{"gene":"MSMB","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2007,"finding":"The MSMB gene (encoding PSP94) is epigenetically silenced in androgen-refractory prostate cancer cells by EZH2-mediated trimethylation of histone H3 on Lys27 (H3K27me3), as well as by histone H3K9 hypoacetylation and CpG island hypermethylation in the MSMB promoter. RNAi knockdown of EZH2 reduced H3K27 trimethylation and increased MSMB expression, while EZH2 overexpression decreased MSMB expression. Chromatin immunoprecipitation confirmed EZH2 association with the MSMB gene.","method":"ChIP, RNAi knockdown, overexpression, bisulfite sequencing","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, RNAi, overexpression, bisulfite sequencing) in a single rigorous study","pmids":["17237810"],"is_preprint":false},{"year":2009,"finding":"The rs10993994 SNP, located 57 bp upstream of the first exon of MSMB, regulates MSMB promoter activity; the C allele preferentially binds the CREB transcription factor (shown by EMSA), and cell lines with CC or CT genotypes exhibit higher MSMB expression than TT genotype lines. Luciferase reporter assays confirmed the T variant reduces transcriptional activity.","method":"Luciferase reporter assay, EMSA, genotype-expression analysis in tumor cell lines","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — two orthogonal functional assays (luciferase + EMSA) with genotype-stratified cell line data","pmids":["19383797"],"is_preprint":false},{"year":2010,"finding":"Suppression of MSMB expression promotes anchorage-independent growth of prostate epithelial cells, establishing a tumor-suppressive role for MSMB/PSP94 in prostate-specific cellular context. The rs10993994 risk allele is associated with decreased expression of MSMB isoforms in both histologically normal and malignant prostate tissue.","method":"Loss-of-function (MSMB suppression) with anchorage-independent growth assay; genotype-expression correlation in prostate tissue cohort","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2/3 — functional loss-of-function phenotype in prostate cells, but tissue expression data is correlative","pmids":["21085629"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of human PSP94 (MSMB gene product) at 2.3 Å resolution reveals that the N- and C-termini are held in close proximity by a hydrogen bond between the first and last beta-strands, forming a straight edge. Two monomers associate antiparallel via this edge to form a homodimer. Dimers dissociate to monomers at acidic pH. The same edge is proposed to mediate binding to cysteine-rich secretory proteins (e.g., CRISP-3) and IgG.","method":"X-ray crystallography, biochemical dissociation assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure at 2.3 Å with biochemical validation of dimer formation and pH-dependent dissociation","pmids":["20184897"],"is_preprint":false},{"year":1987,"finding":"Beta-microseminoprotein (beta-MSP/PSP94), despite near-identical sequence to so-called 'beta-inhibin', does not inhibit FSH secretion from rat pituitary cells in culture, demonstrating that PSP94 lacks inhibin activity.","method":"In vitro FSH secretion bioassay using rat pituitary cell culture","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 — direct in vitro functional bioassay with positive controls","pmids":["3109514"],"is_preprint":false},{"year":1988,"finding":"PSP94 (MSMB gene product) is synthesized in the epithelial cells of the prostate gland, as shown by co-localization of immunoreactive PSP94 protein and its mRNA in prostatic epithelial cells by immunohistochemistry and in situ hybridization.","method":"Immunohistochemistry, in situ hybridization histochemistry","journal":"Journal of andrology","confidence":"Medium","confidence_rationale":"Tier 3 — direct localization by two complementary methods but no functional consequence tested","pmids":["3182395"],"is_preprint":false},{"year":1995,"finding":"Alternative splicing of the MSMB/PSP94 mRNA produces a shorter isoform (PSP57) in which exon III is deleted, encoding a 57-amino acid protein with a novel basic C-terminus. PSP57 mRNA is detected in urogenital tissues and tumor cell lines but not breast or lung, and in prostate tumor cell lines it is aberrantly spliced and localizes to the nuclear fraction.","method":"RT-PCR, Southern blotting, cloning and sequencing, nuclear fractionation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — multiple molecular methods defining a novel splice isoform with distinct localization","pmids":["7566962"],"is_preprint":false},{"year":2012,"finding":"Promoter variants at the MSMB locus associated with prostate cancer regulate expression of full-length MSMB-NCOA4 fusion transcripts. The predominant fusion arises from splicing of MSMB 5'UTR and exons 1-2 to NCOA4 exons 2-10, producing a stable fusion protein containing essential NCOA4 domains. A core MSMB promoter element between -27 and -236 and a negative regulatory element immediately upstream of the start codon were mapped by deletion/luciferase assays.","method":"RT-PCR/sequencing of fusion transcripts, luciferase reporter deletion assays, computational analysis","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — fusion transcript characterized by sequencing and promoter functionally mapped by reporter assays","pmids":["22661295"],"is_preprint":false},{"year":2005,"finding":"PCK3145 (a synthetic peptide from PSP94/MSMB amino acids 31-45) inhibits MMP-9 secretion and triggers CD44 shedding from the cell surface of HT-1080 fibrosarcoma cells. This involves RhoA signaling and MT1-MMP-mediated CD44 ectodomain shedding, and inhibits cell adhesion to hyaluronic acid, laminin-1, and type-I collagen.","method":"Gelatin zymography, RT-PCR, flow cytometry, immunoblotting, cell adhesion assay","journal":"Clinical & experimental