{"gene":"PROS1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2018,"finding":"Tumor-secreted Protein S (PROS1) acts as a ligand for Mer and Tyro3 (but not Axl) receptor tyrosine kinases on macrophages, suppressing M1 polarization (inhibiting IFN-γ/LPS-induced pro-inflammatory cytokine expression). The suppressive signaling involves PTP1b complexing with Mer, as M1 cytokine suppression was lost in PTP1b-KO macrophages and Mer-KO or Tyro3-KO macrophages but not Axl-KO macrophages.","method":"CRISPR-based deletion of Pros1 in tumor cells, macrophage KO mice (Mer, Tyro3, Axl, PTP1b), in vitro cytokine assays, in vivo tumor models with survival readout","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic knockouts (tumor Pros1 CRISPR, macrophage receptor KOs, PTP1b-KO) with multiple orthogonal readouts (cytokine expression, survival, immune infiltration) in both in vitro and in vivo models","pmids":["29708510"],"is_preprint":false},{"year":2021,"finding":"Myeloid cell-derived PROS1 suppresses metastatic seeding via the PROS1/MERTK axis in bone marrow-derived macrophages. Pros1 deletion in myeloid cells elevated TNF-α, IL-6, Nos2, and IL-10 through modulation of the Socs3/NF-κB pathway. Conditioned medium from PROS1-cKO macrophages promoted tumor cell EMT and invasion in an IL-10-dependent manner. Notably, MERTK kinase activity was required for PROS1-mediated suppression of TNF-α and IL-6, but IL-10 regulation by PROS1 was MERTK-independent.","method":"Conditional myeloid-specific Pros1 knockout mice, bone marrow-derived macrophage conditioned medium assays, MERTK kinase inhibition, Western blot (Socs3/NF-κB pathway), lung and breast cancer metastasis models","journal":"The Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multiple orthogonal methods (pathway analysis, conditioned medium functional assays, MERTK inhibition) replicated across two tumor models in a single rigorous study","pmids":["33848267"],"is_preprint":false},{"year":2019,"finding":"PROS1 (ProS1) is a functional ligand for Tyro3 receptor tyrosine kinase in cancer cells, primarily coupling to Erk signaling rather than Axl/Akt signaling. In cells expressing both Tyro3 and Axl, ProS1 preferentially activated Tyro3-Erk phosphorylation while Gas6 was the sole activator of Axl-Akt. In cells expressing Tyro3 alone, ProS1 additionally activated Akt. ProS1-Tyro3 signaling protected cancer cells from apoptosis (staurosporine-induced and serum starvation-induced).","method":"Western blotting of receptor and kinase phosphorylation in multiple cancer cell lines (SCC-25, MGH-U3, 786-0), conditioned medium from ProS1-secreting cells, ProS1 ligand traps and warfarin specificity controls, apoptosis assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal ligand-receptor specificity demonstrated across multiple cell lines with inhibitor controls, single laboratory","pmids":["31766614"],"is_preprint":false},{"year":2016,"finding":"Knockdown of PROS1 in glioblastoma LN18 cells induced apoptosis via activation of both extrinsic (FasL/death receptor) and intrinsic apoptotic pathways, reduced migration and invasion, and decreased proliferation. PROS1 silencing also caused downregulation of GAS6 and TAM family receptors, suggesting PROS1 supports GBM cell survival partly through autocrine/paracrine TAM receptor signaling.","method":"siRNA knockdown of PROS1 in LN18 glioblastoma cells, apoptosis assays, wound-healing migration assay, invasion assay, proliferation assay, pathway analysis","journal":"International Journal of Oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts (apoptosis, migration, invasion, proliferation) with pathway identification, single laboratory, single cell line","pmids":["27840905"],"is_preprint":false},{"year":2019,"finding":"Exogenous PROS1 inhibited P. gingivalis LPS-induced production of TNF-α, IL-6, IL-1β, MMP9/2, and RANKL in human gingival epithelial cells in a Tyro3-dependent manner. The anti-inflammatory mechanism involved SOCS1/3 upregulation and modulation of STAT1/3 signaling. PROS1 also restored Tyro3 expression downregulated by LPS stimulation. In a rat periodontitis model, PROS1 administration attenuated gingival inflammation and alveolar bone loss.","method":"In vitro LPS stimulation of human gingival epithelial cells, Tyro3 dependency established by knockdown, PCR/Western blot/ELISA/gelatin zymography, rat ligature+LPS periodontitis model with PROS1 administration","journal":"Journal of Cellular and Molecular Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Tyro3-dependent mechanism established by knockdown with multiple molecular readouts and in vivo validation, single laboratory","pmids":["30729671"],"is_preprint":false},{"year":2001,"finding":"Five novel PROS1 mutations (W108C, W342R, E349K, L485S missense and a 4 bp deletion causing frameshift) cause protein S type I or III deficiency. Analysis of platelet mRNA showed mutant transcripts are expressed in significant