{"gene":"MSMP","run_date":"2026-06-10T02:59:51","timeline":{"discoveries":[{"year":2019,"finding":"PSMP/MSMP signals through its receptor CCR2 to promote hepatic fibrosis: PSMP deficiency in knockout mice markedly reduced CCl4-induced macrophage/CCR2+ monocyte infiltration into liver, proinflammatory cytokines, and fibrosis; AAV8-mediated re-expression of human PSMP in Psmp-/- mice restored liver injury and fibrosis in a CCR2-dependent manner. At the cellular level, PSMP directly promoted M1 polarization of macrophages and activation of hepatic stellate cells (LX-2 cells). A PSMP-neutralizing antibody (3D5) prevented CCl4-induced liver injury and fibrosis in vivo.","method":"Psmp knockout mice, AAV8 PSMP re-expression rescue, in vitro macrophage polarization and stellate cell activation assays, neutralizing antibody treatment in three murine fibrosis models","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic rescue (KO + AAV re-expression), multiple orthogonal in vitro and in vivo methods across three disease models, CCR2-dependence confirmed by AAV rescue experiment","pmids":["31813573"],"is_preprint":false},{"year":2017,"finding":"PSMP/MSMP acts as a CCR2 ligand that chemo-attracts Ly6C-hi monocytes in a CCR2-dependent manner, driving monocyte/macrophage-dependent colitis; PSMP is induced in colonic epithelial cells by LPS and muramyl dipeptide, is upregulated before IL-6/TNF-α/CCL2 in DSS colitis, and its overexpression in colon aggravated DSS-induced colitis while a PSMP-neutralizing antibody reduced macrophage infiltration and attenuated colitis. PSMP also promoted M1 macrophages to produce CCL2.","method":"In situ chemotaxis assay, adoptive transfer assay, PSMP overexpression in mouse colon, neutralizing antibody treatment, DSS-induced colitis model","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — CCR2-dependence confirmed by in situ chemotaxis and adoptive transfer, gain-of-function and antibody-blockade approaches in vivo, multiple orthogonal methods","pmids":["28698550"],"is_preprint":false},{"year":2017,"finding":"MSMP is secreted by cancer cells under hypoxia (via decreased CTCF recruitment to the MSMP enhancer due to histone acetylation) and acts on endothelial cells to promote tube formation by triggering MAPK signaling, thereby mediating resistance to anti-VEGF therapy; MSMP siRNA delivered via DOPC nanoliposomes restored tumor sensitivity to anti-VEGF therapy in vivo.","method":"Genomic analysis of anti-VEGF-resistant tumors, hypoxia-induced secretion assays, CTCF ChIP, in vitro endothelial tube formation assay, siRNA knockdown in vivo with DOPC nanoliposomes, serum MSMP measurement in bevacizumab-treated patients","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional in vitro and in vivo rescue with siRNA, CTCF ChIP for mechanism, single lab with multiple orthogonal methods but no receptor identification for endothelial MAPK signaling","pmids":["29059175"],"is_preprint":false}],"current_model":"MSMP/PSMP is a secreted chemokine/microprotein that binds CCR2 on monocytes/macrophages to drive their recruitment and M1 polarization, promoting inflammatory tissue damage in colitis and liver fibrosis; it is also induced by hypoxia in cancer cells and activates MAPK signaling in endothelial cells to stimulate angiogenesis and confer resistance to anti-VEGF therapy."},"narrative":{"mechanistic_narrative":"MSMP (PSMP) is a secreted microprotein that functions as a chemokine-like ligand for the receptor CCR2, coupling epithelial damage signals to monocyte/macrophage recruitment and inflammatory tissue injury [PMID:31813573, PMID:28698550]. In intestinal and hepatic disease, MSMP is induced in epithelial cells by inflammatory stimuli such as LPS and muramyl dipeptide, and acts through CCR2 to chemo-attract Ly6C-hi inflammatory monocytes, drive M1 macrophage polarization, and amplify proinflammatory cytokine output; in the liver this CCR2-dependent macrophage influx further activates hepatic stellate cells to produce fibrosis, and PSMP neutralization or genetic deletion blunts colitis and CCl4-induced liver injury [PMID:31813573, PMID:28698550]. Independently, MSMP is secreted by cancer cells under hypoxia—through loss of CTCF binding at its enhancer following histone acetylation—and acts on endothelial cells to trigger MAPK signaling and tube formation, mediating resistance to