metastasis","confidence":"Medium","confidence_rationale":"Tier 2/3 — multiple molecular readouts from a single lab establishing mechanism of PSP94-derived peptide action","pmids":["16283486"],"is_preprint":false},{"year":2006,"finding":"The PCK3145 PSP94-derived peptide binds the HT-1080 cell surface through the 37-kDa laminin receptor precursor (37LRP), as demonstrated by far-Western ligand binding studies; overexpression of 37LRP increases PCK3145 binding. This cell surface binding triggers ERK phosphorylation and leads to downregulation of HuR protein (an mRNA stabilizer), resulting in MMP-9 mRNA destabilization and reduced MMP-9 secretion.","method":"Far-Western ligand binding, overexpression, flow cytometry, immunoblotting, gelatin zymography, MEK inhibitor experiment","journal":"Anti-cancer drugs","confidence":"Medium","confidence_rationale":"Tier 2/3 — binding partner identified by far-Western and overexpression with downstream signaling pathway delineated","pmids":["16550001"],"is_preprint":false},{"year":2010,"finding":"MSMB/PSP94 and its binding protein CRISP-3 individually inhibit prostate cancer cell growth in a cell-line-specific manner. PSP94 inhibits growth of CRISP-3-positive cell lines, while CRISP-3-mediated growth inhibition is independent of PSP94 presence, as determined by clonogenic survival assays with ectopic expression of each protein.","method":"Clonogenic survival assay, stable transfection, Western blot, immunofluorescence","journal":"Asian journal of andrology","confidence":"Medium","confidence_rationale":"Tier 2/3 — functional loss/gain-of-function with defined phenotypic readout in multiple cell lines","pmids":["20676114"],"is_preprint":false},{"year":2000,"finding":"PSP94 (MSMB gene product) mRNA and protein expression in rat lateral prostate is under androgen regulation: castration abolishes expression while testosterone replacement restores it. Expression is also induced by glucocorticoid (dexamethasone) and progestin (medroxyprogesterone acetate), but not by zinc, distinguishing it from probasin regulation.","method":"In situ hybridization, semiquantitative RT-PCR, Western blotting, hormone manipulation in castrated rats","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo hormonal manipulation with multiple readouts (RNA and protein) in a defined physiological model","pmids":["11108266"],"is_preprint":false}],"current_model":"MSMB encodes PSP94 (beta-microseminoprotein), a prostate epithelial secretory protein whose expression is regulated by androgens, the CREB transcription factor (via the rs10993994 promoter SNP), and epigenetic silencing by EZH2-mediated H3K27 trimethylation; structurally, PSP94 forms an antiparallel homodimer through its terminal beta-strand edge, which also mediates binding to CRISP family proteins, and PSP94 or its derived peptide PCK3145 suppresses tumor cell growth and MMP-9-dependent invasion via laminin receptor/ERK signaling and RhoA/MT1-MMP-mediated CD44 shedding."},"narrative":{"teleology":[{"year":1987,"claim":"Despite sequence similarity to 'beta-inhibin', PSP94 was shown to lack FSH-inhibiting activity, ruling out an endocrine role and redirecting investigation toward its prostatic function.","evidence":"In vitro FSH secretion bioassay using rat pituitary cell cultures with positive controls","pmids":["3109514"],"confidence":"Medium","gaps":["No alternative biological activity was identified at this stage","Only one endocrine endpoint tested"]},{"year":1988,"claim":"Demonstration that PSP94 mRNA and protein co-localize in prostatic epithelial cells established the prostate as the primary site of synthesis, framing MSMB as a prostate-specific secretory gene.","evidence":"Immunohistochemistry and in situ hybridization in human prostate tissue","pmids":["3182395"],"confidence":"Medium","gaps":["Mechanism of secretion not addressed","Expression in non-prostatic tissues not systematically surveyed"]},{"year":1995,"claim":"Discovery of an alternative splice isoform (PSP57) lacking exon III, with a novel basic C-terminus and nuclear localization in tumor cells, revealed MSMB generates functionally distinct isoforms with potentially different subcellular roles.","evidence":"RT-PCR, cloning/sequencing, and nuclear fractionation in urogenital tissues and tumor cell lines","pmids":["7566962"],"confidence":"Medium","gaps":["Function of PSP57 isoform not determined","Nuclear role remains uncharacterized","Only demonstrated in cell lines, not validated in vivo"]},{"year":2000,"claim":"In vivo hormonal manipulation established that PSP94 expression is androgen-dependent and also responsive to glucocorticoids and progestins, defining MSMB as a steroid-regulated gene.","evidence":"Castration/testosterone replacement in rats with RT-PCR, in situ hybridization, and Western blotting","pmids":["11108266"],"confidence":"Medium","gaps":["Direct hormone-responsive elements in the MSMB promoter not mapped","Relevance to human prostate hormone regulation assumed but not directly tested"]},{"year":2005,"claim":"A PSP94-derived peptide (PCK3145) was shown to inhibit MMP-9 secretion and trigger MT1-MMP/RhoA-dependent CD44 shedding, providing the first mechanistic link between PSP94 and suppression of cell invasion.","evidence":"Zymography, RT-PCR, flow cytometry, immunoblotting, and adhesion assays in HT-1080 cells","pmids":["16283486"],"confidence":"Medium","gaps":["Activity demonstrated with a synthetic peptide fragment, not full-length PSP94","Relevance to prostate cancer cells not shown","Mechanism of RhoA activation unknown"]},{"year":2006,"claim":"Identification of the 37-kDa laminin receptor precursor as the cell-surface receptor for PSP94-derived peptide, with downstream ERK activation and HuR-dependent MMP-9 mRNA destabilization, defined the signaling pathway mediating anti-invasive