amounts, suggesting the molecular disease mechanism is defective protein folding/instability and impaired secretion with intracellular degradation, rather than absence of mRNA. Structural modeling predicted the substitutions disrupt protein folding and/or stability.","method":"PROS1 mutation identification by sequencing, haplotype analysis with microsatellite markers, platelet mRNA analysis (RT-PCR), computer-based structural modeling of protein S","journal":"Thrombosis and Haemostasis","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — mRNA expression analysis plus computational structural modeling across multiple families; mechanism (impaired folding/secretion) is inferred rather than directly demonstrated biochemically","pmids":["11776305"],"is_preprint":false},{"year":2009,"finding":"Gross copy number variations (CNVs) including complete deletions, partial deletions, and duplications of the PROS1 gene are found in approximately one-third of hereditary protein S-deficient patients who are negative for point mutations by conventional sequencing, establishing large genomic rearrangements as a common molecular mechanism of PROS1-associated protein S deficiency.","method":"Multiplex ligation-dependent probe amplification (MLPA) and confirmatory quantitative PCR for copy number analysis of PROS1 in 18 protein S-deficient probands","journal":"Human Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MLPA with independent qPCR confirmation across 18 probands, single laboratory, establishes CNVs as a defined molecular mechanism","pmids":["19466456"],"is_preprint":false},{"year":2005,"finding":"Large genomic deletions of PROS1 (encompassing at least 35 kb to 449 kb) were identified in 3 of 8 (38%) protein S-deficient families lacking detectable point mutations, confirming that large deletions are a relatively common and distinct molecular mechanism causing hereditary protein S deficiency.","method":"SNP and microsatellite marker segregation analysis to identify deletions, confirmed by quantitative PCR; haplotype analysis showed all three deletions were independent events","journal":"Thrombosis and Haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genomic deletion mapping with qPCR confirmation and haplotype analysis, independent replication of large-deletion mechanism (corroborated by PMID 19466456)","pmids":["16363235"],"is_preprint":false},{"year":2000,"finding":"Seven novel PROS1 mutations causing protein S deficiency were identified including missense, nonsense, and frameshift variants. The P460 allele (S/P460 variant) was found in heterozygous form in type III PS-deficient patients but also in normal individuals, suggesting it does not co-segregate as a disease-causing mutation for type III deficiency.","method":"Optimized non-isotopic SSCA/SSCP mutation detection across 15 PCR segments covering all PROS1 exons and boundaries, heteroduplex analysis, co-segregation analysis in 31 propositi","journal":"Human Mutation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mutation identification by SSCP with co-segregation, limited mechanistic follow-up beyond mutation catalog; negative finding on P460 mechanistically informative but single-laboratory study","pmids":["10790208"],"is_preprint":false}],"current_model":"PROS1 (Protein S) functions as a secreted ligand for TAM receptor tyrosine kinases (Tyro3 and Mer/MERTK, but not Axl) on immune cells and cancer cells: in macrophages, tumor- or myeloid-derived PROS1 signals through Mer-PTP1b and Tyro3 to suppress M1 pro-inflammatory cytokine production and modulate adaptive immunity via Socs3/NF-κB and STAT/SOCS pathways, thereby regulating tumor immune evasion and metastatic potential; in cancer cells, PROS1 activates Tyro3-Erk (and context-dependently Akt) signaling to promote survival and suppress apoptosis; hereditary protein S deficiency is caused by PROS1 point mutations that lead to defective protein folding and impaired secretion, as well as by large genomic deletions/duplications that account for a substantial fraction (~35–38%) of mutation-negative cases."},"narrative":{"mechanistic_narrative":"PROS1 (Protein S) is a secreted ligand for the TAM-family receptor tyrosine kinases Tyro3 and Mer/MERTK — but not Axl — through which it regulates innate immune polarization and cancer-cell survival [PMID:29708510, PMID:31766614]. In macrophages, tumor- or myeloid-derived PROS1 engages Mer and Tyro3 to suppress M1 pro-inflammatory polarization, an effect requiring a PTP1b-Mer complex and lost in PTP1b-, Mer-, or Tyro3-deficient (but not Axl-deficient) macrophages [PMID:29708510]. Myeloid-specific PROS1 acts via MERTK kinase activity and the Socs3/NF-κB pathway to restrain TNF-α and IL-6, while restraining IL-10 in a MERTK-independent manner; loss of myeloid PROS1 drives a pro-metastatic, EMT-promoting, IL-10-dependent macrophage secretome [PMID:33848267]. In epithelial and gingival cells, exogenous PROS1 dampens LPS-induced