anti-VEGF therapy [PMID:29059175]. The receptor mediating MSMP's endothelial MAPK signaling has not been identified in the available corpus.","teleology":[{"year":2017,"claim":"Established MSMP/PSMP as a functional CCR2 ligand whose epithelial induction drives monocyte-dependent inflammation, defining its core chemoattractant role.","evidence":"In situ chemotaxis and adoptive transfer in a DSS colitis model, plus colonic overexpression and neutralizing antibody blockade","pmids":["28698550"],"confidence":"High","gaps":["Did not resolve structural basis of MSMP-CCR2 binding","Did not establish whether MSMP acts in human inflammatory disease"]},{"year":2017,"claim":"Identified a separate, hypoxia-driven secretion of MSMP by tumor cells that promotes angiogenesis and anti-VEGF resistance, expanding its role beyond immune chemoattraction.","evidence":"Genomic analysis of anti-VEGF-resistant tumors, CTCF ChIP, endothelial tube-formation assays, and in vivo siRNA knockdown via DOPC nanoliposomes","pmids":["29059175"],"confidence":"Medium","gaps":["The endothelial receptor mediating MSMP-induced MAPK signaling was not identified","Whether CCR2 is involved in the endothelial/angiogenic effect was not tested"]},{"year":2019,"claim":"Demonstrated through reciprocal genetic rescue that MSMP drives hepatic fibrosis via CCR2-dependent macrophage recruitment and stellate cell activation, solidifying its causal role in fibrotic disease.","evidence":"Psmp knockout mice with AAV8 human PSMP re-expression rescue, M1 polarization and LX-2 stellate cell assays, and neutralizing antibody (3D5) treatment across murine fibrosis models","pmids":["31813573"],"confidence":"High","gaps":["Did not determine whether stellate cell activation is direct or secondary to macrophage recruitment","No structural characterization of the MSMP-CCR2 interaction"]},{"year":null,"claim":"The receptor and signaling pathway mediating MSMP's CCR2-independent endothelial/angiogenic activity remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Endothelial MSMP receptor unknown","Relationship between the CCR2-dependent inflammatory axis and the angiogenic axis unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1,2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]}],"complexes":[],"partners":["CCR2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q1L6U9","full_name":"Prostate-associated microseminoprotein","aliases":["PC3-secreted microprotein"],"length_aa":139,"mass_kda":15.0,"function":"Acts as a ligand for C-C chemokine receptor CCR2 (PubMed:24442440). Signals through binding and activation of CCR2 and induces a strong chemotactic response and mobilization of intracellular calcium ions (PubMed:24442440). Exhibits a chemotactic activity for monocytes and lymphocytes but not neutrophils (PubMed:24442440)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q1L6U9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MSMP","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MSMP","total_profiled":1310},"omim":[{"mim_id":"612191","title":"MICROSEMINOPROTEIN, PROSTATE-ASSOCIATED; MSMP","url":"https://www.omim.org/entry/612191"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"choroid plexus","ntpm":3.1},{"tissue":"pituitary gland","ntpm":1.3},{"tissue":"placenta","ntpm":1.1}],"url":"https://www.proteinatlas.org/search/MSMP"},"hgnc":{"alias_symbol":["PC-3","PSMP"],"prev_symbol":[]},"alphafold":{"accession":"Q1L6U9","domains":[{"cath_id":"2.10.70.10","chopping":"37-78","consensus_level":"high","plddt":95.445,"start":37,"end":78},{"cath_id":"-","chopping":"82-117","consensus_level":"medium","plddt":86.8908,"start":82,"end":117}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q1L6U9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q1L6U9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q1L6U9-F1-predicted_aligned_error_v6.png","plddt_mean":77.