activity.","evidence":"Far-Western binding, 37LRP overexpression, MEK inhibitor experiments in HT-1080 cells","pmids":["16550001"],"confidence":"Medium","gaps":["Binding of full-length PSP94 to 37LRP not confirmed","Pathway not validated in prostate epithelial cells","Single far-Western approach for receptor identification"]},{"year":2007,"claim":"EZH2-mediated H3K27 trimethylation, combined with H3K9 hypoacetylation and CpG island hypermethylation, was identified as the mechanism of MSMB silencing in androgen-refractory prostate cancer, establishing epigenetic regulation as a key control layer.","evidence":"ChIP, EZH2 RNAi knockdown and overexpression, bisulfite sequencing in prostate cancer cell lines","pmids":["17237810"],"confidence":"High","gaps":["Whether epigenetic silencing is causally linked to disease progression not established","Relative contribution of H3K27me3 versus DNA methylation not dissected"]},{"year":2009,"claim":"The prostate cancer risk SNP rs10993994 was shown to directly modulate MSMB transcription via differential CREB binding, connecting a GWAS-identified genetic variant to a specific transcription factor mechanism.","evidence":"Luciferase reporter assays and EMSA in prostate cancer cell lines stratified by genotype","pmids":["19383797"],"confidence":"High","gaps":["ChIP confirmation of CREB occupancy at the endogenous locus not shown","Additional transcription factors at this site not excluded"]},{"year":2010,"claim":"Structural determination of PSP94 revealed a homodimer formed through antiparallel beta-strand edge interactions and identified this same interface as the binding site for CRISP family proteins, unifying oligomerization and partner recognition.","evidence":"X-ray crystallography at 2.3 Å resolution with biochemical pH-dependent dissociation assays","pmids":["20184897"],"confidence":"High","gaps":["No co-crystal structure of PSP94-CRISP-3 complex","Functional consequence of dimer versus monomer form unknown","IgG binding via same edge is inferred, not structurally proven"]},{"year":2010,"claim":"Functional evidence that MSMB suppression promotes anchorage-independent growth established a direct tumor-suppressive role, while PSP94 and CRISP-3 were shown to independently inhibit prostate cancer cell growth.","evidence":"Loss-of-function growth assays in prostate epithelial cells; clonogenic survival with ectopic PSP94/CRISP-3 expression","pmids":["21085629","20676114"],"confidence":"Medium","gaps":["Downstream pathway by which loss of PSP94 permits anchorage independence not identified","In vivo tumor suppression not demonstrated","PSP94-CRISP-3 functional interplay not mechanistically resolved"]},{"year":2012,"claim":"Discovery of MSMB-NCOA4 fusion transcripts regulated by the same promoter variants linked to prostate cancer risk expanded the functional output of the MSMB locus beyond PSP94 alone.","evidence":"RT-PCR/sequencing of fusion transcripts, luciferase promoter deletion mapping","pmids":["22661295"],"confidence":"Medium","gaps":["Biological function of the MSMB-NCOA4 fusion protein not tested","Protein-level expression and stability in vivo not confirmed","Whether fusion contributes to prostate cancer risk independently of PSP94 unknown"]},{"year":null,"claim":"The mechanism by which full-length secreted PSP94 exerts tumor-suppressive activity in vivo, the identity of its physiological receptor on prostate epithelial cells, and the functional significance of the PSP94-CRISP-3 interaction remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No in vivo knockout or transgenic tumor model published","Receptor for intact PSP94 on prostate cells not identified","Structural basis of CRISP-3 binding not determined at atomic resolution"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,8,9,10]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,5,8]}],"pathway":[],"complexes":[],"partners":["CRISP3","NCOA4","RPSA","EZH2","CREB1"],"other_free_text":[]},"mechanistic_narrative":"MSMB encodes PSP94 (beta-microseminoprotein), a prostate epithelial secretory protein that functions as a tumor suppressor by inhibiting anchorage-independent growth and suppressing MMP-9-dependent invasion through laminin receptor/ERK signaling and RhoA/MT1-MMP-mediated CD44 shedding [PMID:21085629, PMID:16283486, PMID:16550001]. PSP94 is synthesized in prostatic epithelial cells under androgen and steroid hormone regulation, and its expression is epigenetically silenced in androgen-refractory prostate cancer through EZH2-mediated H3K27 trimethylation and promoter CpG hypermethylation [PMID:3182395, PMID:11108266, PMID:17237810]. The crystal structure reveals a two-domain Greek-key fold in which terminal beta-strands form an antiparallel homodimer interface that also mediates binding to CRISP-3, with pH-dependent dissociation [PMID:20184897]. Transcriptional output is modulated by the prostate cancer risk SNP rs10993994, where the C allele preferentially binds CREB to drive higher expression, and the locus also generates MSMB-NCOA4 fusion transcripts whose expression is governed by the same promoter variants [PMID:19383797, PMID:22661295]."