inflammatory cytokine and MMP production in a Tyro3-dependent fashion through SOCS1/3 upregulation and STAT1/3 modulation, with protective effects in a rat periodontitis model [PMID:30729671]. In cancer cells, PROS1 preferentially activates Tyro3-Erk signaling (and Akt where Tyro3 is expressed alone), promoting survival and suppressing apoptosis, and its loss triggers both extrinsic and intrinsic apoptotic pathways and reduces migration, invasion, and proliferation [PMID:31766614, PMID:27840905]. Hereditary protein S deficiency arises from PROS1 point mutations that cause defective folding, instability, and impaired secretion despite normal transcript levels [PMID:11776305], and from large genomic deletions and duplications that account for roughly one-third of mutation-negative cases [PMID:19466456, PMID:16363235].","teleology":[{"year":2000,"claim":"Establishing the spectrum of disease-causing PROS1 variants was needed to define the genetic basis of hereditary protein S deficiency; cataloging missense, nonsense, and frameshift mutations and clarifying that the P460 variant is a non-causal polymorphism sharpened genotype interpretation.","evidence":"SSCP/heteroduplex mutation detection across all PROS1 exons with co-segregation analysis in 31 propositi","pmids":["10790208"],"confidence":"Low","gaps":["Mutation catalog by SSCP without biochemical demonstration of the consequence of each variant","No functional assay distinguishing folding versus secretion defects"]},{"year":2001,"claim":"The molecular mechanism by which point mutations cause protein S deficiency was unresolved; demonstrating that mutant transcripts are present at normal levels reframed the defect as one of protein folding/stability and impaired secretion rather than absent mRNA.","evidence":"Sequencing of five novel mutations, platelet mRNA RT-PCR, and computational structural modeling across multiple families","pmids":["11776305"],"confidence":"Medium","gaps":["Folding/secretion defect inferred from modeling and mRNA presence, not directly measured biochemically","No cellular trafficking or degradation assay for the mutant proteins"]},{"year":2005,"claim":"A substantial fraction of protein S-deficient families lack detectable point mutations; identifying large genomic deletions in 38% of such families established gross rearrangements as a distinct disease mechanism.","evidence":"SNP/microsatellite segregation mapping confirmed by qPCR, with haplotype analysis showing independent deletion events","pmids":["16363235"],"confidence":"Medium","gaps":["Small family number","Breakpoint architecture and recurrence mechanism not defined"]},{"year":2009,"claim":"The frequency and types of PROS1 copy number variation in mutation-negative patients were unknown; systematic MLPA confirmed complete/partial deletions and duplications in roughly one-third of cases, consolidating CNVs as a common mechanism.","evidence":"MLPA with confirmatory qPCR for copy number analysis across 18 protein S-deficient probands","pmids":["19466456"],"confidence":"Medium","gaps":["Single-laboratory cohort","Functional consequence of duplications not characterized"]},{"year":2016,"claim":"Whether PROS1 has a cell-autonomous role in tumor survival was unclear; silencing PROS1 in glioblastoma cells showed it supports proliferation, migration, invasion, and survival, linking its loss to apoptosis via both extrinsic and intrinsic pathways and to downregulation of GAS6 and TAM receptors.","evidence":"siRNA knockdown in LN18 glioblastoma cells with apoptosis, migration, invasion, proliferation, and pathway assays","pmids":["27840905"],"confidence":"Medium","gaps":["Single cell line, single laboratory","Autocrine/paracrine TAM signaling inferred, not directly demonstrated","Receptor specificity not resolved"]},{"year":2018,"claim":"The receptor and downstream wiring of PROS1 immune signaling was undefined; reciprocal genetic knockouts established PROS1 as a ligand for Mer and Tyro3 (not Axl) that suppresses macrophage M1 polarization via a PTP1b-Mer complex, defining a tumor immune-evasion axis.","evidence":"CRISPR deletion of tumor Pros1, macrophage Mer/Tyro3/Axl/PTP1b knockouts, cytokine assays, and in vivo tumor/survival models","pmids":["29708510"],"confidence":"High","gaps":["Structural basis of Tyro3/Mer selectivity over Axl not defined","Direct PROS1-receptor binding affinities not quantified"]},{"year":2019,"claim":"Whether PROS1-TAM signaling is restricted to immune cells was open; in cancer cells PROS1 was shown to preferentially activate Tyro3-Erk (and Akt when Tyro3 is alone) while Gas6 drives Axl-Akt, and to protect cells from apoptosis, establishing ligand-receptor specificity within the TAM family.","evidence":"Receptor/kinase phosphorylation Western blots across multiple cancer cell lines with ligand traps, warfarin controls, and apoptosis assays","pmids":["31766614"],"confidence":"Medium","gaps":["Single laboratory","Mechanism of