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MSMP","jax_strain_url":"https://www.jax.org/strain/search?query=MSMP"},"sequence":{"accession":"Q1L6U9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q1L6U9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q1L6U9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q1L6U9"}},"corpus_meta":[{"pmid":"447482","id":"PMC_447482","title":"Establishment 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biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29236328","citation_count":29,"is_preprint":false},{"pmid":"27107935","id":"PMC_27107935","title":"Estrogen receptor beta (ERβ) mediates expression of β-catenin and proliferation in prostate cancer cell line PC-3.","date":"2016","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/27107935","citation_count":28,"is_preprint":false},{"pmid":"19885607","id":"PMC_19885607","title":"Down-regulation of Egr-1 by siRNA inhibits growth of human prostate carcinoma cell line PC-3.","date":"2009","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/19885607","citation_count":27,"is_preprint":false},{"pmid":"19415685","id":"PMC_19415685","title":"FGF-8b induces growth and rich vascularization in an orthotopic PC-3 model of prostate cancer.","date":"2009","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19415685","citation_count":26,"is_preprint":false},{"pmid":"23426586","id":"PMC_23426586","title":"Isolation and enrichment of PC-3 prostate cancer stem-like cells using MACS and serum-free medium.","date":"2012","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/23426586","citation_count":25,"is_preprint":false},{"pmid":"12949936","id":"PMC_12949936","title":"TR2 orphan receptor functions as negative modulator for androgen receptor in prostate cancer cells PC-3.","date":"2003","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/12949936","citation_count":24,"is_preprint":false},{"pmid":"10861858","id":"PMC_10861858","title":"Secretory products from PC-3 and MCF-7 tumor cell lines upregulate osteopontin in MC3T3-E1 cells.","date":"2000","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10861858","citation_count":23,"is_preprint":false},{"pmid":"17046135","id":"PMC_17046135","title":"Effects of interactions of EGCG and Cd(2+) on the growth of PC-3 cells and their mechanisms.","date":"2006","source":"Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/17046135","citation_count":23,"is_preprint":false},{"pmid":"30797819","id":"PMC_30797819","title":"Serum promotes vasculogenic mimicry through the EphA2/VE-cadherin/AKT pathway in PC-3 human prostate cancer cells.","date":"2019","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30797819","citation_count":22,"is_preprint":false},{"pmid":"18594829","id":"PMC_18594829","title":"Docetaxel and bortezomib downregulate Bcl-2 and sensitize PC-3-Bcl-2 expressing prostate cancer cells to irradiation.","date":"2008","source":"World journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/18594829","citation_count":22,"is_preprint":false},{"pmid":"23476651","id":"PMC_23476651","title":"Zinc Protoporphyrin Upregulates Heme Oxygenase-1 in PC-3 Cells via the Stress Response Pathway.","date":"2013","source":"International journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/23476651","citation_count":22,"is_preprint":false},{"pmid":"28698550","id":"PMC_28698550","title":"The PSMP-CCR2 interactions trigger monocyte/macrophage-dependent colitis.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28698550","citation_count":21,"is_preprint":false},{"pmid":"18304460","id":"PMC_18304460","title":"Expression of nucleostemin in prostate cancer and its effect on the proliferation of PC-3 cells.","date":"2008","source":"Chinese medical journal","url":"https://pubmed.ncbi.nlm.nih.gov/18304460","citation_count":21,"is_preprint":false},{"pmid":"36139362","id":"PMC_36139362","title":"SPHK/HIF-1α Signaling Pathway Has a Critical Role in Chrysin-Induced Anticancer Activity in Hypoxia-Induced PC-3 Cells.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36139362","citation_count":20,"is_preprint":false},{"pmid":"34474113","id":"PMC_34474113","title":"Pro-angiogenic effect of PC-3 exosomes in endothelial cells in vitro.","date":"2021","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/34474113","citation_count":20,"is_preprint":false},{"pmid":"36674697","id":"PMC_36674697","title":"Inhibition of ANO1 by Cis- and Trans-Resveratrol and Their Anticancer Activity in Human Prostate Cancer PC-3 Cells.