},"prefetch_data":{"uniprot":{"accession":"P08118","full_name":"Beta-microseminoprotein","aliases":["Immunoglobulin-binding factor","IGBF","PN44","Prostate secreted seminal plasma protein","Prostate secretory protein of 94 amino acids","PSP-94","PSP94","Seminal plasma beta-inhibin"],"length_aa":114,"mass_kda":12.9,"function":"","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P08118/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MSMB","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/MSMB","total_profiled":1310},"omim":[{"mim_id":"618062","title":"CYSTEINE-RICH SECRETORY PROTEIN 3; CRISP3","url":"https://www.omim.org/entry/618062"},{"mim_id":"612191","title":"MICROSEMINOPROTEIN, PROSTATE-ASSOCIATED; MSMP","url":"https://www.omim.org/entry/612191"},{"mim_id":"611928","title":"PROSTATE CANCER, HEREDITARY, 13; HPC13","url":"https://www.omim.org/entry/611928"},{"mim_id":"605097","title":"SOLUTE CARRIER FAMILY 45, MEMBER 3; SLC45A3","url":"https://www.omim.org/entry/605097"},{"mim_id":"605094","title":"STEAP2 METALLOREDUCTASE; STEAP2","url":"https://www.omim.org/entry/605094"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"prostate","ntpm":8771.6}],"url":"https://www.proteinatlas.org/search/MSMB"},"hgnc":{"alias_symbol":["PSP-94","PSP57","PSP94","IGBF","MSP","MSPB","PN44","PRPS","PSP"],"prev_symbol":[]},"alphafold":{"accession":"P08118","domains":[{"cath_id":"2.10.70.10","chopping":"23-72","consensus_level":"high","plddt":91.238,"start":23,"end":72},{"cath_id":"2.20.25.590","chopping":"76-114","consensus_level":"high","plddt":96.6262,"start":76,"end":114}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P08118","model_url":"https://alphafold.ebi.ac.uk/files/AF-P08118-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P08118-F1-predicted_aligned_error_v6.png","plddt_mean":88.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MSMB","jax_strain_url":"https://www.jax.org/strain/search?query=MSMB"},"sequence":{"accession":"P08118","fasta_url":"https://rest.uniprot.org/uniprotkb/P08118.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P08118/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P08118"}},"corpus_meta":[{"pmid":"8062829","id":"PMC_8062829","title":"RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP.","date":"1994","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8062829","citation_count":280,"is_preprint":false},{"pmid":"1726950","id":"PMC_1726950","title":"Human CYP1A1 (cytochrome P(1)450) gene: lack of association between the Msp I restriction fragment length polymorphism and incidence of lung cancer in a Norwegian population.","date":"1991","source":"Pharmacogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/1726950","citation_count":194,"is_preprint":false},{"pmid":"12919677","id":"PMC_12919677","title":"The MSP receptor regulates alpha6beta4 and alpha3beta1 integrins via 14-3-3 proteins in keratinocyte migration.","date":"2003","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/12919677","citation_count":168,"is_preprint":false},{"pmid":"23792360","id":"PMC_23792360","title":"MSP-RON signalling in cancer: pathogenesis and therapeutic potential.","date":"2013","source":"Nature reviews. 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RNAi knockdown of EZH2 reduced H3K27 trimethylation and increased MSMB expression, while EZH2 overexpression decreased MSMB expression. Chromatin immunoprecipitation confirmed EZH2 association with the MSMB gene.\",\n      \"method\": \"ChIP, RNAi knockdown, overexpression, bisulfite sequencing\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, RNAi, overexpression, bisulfite sequencing) in a single rigorous study\",\n      \"pmids\": [\"17237810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The rs10993994 SNP, located 57 bp upstream of the first exon of MSMB, regulates MSMB promoter activity; the C allele preferentially binds the CREB transcription factor (shown by EMSA), and cell lines with CC or CT genotypes exhibit higher MSMB expression than TT genotype lines. Luciferase reporter assays confirmed the T variant reduces transcriptional activity.\",\n      \"method\": \"Luciferase reporter assay, EMSA, genotype-expression analysis in tumor cell lines\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two orthogonal functional assays (luciferase + EMSA) with genotype-stratified cell line data\",\n      \"pmids\": [\"19383797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Suppression of MSMB expression promotes anchorage-independent growth of prostate epithelial cells, establishing a tumor-suppressive role for MSMB/PSP94 in prostate-specific cellular context. The rs10993994 risk allele is associated with decreased expression of MSMB isoforms in both histologically normal and malignant prostate tissue.\",\n      \"method\": \"Loss-of-function (MSMB suppression) with anchorage-independent growth assay; genotype-expression correlation in prostate tissue cohort\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — functional loss-of-function phenotype in prostate cells, but tissue expression data is correlative\",\n      \"pmids\": [\"21085629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of human PSP94 (MSMB gene product) at 2.3 Å resolution reveals that the N- and C-termini are held in close proximity by a hydrogen bond between the first and last beta-strands, forming a straight edge. Two monomers associate antiparallel via this edge to form a homodimer. Dimers dissociate to monomers at acidic pH. The same edge is proposed to mediate binding to cysteine-rich secretory proteins (e.g., CRISP-3) and IgG.\",\n      \"method\": \"X-ray crystallography, biochemical dissociation assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure at 2.3 Å with biochemical validation of dimer formation and pH-dependent dissociation\",\n      \"pmids\": [\"20184897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"Beta-microseminoprotein (beta-MSP/PSP94), despite near-identical sequence to so-called 'beta-inhibin', does not inhibit FSH secretion from rat pituitary cells in culture, demonstrating that PSP94 lacks inhibin activity.\",\n      \"method\": \"In vitro FSH secretion bioassay using rat pituitary cell culture\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vitro functional bioassay with positive controls\",\n      \"pmids\": [\"3109514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1988,\n      \"finding\": \"PSP94 (MSMB gene product) is synthesized in the epithelial cells of the prostate gland, as shown by co-localization of immunoreactive PSP94 protein and its mRNA in prostatic epithelial cells by immunohistochemistry and in situ hybridization.