context-dependent Akt activation when Tyro3 is alone not resolved"]},{"year":2019,"claim":"The anti-inflammatory mechanism of PROS1 in non-immune epithelium was unknown; exogenous PROS1 was shown to suppress LPS-induced cytokines and MMPs in a Tyro3-dependent manner via SOCS1/3 and STAT1/3 modulation, with protective effects in vivo.","evidence":"LPS stimulation of human gingival epithelial cells with Tyro3 knockdown, molecular readouts, and a rat periodontitis model","pmids":["30729671"],"confidence":"Medium","gaps":["Single laboratory","Direct Tyro3 engagement by PROS1 in epithelium not biochemically demonstrated"]},{"year":2021,"claim":"The in vivo source and effector pathway of immunosuppressive PROS1 in metastasis were unresolved; conditional myeloid Pros1 deletion showed MERTK kinase-dependent control of TNF-α/IL-6 via Socs3/NF-κB and MERTK-independent IL-10 regulation, linking the PROS1/MERTK axis to suppression of metastatic seeding.","evidence":"Myeloid-specific conditional Pros1 knockout, BMDM conditioned-medium EMT/invasion assays, MERTK inhibition, and two metastasis models","pmids":["33848267"],"confidence":"High","gaps":["Mechanism of MERTK-independent IL-10 regulation not identified","Receptor mediating IL-10 control not defined"]},{"year":null,"claim":"How the same PROS1 ligand achieves cell-type- and context-dependent selectivity among Tyro3/Mer/MERTK receptors and divergent downstream outputs (Erk vs Akt; MERTK-dependent vs -independent cytokines) remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of PROS1-receptor binding","Determinants of receptor selectivity unknown","Connection between coagulation function and TAM-ligand function not addressed in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,4]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6,7]}],"complexes":[],"partners":["MERTK","TYRO3","PTPN1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P07225","full_name":"Vitamin K-dependent protein S","aliases":[],"length_aa":676,"mass_kda":75.1,"function":"Anticoagulant plasma protein; it is a cofactor to activated protein C in the degradation of coagulation factors Va and VIIIa. It helps to prevent coagulation and stimulating fibrinolysis","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P07225/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PROS1","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PROS1","total_profiled":1310},"omim":[{"mim_id":"619525","title":"CONGENITAL DISORDER OF GLYCOSYLATION, TYPE IIw; CDG2W","url":"https://www.omim.org/entry/619525"},{"mim_id":"614514","title":"THROMBOPHILIA DUE TO PROTEIN S DEFICIENCY, AUTOSOMAL RECESSIVE; THPH6","url":"https://www.omim.org/entry/614514"},{"mim_id":"614507","title":"CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ir; CDG1R","url":"https://www.omim.org/entry/614507"},{"mim_id":"613878","title":"COAGULATION FACTOR VII; F7","url":"https://www.omim.org/entry/613878"},{"mim_id":"613872","title":"COAGULATION FACTOR X; F10","url":"https://www.omim.org/entry/613872"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":133.4},{"tissue":"liver","ntpm":264.9}],"url":"https://www.proteinatlas.org/search/PROS1"},"hgnc":{"alias_symbol":[],"prev_symbol":["PROS"]},"alphafold":{"accession":"P07225","domains":[{"cath_id":"2.10.25","chopping":"206-242","consensus_level":"medium","plddt":89.1405,"start":206,"end":242},{"cath_id":"2.10.25.10","chopping":"159-200","consensus_level":"medium","plddt":86.9038,"start":159,"end":200},{"cath_id":"2.10.25.10","chopping":"245-283","consensus_level":"medium","plddt":91.1638,"start":245,"end":283},{"cath_id":"2.60.120.200","chopping":"295-477","consensus_level":"high","plddt":87.4566,"start":295,"end":477},{"cath_id":"2.60.120.200","chopping":"483-666","consensus_level":"high","plddt":88.2542,"start":483,"end":666}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P07225","model_url":"https://alphafold.ebi.ac.uk/files/AF-P07225-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P07225-F1-predicted_aligned_error_v6.png","plddt_mean":82.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PROS1","jax_strain_url":"https://www.jax.org/strain/search?query=PROS1"},"sequence":{"accession":"P07225","fasta_url":"https://rest.uniprot.org/uniprotkb/P07225.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P07225/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P07225"}},"corpus_meta":[{"pmid":"18457993","id":"PMC_18457993","title":"The proPO-system: pros and cons for its role in invertebrate immunity.","date":"2008","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/18457993","citation_count":808,"is_preprint":false},{"pmid":"25557259","id":"PMC_25557259","title":"PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation.","date":"2014","source":"American journal of medical genetics. 