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36674697","citation_count":20,"is_preprint":false},{"pmid":"31217781","id":"PMC_31217781","title":"MCT4 promotes cell proliferation and invasion of castration-resistant prostate cancer PC-3 cell line.","date":"2019","source":"EXCLI journal","url":"https://pubmed.ncbi.nlm.nih.gov/31217781","citation_count":19,"is_preprint":false},{"pmid":"31023247","id":"PMC_31023247","title":"Salinomycin triggers endoplasmic reticulum stress through ATP2A3 upregulation in PC-3 cells.","date":"2019","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31023247","citation_count":19,"is_preprint":false},{"pmid":"33528589","id":"PMC_33528589","title":"5-HT7 receptors as a new target for prostate cancer physiopathology and treatment: an experimental study on PC-3 cells and FFPE tissues.","date":"2021","source":"Naunyn-Schmiedeberg's archives of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/33528589","citation_count":19,"is_preprint":false},{"pmid":"36365221","id":"PMC_36365221","title":"Quality by Design Based Formulation of Xanthohumol Loaded Solid Lipid Nanoparticles with Improved Bioavailability and Anticancer Effect against PC-3 Cells.","date":"2022","source":"Pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/36365221","citation_count":19,"is_preprint":false},{"pmid":"30609788","id":"PMC_30609788","title":"Extracellular Electrophysiology in the Prostate Cancer Cell Model PC-3.","date":"2019","source":"Sensors (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/30609788","citation_count":18,"is_preprint":false},{"pmid":"19530225","id":"PMC_19530225","title":"Changes in expression of cell-cycle-related genes in PC-3 prostate cancer cells caused by ovine uterine serpin.","date":"2009","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19530225","citation_count":18,"is_preprint":false},{"pmid":"16886623","id":"PMC_16886623","title":"Inhibition of caveolin-1 expression by incadronate in PC-3 prostate cells.","date":"2006","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/16886623","citation_count":18,"is_preprint":false},{"pmid":"20446922","id":"PMC_20446922","title":"Inhibition of GGTase-I and FTase disrupts cytoskeletal organization of human PC-3 prostate cancer cells.","date":"2010","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/20446922","citation_count":18,"is_preprint":false},{"pmid":"16752910","id":"PMC_16752910","title":"Acetylation and phosphorylation of high-mobility group A1 proteins in PC-3 human tumor cells.","date":"2006","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16752910","citation_count":18,"is_preprint":false},{"pmid":"30808588","id":"PMC_30808588","title":"Calcilytics inhibit the proliferation and migration of human prostate cancer PC-3 cells.","date":"2019","source":"Journal of pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30808588","citation_count":17,"is_preprint":false},{"pmid":"24951955","id":"PMC_24951955","title":"HoxA10 induces proliferation in human prostate carcinoma PC-3 cell line.","date":"2014","source":"Cell biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/24951955","citation_count":17,"is_preprint":false},{"pmid":"26028116","id":"PMC_26028116","title":"Inhibition of Transient Receptor Potential Melastain 7 Enhances Apoptosis Induced by TRAIL in PC-3 cells.","date":"2015","source":"Asian Pacific journal of cancer prevention : APJCP","url":"https://pubmed.ncbi.nlm.nih.gov/26028116","citation_count":17,"is_preprint":false},{"pmid":"32883962","id":"PMC_32883962","title":"MicroRNA-107 enhances radiosensitivity by suppressing granulin in PC-3 prostate cancer cells.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32883962","citation_count":17,"is_preprint":false},{"pmid":"17217378","id":"PMC_17217378","title":"Expression profiling of PC-3 cell line variants and comparison of MIC-1 transcript levels in benign and malignant prostate.","date":"2007","source":"European journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/17217378","citation_count":17,"is_preprint":false},{"pmid":"32841893","id":"PMC_32841893","title":"Induction of proliferative and mutagenic activity by benzo(a)pyrene in PC-3 cells via JAK2/STAT3 pathway.","date":"2020","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/32841893","citation_count":16,"is_preprint":false},{"pmid":"21640705","id":"PMC_21640705","title":"Ribonucleotide reductase subunit p53R2 regulates mitochondria homeostasis and function in KB and PC-3 cancer cells.","date":"2011","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/21640705","citation_count":16,"is_preprint":false},{"pmid":"32698736","id":"PMC_32698736","title":"Apoptosis-Inducing Activity and Antiproliferative Effect of Gossypin