\",\n      \"method\": \"Immunohistochemistry, in situ hybridization histochemistry\",\n      \"journal\": \"Journal of andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization by two complementary methods but no functional consequence tested\",\n      \"pmids\": [\"3182395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Alternative splicing of the MSMB/PSP94 mRNA produces a shorter isoform (PSP57) in which exon III is deleted, encoding a 57-amino acid protein with a novel basic C-terminus. PSP57 mRNA is detected in urogenital tissues and tumor cell lines but not breast or lung, and in prostate tumor cell lines it is aberrantly spliced and localizes to the nuclear fraction.\",\n      \"method\": \"RT-PCR, Southern blotting, cloning and sequencing, nuclear fractionation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple molecular methods defining a novel splice isoform with distinct localization\",\n      \"pmids\": [\"7566962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Promoter variants at the MSMB locus associated with prostate cancer regulate expression of full-length MSMB-NCOA4 fusion transcripts. The predominant fusion arises from splicing of MSMB 5'UTR and exons 1-2 to NCOA4 exons 2-10, producing a stable fusion protein containing essential NCOA4 domains. A core MSMB promoter element between -27 and -236 and a negative regulatory element immediately upstream of the start codon were mapped by deletion/luciferase assays.\",\n      \"method\": \"RT-PCR/sequencing of fusion transcripts, luciferase reporter deletion assays, computational analysis\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — fusion transcript characterized by sequencing and promoter functionally mapped by reporter assays\",\n      \"pmids\": [\"22661295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PCK3145 (a synthetic peptide from PSP94/MSMB amino acids 31-45) inhibits MMP-9 secretion and triggers CD44 shedding from the cell surface of HT-1080 fibrosarcoma cells. This involves RhoA signaling and MT1-MMP-mediated CD44 ectodomain shedding, and inhibits cell adhesion to hyaluronic acid, laminin-1, and type-I collagen.\",\n      \"method\": \"Gelatin zymography, RT-PCR, flow cytometry, immunoblotting, cell adhesion assay\",\n      \"journal\": \"Clinical & experimental metastasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — multiple molecular readouts from a single lab establishing mechanism of PSP94-derived peptide action\",\n      \"pmids\": [\"16283486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The PCK3145 PSP94-derived peptide binds the HT-1080 cell surface through the 37-kDa laminin receptor precursor (37LRP), as demonstrated by far-Western ligand binding studies; overexpression of 37LRP increases PCK3145 binding. This cell surface binding triggers ERK phosphorylation and leads to downregulation of HuR protein (an mRNA stabilizer), resulting in MMP-9 mRNA destabilization and reduced MMP-9 secretion.\",\n      \"method\": \"Far-Western ligand binding, overexpression, flow cytometry, immunoblotting, gelatin zymography, MEK inhibitor experiment\",\n      \"journal\": \"Anti-cancer drugs\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — binding partner identified by far-Western and overexpression with downstream signaling pathway delineated\",\n      \"pmids\": [\"16550001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MSMB/PSP94 and its binding protein CRISP-3 individually inhibit prostate cancer cell growth in a cell-line-specific manner. PSP94 inhibits growth of CRISP-3-positive cell lines, while CRISP-3-mediated growth inhibition is independent of PSP94 presence, as determined by clonogenic survival assays with ectopic expression of each protein.\",\n      \"method\": \"Clonogenic survival assay, stable transfection, Western blot, immunofluorescence\",\n      \"journal\": \"Asian journal of andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — functional loss/gain-of-function with defined phenotypic readout in multiple cell lines\",\n      \"pmids\": [\"20676114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"PSP94 (MSMB gene product) mRNA and protein expression in rat lateral prostate is under androgen regulation: castration abolishes expression while testosterone replacement restores it. Expression is also induced by glucocorticoid (dexamethasone) and progestin (medroxyprogesterone acetate), but not by zinc, distinguishing it from probasin regulation.\",\n      \"method\": \"In situ hybridization, semiquantitative RT-PCR, Western blotting, hormone manipulation in castrated rats\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo hormonal manipulation with multiple readouts (RNA and protein) in a defined physiological model\",\n      \"pmids\": [\"11108266\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MSMB encodes PSP94 (beta-microseminoprotein), a prostate epithelial secretory protein whose expression is regulated by androgens, the CREB transcription factor (via the rs10993994 promoter SNP), and epigenetic silencing by EZH2-mediated H3K27 trimethylation; structurally, PSP94 forms an antiparallel homodimer through its terminal beta-strand edge, which also mediates binding to CRISP family proteins, and PSP94 or its derived peptide PCK3145 suppresses tumor cell growth and MMP-9-dependent invasion via laminin receptor/ERK signaling and RhoA/MT1-MMP-mediated CD44 shedding.