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B, Biochemical, systemic, and environmental physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33860348","citation_count":15,"is_preprint":false},{"pmid":"8941500","id":"PMC_8941500","title":"Oral vs inhaled asthma therapy. Pros, cons and combinations.","date":"1996","source":"Drugs","url":"https://pubmed.ncbi.nlm.nih.gov/8941500","citation_count":15,"is_preprint":false},{"pmid":"34283001","id":"PMC_34283001","title":"Early approval of COVID-19 vaccines: Pros and cons.","date":"2021","source":"Human vaccines & immunotherapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/34283001","citation_count":15,"is_preprint":false},{"pmid":"22189678","id":"PMC_22189678","title":"Pros and cons of using aberrant glycosylation as companion biomarkers for therapeutics in cancer.","date":"2011","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/22189678","citation_count":15,"is_preprint":false},{"pmid":"38867442","id":"PMC_38867442","title":"The rise of medical influencers: The pros and the cons.","date":"2024","source":"The journal of the Royal College of Physicians of Edinburgh","url":"https://pubmed.ncbi.nlm.nih.gov/38867442","citation_count":14,"is_preprint":false},{"pmid":"36641897","id":"PMC_36641897","title":"EBCC-13 manifesto: Balancing pros and cons for contralateral prophylactic mastectomy.","date":"2022","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/36641897","citation_count":14,"is_preprint":false},{"pmid":"24741274","id":"PMC_24741274","title":"Pros and cons of phospholipid asymmetry in erythrocytes.","date":"2014","source":"Journal of pharmacy & bioallied sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24741274","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":40227,"output_tokens":3034,"usd":0.083096,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10256,"output_tokens":3608,"usd":0.07074,"stage2_stop_reason":"end_turn"},"total_usd":0.153836,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts, I need to identify papers about the canonical PROS1 gene (protein S, encoded by PROS1/PROS) and extract mechanistic findings.\n\nRelevant papers: 12, 30, 51, 54, 56, 62, 71, 80, 86, 92\n\nPapers 1-11, 13-29, 31-50, 52-53, 55, 57-61, 63-70, 72-79, 81-85, 87-100 are either \"pros and cons\" review articles, PIK3CA-PROS overgrowth syndrome papers, or completely unrelated topics — all excluded.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"Tumor-secreted Protein S (PROS1) acts as a ligand for Mer and Tyro3 (but not Axl) receptor tyrosine kinases on macrophages, suppressing M1 polarization (inhibiting IFN-γ/LPS-induced pro-inflammatory cytokine expression). The suppressive signaling involves PTP1b complexing with Mer, as M1 cytokine suppression was lost in PTP1b-KO macrophages and Mer-KO or Tyro3-KO macrophages but not Axl-KO macrophages.\",\n      \"method\": \"CRISPR-based deletion of Pros1 in tumor cells, macrophage KO mice (Mer, Tyro3, Axl, PTP1b), in vitro cytokine assays, in vivo tumor models with survival readout\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic knockouts (tumor Pros1 CRISPR, macrophage receptor KOs, PTP1b-KO) with multiple orthogonal readouts (cytokine expression, survival, immune infiltration) in both in vitro and in vivo models\",\n      \"pmids\": [\"29708510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Myeloid cell-derived PROS1 suppresses metastatic seeding via the PROS1/MERTK axis in bone marrow-derived macrophages. Pros1 deletion in myeloid cells elevated TNF-α, IL-6, Nos2, and IL-10 through modulation of the Socs3/NF-κB pathway. Conditioned medium from PROS1-cKO macrophages promoted tumor cell EMT and invasion in an IL-10-dependent manner. Notably, MERTK kinase activity was required for PROS1-mediated suppression of TNF-α and IL-6, but IL-10 regulation by PROS1 was MERTK-independent.\",\n      \"method\": \"Conditional myeloid-specific Pros1 knockout mice, bone marrow-derived macrophage conditioned medium assays, MERTK kinase inhibition, Western blot (Socs3/NF-κB pathway), lung and breast cancer metastasis models\",\n      \"journal\": \"The Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multiple orthogonal methods (pathway analysis, conditioned medium functional assays, MERTK inhibition) replicated across two tumor models in a single rigorous study\",\n      \"pmids\": [\"33848267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PROS1 (ProS1) is a functional ligand for Tyro3 receptor tyrosine kinase in cancer cells, primarily coupling to Erk signaling rather than Axl/Akt signaling. In cells expressing both Tyro3 and Axl, ProS1 preferentially activated Tyro3-Erk phosphorylation while Gas6 was the sole activator of Axl-Akt. In cells expressing Tyro3 alone, ProS1 additionally activated Akt. ProS1-Tyro3 signaling protected cancer cells from apoptosis (staurosporine-induced and serum starvation-induced).