on PC-3 Prostate Cancer Cells.","date":"2021","source":"Anti-cancer agents in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32698736","citation_count":15,"is_preprint":false},{"pmid":"24293374","id":"PMC_24293374","title":"Effect of cyclin G2 on proliferative ability of prostate cancer PC-3 cell.","date":"2013","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24293374","citation_count":15,"is_preprint":false},{"pmid":"32851890","id":"PMC_32851890","title":"Investigating the Impact of OGT Inhibition on Doxorubicin- and Docetaxel-Induced Cytotoxicity in PC-3 and WPMY-1 Cells.","date":"2020","source":"International journal of toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/32851890","citation_count":15,"is_preprint":false},{"pmid":"12767274","id":"PMC_12767274","title":"Secretion of endogenous kallikreins 2 and 3 by androgen receptor-transfected PC-3 prostate cancer cells.","date":"2003","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12767274","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52159,"output_tokens":1321,"usd":0.088146,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7683,"output_tokens":1629,"usd":0.03957,"stage2_stop_reason":"end_turn"},"total_usd":0.127716,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about the canonical MSMP/PSMP protein (PC3-secreted microprotein/microseminoprotein), not the PC-3 prostate cancer cell line (which is a different \"PC-3\" - an alias collision for most of these papers).\n\nThe relevant papers about MSMP/PSMP as a protein are:\n- PMID 31813573 (paper [19]): PSMP/MSMP promotes hepatic fibrosis through CCR2\n- PMID 28698550 (paper [76]): PSMP-CCR2 interactions trigger monocyte/macrophage-dependent colitis\n- PMID 29059175 (paper [35]): Induction of anti-VEGF therapy resistance by upregulated expression of MSMP\n\nAll other papers describe the PC-3 prostate cancer cell line, not the MSMP/PSMP protein itself.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"PSMP/MSMP signals through its receptor CCR2 to promote hepatic fibrosis: PSMP deficiency in knockout mice markedly reduced CCl4-induced macrophage/CCR2+ monocyte infiltration into liver, proinflammatory cytokines, and fibrosis; AAV8-mediated re-expression of human PSMP in Psmp-/- mice restored liver injury and fibrosis in a CCR2-dependent manner. At the cellular level, PSMP directly promoted M1 polarization of macrophages and activation of hepatic stellate cells (LX-2 cells). A PSMP-neutralizing antibody (3D5) prevented CCl4-induced liver injury and fibrosis in vivo.\",\n      \"method\": \"Psmp knockout mice, AAV8 PSMP re-expression rescue, in vitro macrophage polarization and stellate cell activation assays, neutralizing antibody treatment in three murine fibrosis models\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic rescue (KO + AAV re-expression), multiple orthogonal in vitro and in vivo methods across three disease models, CCR2-dependence confirmed by AAV rescue experiment\",\n      \"pmids\": [\"31813573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PSMP/MSMP acts as a CCR2 ligand that chemo-attracts Ly6C-hi monocytes in a CCR2-dependent manner, driving monocyte/macrophage-dependent colitis; PSMP is induced in colonic epithelial cells by LPS and muramyl dipeptide, is upregulated before IL-6/TNF-α/CCL2 in DSS colitis, and its overexpression in colon aggravated DSS-induced colitis while a PSMP-neutralizing antibody reduced macrophage infiltration and attenuated colitis. PSMP also promoted M1 macrophages to produce CCL2.\",\n      \"method\": \"In situ chemotaxis assay, adoptive transfer assay, PSMP overexpression in mouse colon, neutralizing antibody treatment, DSS-induced colitis model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CCR2-dependence confirmed by in situ chemotaxis and adoptive transfer, gain-of-function and antibody-blockade approaches in vivo, multiple orthogonal methods\",\n      \"pmids\": [\"28698550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MSMP is secreted by cancer cells under hypoxia (via decreased CTCF recruitment to the MSMP enhancer due to histone acetylation) and acts on endothelial cells to promote tube formation by triggering MAPK signaling, thereby mediating resistance to anti-VEGF therapy; MSMP siRNA delivered via DOPC nanoliposomes restored tumor sensitivity to anti-VEGF therapy in vivo.