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MSMB encodes PSP94 (beta-microseminoprotein), a prostate epithelial secretory protein that functions as a tumor suppressor by inhibiting anchorage-independent growth and suppressing MMP-9-dependent invasion through laminin receptor/ERK signaling and RhoA/MT1-MMP-mediated CD44 shedding [PMID:21085629, PMID:16283486, PMID:16550001]. PSP94 is synthesized in prostatic epithelial cells under androgen and steroid hormone regulation, and its expression is epigenetically silenced in androgen-refractory prostate cancer through EZH2-mediated H3K27 trimethylation and promoter CpG hypermethylation [PMID:3182395, PMID:11108266, PMID:17237810]. The crystal structure reveals a two-domain Greek-key fold in which terminal beta-strands form an antiparallel homodimer interface that also mediates binding to CRISP-3, with pH-dependent dissociation [PMID:20184897]. Transcriptional output is modulated by the prostate cancer risk SNP rs10993994, where the C allele preferentially binds CREB to drive higher expression, and the locus also generates MSMB-NCOA4 fusion transcripts whose expression is governed by the same promoter variants [PMID:19383797, PMID:22661295].\",\n  \"teleology\": [\n    {\n      \"year\": 1987,\n      \"claim\": \"Despite sequence similarity to 'beta-inhibin', PSP94 was shown to lack FSH-inhibiting activity, ruling out an endocrine role and redirecting investigation toward its prostatic function.\",\n      \"evidence\": \"In vitro FSH secretion bioassay using rat pituitary cell cultures with positive controls\",\n      \"pmids\": [\"3109514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No alternative biological activity was identified at this stage\", \"Only one endocrine endpoint tested\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Demonstration that PSP94 mRNA and protein co-localize in prostatic epithelial cells established the prostate as the primary site of synthesis, framing MSMB as a prostate-specific secretory gene.\",\n      \"evidence\": \"Immunohistochemistry and in situ hybridization in human prostate tissue\",\n      \"pmids\": [\"3182395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of secretion not addressed\", \"Expression in non-prostatic tissues not systematically surveyed\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Discovery of an alternative splice isoform (PSP57) lacking exon III, with a novel basic C-terminus and nuclear localization in tumor cells, revealed MSMB generates functionally distinct isoforms with potentially different subcellular roles.\",\n      \"evidence\": \"RT-PCR, cloning/sequencing, and nuclear fractionation in urogenital tissues and tumor cell lines\",\n      \"pmids\": [\"7566962\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of PSP57 isoform not determined\", \"Nuclear role remains uncharacterized\", \"Only demonstrated in cell lines, not validated in vivo\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"In vivo hormonal manipulation established that PSP94 expression is androgen-dependent and also responsive to glucocorticoids and progestins, defining MSMB as a steroid-regulated gene.\",\n      \"evidence\": \"Castration/testosterone replacement in rats with RT-PCR, in situ hybridization, and Western blotting\",\n      \"pmids\": [\"11108266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct hormone-responsive elements in the MSMB promoter not mapped\", \"Relevance to human prostate hormone regulation assumed but not directly tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"A PSP94-derived peptide (PCK3145) was shown to inhibit MMP-9 secretion and trigger MT1-MMP/RhoA-dependent CD44 shedding, providing the first mechanistic link between PSP94 and suppression of cell invasion.\",\n      \"evidence\": \"Zymography, RT-PCR, flow cytometry, immunoblotting, and adhesion assays in HT-1080 cells\",\n      \"pmids\": [\"16283486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Activity demonstrated with a synthetic peptide fragment, not full-length PSP94\", \"Relevance to prostate cancer cells not shown\", \"Mechanism of RhoA activation unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of the 37-kDa laminin receptor precursor as the cell-surface receptor for PSP94-derived peptide, with downstream ERK activation and HuR-dependent MMP-9 mRNA destabilization, defined the signaling pathway mediating anti-invasive activity.\",\n      \"evidence\": \"Far-Western binding, 37LRP overexpression, MEK inhibitor experiments in HT-1080 cells\",\n      \"pmids\": [\"16550001\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding of full-length PSP94 to 37LRP not confirmed\", \"Pathway not validated in prostate epithelial cells\", \"Single far-Western approach for receptor identification\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"EZH2-mediated H3K27 trimethylation, combined with H3K9 hypoacetylation and CpG island hypermethylation, was identified as the mechanism of MSMB silencing in androgen-refractory prostate cancer, establishing epigenetic regulation as a key control layer.\",\n      \"evidence\": \"ChIP, EZH2 RNAi knockdown and overexpression, bisulfite sequencing in prostate cancer cell lines\",\n      \"pmids\": [\"17237810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether epigenetic silencing is causally linked to disease progression not established\", \"Relative contribution of H3K27me3 versus DNA methylation not dissected\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The prostate cancer risk SNP rs10993994 was shown to directly modulate MSMB transcription via differential CREB binding, connecting a GWAS-identified genetic variant to a specific transcription factor mechanism.\",\n      \"evidence\": \"Luciferase reporter assays and EMSA in prostate cancer cell lines stratified by genotype\",\n      \"pmids\": [\"19383797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ChIP confirmation of CREB occupancy at the endogenous locus not shown\", \"Additional transcription factors at this site not excluded\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Structural determination of PSP94 revealed a homodimer formed through antiparallel beta-strand edge interactions and identified this same interface as the binding site for CRISP family proteins, unifying oligomerization and partner recognition.