\",\n      \"method\": \"Western blotting of receptor and kinase phosphorylation in multiple cancer cell lines (SCC-25, MGH-U3, 786-0), conditioned medium from ProS1-secreting cells, ProS1 ligand traps and warfarin specificity controls, apoptosis assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal ligand-receptor specificity demonstrated across multiple cell lines with inhibitor controls, single laboratory\",\n      \"pmids\": [\"31766614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Knockdown of PROS1 in glioblastoma LN18 cells induced apoptosis via activation of both extrinsic (FasL/death receptor) and intrinsic apoptotic pathways, reduced migration and invasion, and decreased proliferation. PROS1 silencing also caused downregulation of GAS6 and TAM family receptors, suggesting PROS1 supports GBM cell survival partly through autocrine/paracrine TAM receptor signaling.\",\n      \"method\": \"siRNA knockdown of PROS1 in LN18 glioblastoma cells, apoptosis assays, wound-healing migration assay, invasion assay, proliferation assay, pathway analysis\",\n      \"journal\": \"International Journal of Oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts (apoptosis, migration, invasion, proliferation) with pathway identification, single laboratory, single cell line\",\n      \"pmids\": [\"27840905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Exogenous PROS1 inhibited P. gingivalis LPS-induced production of TNF-α, IL-6, IL-1β, MMP9/2, and RANKL in human gingival epithelial cells in a Tyro3-dependent manner. The anti-inflammatory mechanism involved SOCS1/3 upregulation and modulation of STAT1/3 signaling. PROS1 also restored Tyro3 expression downregulated by LPS stimulation. In a rat periodontitis model, PROS1 administration attenuated gingival inflammation and alveolar bone loss.\",\n      \"method\": \"In vitro LPS stimulation of human gingival epithelial cells, Tyro3 dependency established by knockdown, PCR/Western blot/ELISA/gelatin zymography, rat ligature+LPS periodontitis model with PROS1 administration\",\n      \"journal\": \"Journal of Cellular and Molecular Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Tyro3-dependent mechanism established by knockdown with multiple molecular readouts and in vivo validation, single laboratory\",\n      \"pmids\": [\"30729671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Five novel PROS1 mutations (W108C, W342R, E349K, L485S missense and a 4 bp deletion causing frameshift) cause protein S type I or III deficiency. Analysis of platelet mRNA showed mutant transcripts are expressed in significant amounts, suggesting the molecular disease mechanism is defective protein folding/instability and impaired secretion with intracellular degradation, rather than absence of mRNA. Structural modeling predicted the substitutions disrupt protein folding and/or stability.\",\n      \"method\": \"PROS1 mutation identification by sequencing, haplotype analysis with microsatellite markers, platelet mRNA analysis (RT-PCR), computer-based structural modeling of protein S\",\n      \"journal\": \"Thrombosis and Haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — mRNA expression analysis plus computational structural modeling across multiple families; mechanism (impaired folding/secretion) is inferred rather than directly demonstrated biochemically\",\n      \"pmids\": [\"11776305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Gross copy number variations (CNVs) including complete deletions, partial deletions, and duplications of the PROS1 gene are found in approximately one-third of hereditary protein S-deficient patients who are negative for point mutations by conventional sequencing, establishing large genomic rearrangements as a common molecular mechanism of PROS1-associated protein S deficiency.\",\n      \"method\": \"Multiplex ligation-dependent probe amplification (MLPA) and confirmatory quantitative PCR for copy number analysis of PROS1 in 18 protein S-deficient probands\",\n      \"journal\": \"Human Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MLPA with independent qPCR confirmation across 18 probands, single laboratory, establishes CNVs as a defined molecular mechanism\",\n      \"pmids\": [\"19466456\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Large genomic deletions of PROS1 (encompassing at least 35 kb to 449 kb) were identified in 3 of 8 (38%) protein S-deficient families lacking detectable point mutations, confirming that large deletions are a relatively common and distinct molecular mechanism causing hereditary protein S deficiency.\",\n      \"method\": \"SNP and microsatellite marker segregation analysis to identify deletions, confirmed by quantitative PCR; haplotype analysis showed all three deletions were independent events\",\n      \"journal\": \"Thrombosis and Haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genomic deletion mapping with qPCR confirmation and haplotype analysis, independent replication of large-deletion mechanism (corroborated by PMID 19466456)\",\n      \"pmids\": [\"16363235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Seven novel PROS1 mutations causing protein S deficiency were identified including missense, nonsense, and frameshift variants. The P460 allele (S/P460 variant) was found in heterozygous form in type III PS-deficient patients but also in normal individuals, suggesting it does not co-segregate as a disease-causing mutation for type III deficiency.