\",\n      \"method\": \"Genomic analysis of anti-VEGF-resistant tumors, hypoxia-induced secretion assays, CTCF ChIP, in vitro endothelial tube formation assay, siRNA knockdown in vivo with DOPC nanoliposomes, serum MSMP measurement in bevacizumab-treated patients\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional in vitro and in vivo rescue with siRNA, CTCF ChIP for mechanism, single lab with multiple orthogonal methods but no receptor identification for endothelial MAPK signaling\",\n      \"pmids\": [\"29059175\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MSMP/PSMP is a secreted chemokine/microprotein that binds CCR2 on monocytes/macrophages to drive their recruitment and M1 polarization, promoting inflammatory tissue damage in colitis and liver fibrosis; it is also induced by hypoxia in cancer cells and activates MAPK signaling in endothelial cells to stimulate angiogenesis and confer resistance to anti-VEGF therapy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MSMP (PSMP) is a secreted microprotein that functions as a chemokine-like ligand for the receptor CCR2, coupling epithelial damage signals to monocyte/macrophage recruitment and inflammatory tissue injury [#0, #1]. In intestinal and hepatic disease, MSMP is induced in epithelial cells by inflammatory stimuli such as LPS and muramyl dipeptide, and acts through CCR2 to chemo-attract Ly6C-hi inflammatory monocytes, drive M1 macrophage polarization, and amplify proinflammatory cytokine output; in the liver this CCR2-dependent macrophage influx further activates hepatic stellate cells to produce fibrosis, and PSMP neutralization or genetic deletion blunts colitis and CCl4-induced liver injury [#0, #1]. Independently, MSMP is secreted by cancer cells under hypoxia—through loss of CTCF binding at its enhancer following histone acetylation—and acts on endothelial cells to trigger MAPK signaling and tube formation, mediating resistance to anti-VEGF therapy [#2]. The receptor mediating MSMP's endothelial MAPK signaling has not been identified in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established MSMP/PSMP as a functional CCR2 ligand whose epithelial induction drives monocyte-dependent inflammation, defining its core chemoattractant role.\",\n      \"evidence\": \"In situ chemotaxis and adoptive transfer in a DSS colitis model, plus colonic overexpression and neutralizing antibody blockade\",\n      \"pmids\": [\"28698550\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve structural basis of MSMP-CCR2 binding\", \"Did not establish whether MSMP acts in human inflammatory disease\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified a separate, hypoxia-driven secretion of MSMP by tumor cells that promotes angiogenesis and anti-VEGF resistance, expanding its role beyond immune chemoattraction.\",\n      \"evidence\": \"Genomic analysis of anti-VEGF-resistant tumors, CTCF ChIP, endothelial tube-formation assays, and in vivo siRNA knockdown via DOPC nanoliposomes\",\n      \"pmids\": [\"29059175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The endothelial receptor mediating MSMP-induced MAPK signaling was not identified\", \"Whether CCR2 is involved in the endothelial/angiogenic effect was not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated through reciprocal genetic rescue that MSMP drives hepatic fibrosis via CCR2-dependent macrophage recruitment and stellate cell activation, solidifying its causal role in fibrotic disease.\",\n      \"evidence\": \"Psmp knockout mice with AAV8 human PSMP re-expression rescue, M1 polarization and LX-2 stellate cell assays, and neutralizing antibody (3D5) treatment across murine fibrosis models\",\n      \"pmids\": [\"31813573\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not determine whether stellate cell activation is direct or secondary to macrophage recruitment\", \"No structural characterization of the MSMP-CCR2 interaction\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The receptor and signaling pathway mediating MSMP's CCR2-independent endothelial/angiogenic activity remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endothelial MSMP receptor unknown\", \"Relationship between the CCR2-dependent inflammatory axis and the angiogenic axis unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CCR2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}