\",\n      \"evidence\": \"X-ray crystallography at 2.3 Å resolution with biochemical pH-dependent dissociation assays\",\n      \"pmids\": [\"20184897\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal structure of PSP94-CRISP-3 complex\", \"Functional consequence of dimer versus monomer form unknown\", \"IgG binding via same edge is inferred, not structurally proven\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Functional evidence that MSMB suppression promotes anchorage-independent growth established a direct tumor-suppressive role, while PSP94 and CRISP-3 were shown to independently inhibit prostate cancer cell growth.\",\n      \"evidence\": \"Loss-of-function growth assays in prostate epithelial cells; clonogenic survival with ectopic PSP94/CRISP-3 expression\",\n      \"pmids\": [\"21085629\", \"20676114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream pathway by which loss of PSP94 permits anchorage independence not identified\", \"In vivo tumor suppression not demonstrated\", \"PSP94-CRISP-3 functional interplay not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery of MSMB-NCOA4 fusion transcripts regulated by the same promoter variants linked to prostate cancer risk expanded the functional output of the MSMB locus beyond PSP94 alone.\",\n      \"evidence\": \"RT-PCR/sequencing of fusion transcripts, luciferase promoter deletion mapping\",\n      \"pmids\": [\"22661295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biological function of the MSMB-NCOA4 fusion protein not tested\", \"Protein-level expression and stability in vivo not confirmed\", \"Whether fusion contributes to prostate cancer risk independently of PSP94 unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which full-length secreted PSP94 exerts tumor-suppressive activity in vivo, the identity of its physiological receptor on prostate epithelial cells, and the functional significance of the PSP94-CRISP-3 interaction remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in vivo knockout or transgenic tumor model published\", \"Receptor for intact PSP94 on prostate cells not identified\", \"Structural basis of CRISP-3 binding not determined at atomic resolution\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 8, 9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 5, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CRISP3\", \"NCOA4\", \"RPSA\", \"EZH2\", \"CREB1\"],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I made an error in the pathway section. Let me fix that. The pathway should use Reactome IDs, not GO IDs. Let me reconsider and provide the correct output:\n\n```json\n{\n  \"mechanistic_narrative\": \"MSMB encodes PSP94 (beta-microseminoprotein), a prostate epithelial secretory protein that functions as a tumor suppressor by inhibiting anchorage-independent growth and suppressing MMP-9-dependent invasion through laminin receptor/ERK signaling and RhoA/MT1-MMP-mediated CD44 shedding [PMID:21085629, PMID:16283486, PMID:16550001]. PSP94 is synthesized in prostatic epithelial cells under androgen and steroid hormone regulation, and its expression is epigenetically silenced in androgen-refractory prostate cancer through EZH2-mediated H3K27 trimethylation and promoter CpG hypermethylation [PMID:3182395, PMID:11108266, PMID:17237810]. The crystal structure reveals a two-domain Greek-key fold in which terminal beta-strands form an antiparallel homodimer interface that also mediates binding to CRISP-3, with pH-dependent dissociation [PMID:20184897]. Transcriptional output is modulated by the prostate cancer risk SNP rs10993994, where the C allele preferentially binds CREB to drive higher expression, and the locus also generates MSMB-NCOA4 fusion transcripts governed by the same promoter variants [PMID:19383797, PMID:22661295].\",\n  \"teleology\": [\n    {\n      \"year\": 1987,\n      \"claim\": \"Despite sequence similarity to 'beta-inhibin', PSP94 was shown to lack FSH-inhibiting activity, ruling out an endocrine role and redirecting investigation toward its prostatic function.\",\n      \"evidence\": \"In vitro FSH secretion bioassay using rat pituitary cell cultures with positive controls\",\n      \"pmids\": [\"3109514\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No alternative biological activity was identified at this stage\", \"Only one endocrine endpoint tested\"]\n    },\n    {\n      \"year\": 1988,\n      \"claim\": \"Demonstration that PSP94 mRNA and protein co-localize in prostatic epithelial cells established the prostate as the primary site of synthesis, framing MSMB as a prostate-specific secretory gene.\",\n      \"evidence\": \"Immunohistochemistry and in situ hybridization in human prostate tissue\",\n      \"pmids\": [\"3182395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of secretion not addressed\", \"Expression in non-prostatic tissues not systematically surveyed\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Discovery of an alternative splice isoform (PSP57) lacking exon III, with a novel basic C-terminus and nuclear localization in tumor cells, revealed MSMB generates functionally distinct isoforms with potentially different subcellular roles.\",\n      \"evidence\": \"RT-PCR, cloning/sequencing, and nuclear fractionation in urogenital tissues and tumor cell lines\",\n      \"pmids\": [\"7566962\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Function of PSP57 isoform not determined\", \"Nuclear role remains uncharacterized\", \"Only demonstrated in cell lines, not validated in vivo\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"In vivo hormonal manipulation established that PSP94 expression is androgen-dependent and also responsive to glucocorticoids and progestins, defining MSMB as a steroid-regulated gene.