\",\n      \"method\": \"Optimized non-isotopic SSCA/SSCP mutation detection across 15 PCR segments covering all PROS1 exons and boundaries, heteroduplex analysis, co-segregation analysis in 31 propositi\",\n      \"journal\": \"Human Mutation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mutation identification by SSCP with co-segregation, limited mechanistic follow-up beyond mutation catalog; negative finding on P460 mechanistically informative but single-laboratory study\",\n      \"pmids\": [\"10790208\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PROS1 (Protein S) functions as a secreted ligand for TAM receptor tyrosine kinases (Tyro3 and Mer/MERTK, but not Axl) on immune cells and cancer cells: in macrophages, tumor- or myeloid-derived PROS1 signals through Mer-PTP1b and Tyro3 to suppress M1 pro-inflammatory cytokine production and modulate adaptive immunity via Socs3/NF-κB and STAT/SOCS pathways, thereby regulating tumor immune evasion and metastatic potential; in cancer cells, PROS1 activates Tyro3-Erk (and context-dependently Akt) signaling to promote survival and suppress apoptosis; hereditary protein S deficiency is caused by PROS1 point mutations that lead to defective protein folding and impaired secretion, as well as by large genomic deletions/duplications that account for a substantial fraction (~35–38%) of mutation-negative cases.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PROS1 (Protein S) is a secreted ligand for the TAM-family receptor tyrosine kinases Tyro3 and Mer/MERTK — but not Axl — through which it regulates innate immune polarization and cancer-cell survival [#0, #2]. In macrophages, tumor- or myeloid-derived PROS1 engages Mer and Tyro3 to suppress M1 pro-inflammatory polarization, an effect requiring a PTP1b-Mer complex and lost in PTP1b-, Mer-, or Tyro3-deficient (but not Axl-deficient) macrophages [#0]. Myeloid-specific PROS1 acts via MERTK kinase activity and the Socs3/NF-\\u03baB pathway to restrain TNF-\\u03b1 and IL-6, while restraining IL-10 in a MERTK-independent manner; loss of myeloid PROS1 drives a pro-metastatic, EMT-promoting, IL-10-dependent macrophage secretome [#1]. In epithelial and gingival cells, exogenous PROS1 dampens LPS-induced inflammatory cytokine and MMP production in a Tyro3-dependent fashion through SOCS1/3 upregulation and STAT1/3 modulation, with protective effects in a rat periodontitis model [#4]. In cancer cells, PROS1 preferentially activates Tyro3-Erk signaling (and Akt where Tyro3 is expressed alone), promoting survival and suppressing apoptosis, and its loss triggers both extrinsic and intrinsic apoptotic pathways and reduces migration, invasion, and proliferation [#2, #3]. Hereditary protein S deficiency arises from PROS1 point mutations that cause defective folding, instability, and impaired secretion despite normal transcript levels [#5], and from large genomic deletions and duplications that account for roughly one-third of mutation-negative cases [#6, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing the spectrum of disease-causing PROS1 variants was needed to define the genetic basis of hereditary protein S deficiency; cataloging missense, nonsense, and frameshift mutations and clarifying that the P460 variant is a non-causal polymorphism sharpened genotype interpretation.\",\n      \"evidence\": \"SSCP/heteroduplex mutation detection across all PROS1 exons with co-segregation analysis in 31 propositi\",\n      \"pmids\": [\"10790208\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mutation catalog by SSCP without biochemical demonstration of the consequence of each variant\", \"No functional assay distinguishing folding versus secretion defects\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The molecular mechanism by which point mutations cause protein S deficiency was unresolved; demonstrating that mutant transcripts are present at normal levels reframed the defect as one of protein folding/stability and impaired secretion rather than absent mRNA.\",\n      \"evidence\": \"Sequencing of five novel mutations, platelet mRNA RT-PCR, and computational structural modeling across multiple families\",\n      \"pmids\": [\"11776305\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Folding/secretion defect inferred from modeling and mRNA presence, not directly measured biochemically\", \"No cellular trafficking or degradation assay for the mutant proteins\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"A substantial fraction of protein S-deficient families lack detectable point mutations; identifying large genomic deletions in 38% of such families established gross rearrangements as a distinct disease mechanism.