce HSPG2 expression [#7]. RARRES2 has additionally been characterized as a host factor supporting respiratory syncytial virus replication [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established RARRES2 (TIG2) as a retinoid-inducible gene and defined an unusual requirement for 3D tissue context, distinguishing it from simple monolayer-inducible retinoid targets.\",\n      \"evidence\": \"Subtraction hybridization and Northern blot in skin raft cultures with RAR- vs RXR-selective retinoid controls\",\n      \"pmids\": [\"9204961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the protein product's function or whether it is secreted\", \"Mechanism of the 3D-dependence of induction not resolved\", \"No receptor or downstream pathway identified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved the function of the RARRES2 product by identifying chemerin as the endogenous ligand for the orphan GPCR ChemR23/CMKLR1 and defining the bioactive circulating species.\",\n      \"evidence\": \"Reverse pharmacology screening of a human hemofiltrate peptide library with receptor binding/activation\",\n      \"pmids\": [\"14675762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the protease(s) generating the bioactive form\", \"Downstream signaling consequences of CMKLR1 activation not characterized here\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Confirmed that C-terminal proteolytic processing of the precursor generates the bioactive chemerin forms, defining the precise residue boundaries.\",\n      \"evidence\": \"Heparin-affinity chromatography, RP-HPLC, Edman sequencing and MALDI-TOF MS of the hamster ortholog\",\n      \"pmids\": [\"15522723\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Performed in hamster ortholog rather than human\", \"Identity of the activating proteases not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrated a receptor-dependent physiological role: chemerin signals through CMKLR1 to suppress ovarian steroidogenesis and MAPK1/3 activation.\",\n      \"evidence\": \"Recombinant chemerin on bovine granulosa cells and cumulus-oocyte complexes with anti-CMKLR1 blockade, steroid assays and Western blot\",\n      \"pmids\": [\"24671882\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"G-protein coupling and proximal signaling steps downstream of CMKLR1 not dissected\", \"Validated in bovine cells; human in vivo relevance not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified an unexpected role for RARRES2 as a host factor supporting RSV replication, separate from its endocrine ligand function.\",\n      \"evidence\": \"cDNA gain-of-function in MDCK cells and siRNA knockdown in HEp-2/A549 with viral replication readout\",\n      \"pmids\": [\"26277777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking RARRES2 to viral replication unknown\", \"Whether secreted or intracellular RARRES2 mediates the effect not determined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed a cell-autonomous, CMKLR1-independent tumor-suppressive function of RARRES2 acting on Wnt/β-catenin and p38 MAPK.\",\n      \"evidence\": \"RARRES2 overexpression in adrenocortical carcinoma lines with Western blot, in vitro proliferation/invasion assays and xenografts\",\n      \"pmids\": [\"28114280\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How intracellular RARRES2 engages β-catenin and p38 pathways mechanistically is unresolved\", \"Generalizability beyond adrenocortical carcinoma not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked RARRES2 loss to lipid metabolic reprogramming via PTEN-mTOR-SREBP1, promoting breast cancer brain metastasis.\",\n      \"evidence\": \"RARRES2 manipulation with multi-omics and lipidomics in TNBC models in vitro and in vivo\",\n      \"pmids\": [\"37491281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical link between RARRES2 and PTEN-mTOR-SREBP1 not established\", \"Single lab, single tumor type\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed RARRES2 in an intercellular IGF-1 axis maintaining osteosarcoma stem cell stemness.\",\n      \"evidence\": \"Single-cell transcriptomics and cell communication analysis with IGF-1 treatment and RARRES2 manipulation\",\n      \"pmids\": [\"38280909\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Primarily computational with limited in vitro validation\", \"Mechanism by which RARRES2 maintains stemness undefined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a RARRES2-STAT3-HSPG2 transcriptional axis driving fibroblast pro-scarring activity.\",\n      \"evidence\": \"Mendelian randomization, multiomics, p-STAT3 promoter binding on HSPG2, and RARRES2 manipulation in primary fibroblasts and animal models\",\n      \"pmids\": [\"42170108\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How RARRES2 triggers STAT3 phosphorylation is not resolved\", \"Not yet independently replicated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Proposed a paracrine role for hepatocyte-secreted Rarres2 in modulating hepatic stellate cells during fibrosis regression.\",\n      \"evidence\": \"Single-cell RNA profiling of TAA-induced mouse liver cirrhosis with NicheNet inference (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Computational inference with limited direct functional validation\", \"Receptor and signaling pathway on stellate cells not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how RARRES2 switches between extracellular CMKLR1-dependent ligand signaling and cell-autonomous intracellular functions, and what proteases and cell-context cues govern this dichotomy.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified mechanism reconciling secreted-ligand and cell-autonomous roles\", \"Activating proteases not mapped across tissues\", \"Structural basis of intracellular signaling functions unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CMKLR1\",\n      \"STAT3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}