\",\n      \"evidence\": \"Castration/testosterone replacement in rats with RT-PCR, in situ hybridization, and Western blotting\",\n      \"pmids\": [\"11108266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct hormone-responsive elements in the MSMB promoter not mapped\", \"Relevance to human prostate hormone regulation assumed but not directly tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"A PSP94-derived peptide (PCK3145) was shown to inhibit MMP-9 secretion and trigger MT1-MMP/RhoA-dependent CD44 shedding, providing the first mechanistic link between PSP94 and suppression of cell invasion.\",\n      \"evidence\": \"Zymography, RT-PCR, flow cytometry, immunoblotting, and adhesion assays in HT-1080 cells\",\n      \"pmids\": [\"16283486\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Activity demonstrated with a synthetic peptide fragment, not full-length PSP94\", \"Relevance to prostate cancer cells not shown\", \"Mechanism of RhoA activation unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification of the 37-kDa laminin receptor precursor as the cell-surface receptor for PSP94-derived peptide, with downstream ERK activation and HuR-dependent MMP-9 mRNA destabilization, defined the signaling pathway mediating anti-invasive activity.\",\n      \"evidence\": \"Far-Western binding, 37LRP overexpression, MEK inhibitor experiments in HT-1080 cells\",\n      \"pmids\": [\"16550001\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding of full-length PSP94 to 37LRP not confirmed\", \"Pathway not validated in prostate epithelial cells\", \"Single far-Western approach for receptor identification\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"EZH2-mediated H3K27 trimethylation, combined with H3K9 hypoacetylation and CpG island hypermethylation, was identified as the mechanism of MSMB silencing in androgen-refractory prostate cancer, establishing epigenetic regulation as a key control layer.\",\n      \"evidence\": \"ChIP, EZH2 RNAi knockdown and overexpression, bisulfite sequencing in prostate cancer cell lines\",\n      \"pmids\": [\"17237810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether epigenetic silencing is causally linked to disease progression not established\", \"Relative contribution of H3K27me3 versus DNA methylation not dissected\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The prostate cancer risk SNP rs10993994 was shown to directly modulate MSMB transcription via differential CREB binding, connecting a GWAS-identified genetic variant to a specific transcription factor mechanism.\",\n      \"evidence\": \"Luciferase reporter assays and EMSA in prostate cancer cell lines stratified by genotype\",\n      \"pmids\": [\"19383797\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ChIP confirmation of CREB occupancy at the endogenous locus not shown\", \"Additional transcription factors at this site not excluded\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Structural determination of PSP94 revealed a homodimer formed through antiparallel beta-strand edge interactions and identified this same interface as the binding site for CRISP family proteins, unifying oligomerization and partner recognition.\",\n      \"evidence\": \"X-ray crystallography at 2.3 Å resolution with biochemical pH-dependent dissociation assays\",\n      \"pmids\": [\"20184897\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal structure of PSP94-CRISP-3 complex\", \"Functional consequence of dimer versus monomer form unknown\", \"IgG binding via same edge is inferred, not structurally proven\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Functional evidence that MSMB suppression promotes anchorage-independent growth established a direct tumor-suppressive role, while PSP94 and CRISP-3 were shown to independently inhibit prostate cancer cell growth.\",\n      \"evidence\": \"Loss-of-function growth assays in prostate epithelial cells; clonogenic survival with ectopic PSP94/CRISP-3 expression\",\n      \"pmids\": [\"21085629\", \"20676114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream pathway by which loss of PSP94 permits anchorage independence not identified\", \"In vivo tumor suppression not demonstrated\", \"PSP94-CRISP-3 functional interplay not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery of MSMB-NCOA4 fusion transcripts regulated by the same promoter variants linked to prostate cancer risk expanded the functional output of the MSMB locus beyond PSP94 alone.\",\n      \"evidence\": \"RT-PCR/sequencing of fusion transcripts, luciferase promoter deletion mapping\",\n      \"pmids\": [\"22661295\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biological function of the MSMB-NCOA4 fusion protein not tested\", \"Protein-level expression and stability in vivo not confirmed\", \"Whether fusion contributes to prostate cancer risk independently of PSP94 unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism by which full-length secreted PSP94 exerts tumor-suppressive activity in vivo, the identity of its physiological receptor on prostate epithelial cells, and the functional significance of the PSP94-CRISP-3 interaction remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No in vivo knockout or transgenic tumor model published\", \"Receptor for intact PSP94 on prostate cells not identified\", \"Structural basis of CRISP-3 binding not determined at atomic resolution\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 8, 9, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CRISP3\", \"NCOA4\", \"RPSA\", \"EZH2\", \"CREB1\"],\n    \"other_free_text\": []\n  }\n}\n```"}