\",\n      \"evidence\": \"SNP/microsatellite segregation mapping confirmed by qPCR, with haplotype analysis showing independent deletion events\",\n      \"pmids\": [\"16363235\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Small family number\", \"Breakpoint architecture and recurrence mechanism not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"The frequency and types of PROS1 copy number variation in mutation-negative patients were unknown; systematic MLPA confirmed complete/partial deletions and duplications in roughly one-third of cases, consolidating CNVs as a common mechanism.\",\n      \"evidence\": \"MLPA with confirmatory qPCR for copy number analysis across 18 protein S-deficient probands\",\n      \"pmids\": [\"19466456\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-laboratory cohort\", \"Functional consequence of duplications not characterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Whether PROS1 has a cell-autonomous role in tumor survival was unclear; silencing PROS1 in glioblastoma cells showed it supports proliferation, migration, invasion, and survival, linking its loss to apoptosis via both extrinsic and intrinsic pathways and to downregulation of GAS6 and TAM receptors.\",\n      \"evidence\": \"siRNA knockdown in LN18 glioblastoma cells with apoptosis, migration, invasion, proliferation, and pathway assays\",\n      \"pmids\": [\"27840905\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cell line, single laboratory\", \"Autocrine/paracrine TAM signaling inferred, not directly demonstrated\", \"Receptor specificity not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The receptor and downstream wiring of PROS1 immune signaling was undefined; reciprocal genetic knockouts established PROS1 as a ligand for Mer and Tyro3 (not Axl) that suppresses macrophage M1 polarization via a PTP1b-Mer complex, defining a tumor immune-evasion axis.\",\n      \"evidence\": \"CRISPR deletion of tumor Pros1, macrophage Mer/Tyro3/Axl/PTP1b knockouts, cytokine assays, and in vivo tumor/survival models\",\n      \"pmids\": [\"29708510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Tyro3/Mer selectivity over Axl not defined\", \"Direct PROS1-receptor binding affinities not quantified\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Whether PROS1-TAM signaling is restricted to immune cells was open; in cancer cells PROS1 was shown to preferentially activate Tyro3-Erk (and Akt when Tyro3 is alone) while Gas6 drives Axl-Akt, and to protect cells from apoptosis, establishing ligand-receptor specificity within the TAM family.\",\n      \"evidence\": \"Receptor/kinase phosphorylation Western blots across multiple cancer cell lines with ligand traps, warfarin controls, and apoptosis assays\",\n      \"pmids\": [\"31766614\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single laboratory\", \"Mechanism of context-dependent Akt activation when Tyro3 is alone not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The anti-inflammatory mechanism of PROS1 in non-immune epithelium was unknown; exogenous PROS1 was shown to suppress LPS-induced cytokines and MMPs in a Tyro3-dependent manner via SOCS1/3 and STAT1/3 modulation, with protective effects in vivo.\",\n      \"evidence\": \"LPS stimulation of human gingival epithelial cells with Tyro3 knockdown, molecular readouts, and a rat periodontitis model\",\n      \"pmids\": [\"30729671\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single laboratory\", \"Direct Tyro3 engagement by PROS1 in epithelium not biochemically demonstrated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The in vivo source and effector pathway of immunosuppressive PROS1 in metastasis were unresolved; conditional myeloid Pros1 deletion showed MERTK kinase-dependent control of TNF-\\u03b1/IL-6 via Socs3/NF-\\u03baB and MERTK-independent IL-10 regulation, linking the PROS1/MERTK axis to suppression of metastatic seeding.\",\n      \"evidence\": \"Myeloid-specific conditional Pros1 knockout, BMDM conditioned-medium EMT/invasion assays, MERTK inhibition, and two metastasis models\",\n      \"pmids\": [\"33848267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of MERTK-independent IL-10 regulation not identified\", \"Receptor mediating IL-10 control not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the same PROS1 ligand achieves cell-type- and context-dependent selectivity among Tyro3/Mer/MERTK receptors and divergent downstream outputs (Erk vs Akt; MERTK-dependent vs -independent cytokines) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of PROS1-receptor binding\", \"Determinants of receptor selectivity unknown\", \"Connection between coagulation function and TAM-ligand function not addressed in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MERTK\", \"TYRO3\", \"PTPN1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}