{"gene":"MPIG6B","run_date":"2026-06-10T02:59:51","timeline":{"discoveries":[{"year":2001,"finding":"G6b-B (MPIG6B) contains two ITIMs in its cytoplasmic tail and undergoes tyrosine phosphorylation upon pervanadate treatment; phosphorylation of tyrosine 211 is critical for interaction with SHP-1 and SHP-2, as shown by mutagenesis.","method":"Site-directed mutagenesis, co-immunoprecipitation, epitope-tagged recombinant protein expression in K562 and COS-7 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct mutagenesis identifying critical tyrosine residue, with co-immunoprecipitation in multiple cell lines by single lab","pmids":["11544253"],"is_preprint":false},{"year":2005,"finding":"The extracellular Ig-like domain of G6b-B binds heparin with high affinity in a predominantly electrostatic, salt-dependent manner, with an IC50 of ~0.5 µg/ml; other sulfated glycans showed weaker or no competition.","method":"ELISA-based heparin binding assay with competitive displacement using soluble heparin and other sulfated glycans","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro binding assay with recombinant extracellular domain, single lab, single method","pmids":["15848171"],"is_preprint":false},{"year":2006,"finding":"G6b-B is expressed on the platelet surface, undergoes tyrosine phosphorylation upon platelet stimulation, and associates with SHP-1 in stimulated platelets.","method":"Proteomics (LC-MS/MS of enriched platelet surface proteins), specific antibody immunoprecipitation, Western blot","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein identification by proteomics plus co-immunoprecipitation of SHP-1 from stimulated platelets, single lab, two orthogonal methods","pmids":["17186946"],"is_preprint":false},{"year":2007,"finding":"Cross-linking of G6b-B on platelet surfaces significantly inhibits platelet aggregation and activation by ADP and collagen-related peptide (CRP) in a calcium-independent manner, demonstrating its function as an inhibitory receptor.","method":"Platelet aggregation assay using polyclonal anti-G6B antisera for cross-linking; calcium flux measurements","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional platelet aggregation assay with receptor cross-linking, single lab, single method","pmids":["17311996"],"is_preprint":false},{"year":2007,"finding":"G6b-B expression in CD4+ T cells is upregulated by interleukin-4 via a STAT6-binding cis-acting element in the 5'-flanking region of the gene.","method":"Luciferase reporter gene assay, electrophoretic mobility shift assay (EMSA), real-time PCR","journal":"Human immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — luciferase reporter and EMSA identifying STAT6 site, single lab, two orthogonal methods","pmids":["17678728"],"is_preprint":false},{"year":2008,"finding":"G6b-B inhibits both constitutive and agonist-induced ITAM/hemi-ITAM signaling by GPVI-FcRγ and CLEC-2 in a cell line model; this inhibition requires the conserved ITIM tyrosines of G6b-B but is independent of SHP-1, SHP-2, and SHIP.","method":"NFAT transcriptional reporter assay in cell lines, ITIM tyrosine mutagenesis, pharmacological inhibitors of Src/Syk family kinases","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis combined with functional reporter assay and pharmacological dissection in cell line model, single lab, multiple orthogonal approaches","pmids":["18955485"],"is_preprint":false},{"year":2012,"finding":"G6b-B associates with both SHP-1 and SHP-2 in human platelets; the tandem SH2 domains of SHP-2 bind G6b-B with ~100-fold higher affinity than SHP-1; SHP-2 can bind when only one ITIM/ITSM motif is phosphorylated (N-terminal SH2 domain with ITIM being most important), whereas SHP-1 requires dual phosphorylation; Syk and PLCγ2 also demonstrate specificity for phosphorylated G6b-B motifs.","method":"Co-immunoprecipitation from human platelets, direct in vitro binding assays (surface plasmon resonance / affinity measurements), SH2 domain specificity profiling","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct binding assays with quantitative affinity measurements combined with reciprocal co-IP from platelets, single lab, multiple orthogonal methods","pmids":["23185356"],"is_preprint":false},{"year":2012,"finding":"G6b-B-deficient mice exhibit macrothrombocytopenia due to increased platelet turnover, enhanced metalloproteinase-mediated shedding of GPVI and GPIbα from megakaryocyte surfaces, reduced integrin-mediated functions, and defective proplatelet formation, establishing G6b-B as a major inhibitory receptor regulating megakaryocyte activation and platelet production.","method":"G6b-B knockout mouse model, flow cytometry, metalloproteinase inhibitor rescue experiments, platelet turnover assays, proplatelet formation assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with multiple specific cellular phenotypic readouts and pharmacological rescue, replicated across multiple assays in a single rigorous study","pmids":["23112346"],"is_preprint":false},{"year":2018,"finding":"Mutation of the two ITIM/ITSM tyrosines (Y212 and Y238) of G6b-B to phenylalanine (uncoupling from Shp1/Shp2) in mice causes macrothrombocytopenia, megakaryocyte clusters, and myelofibrosis similar to full G6b-B knockout; G6b-B inhibits CLEC-2-mediated platelet activation through Shp2.","method":"Transgenic knock-in mouse model (G6b-B diY/F), flow cytometry, platelet aggregation assays, comparison with G6b KO and MK-specific Shp2 KO mice","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous knock-in mutagenesis in vivo with multiple orthogonal readouts and genetic epistasis comparison across three mouse models","pmids":["29891536"],"is_preprint":false},{"year":2019,"finding":"The heparan sulfate proteoglycan perlecan is a G6b-B extracellular binding partner; the interaction is specifically mediated by heparan sulfate (HS) chains (not the protein core); heparin forms a high-affinity complex with G6b-B and mediates dimerization; binding to HS/multivalent heparin induces downstream signaling via Shp1 and Shp2 to inhibit platelet and megakaryocyte function.","method":"Immunohistochemistry, affinity chromatography, proteomics, in vitro biochemical binding assays, cell-based genetic screen, biophysical analysis (dimerization), functional assays with human platelets and genetically modified mice","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (affinity chromatography, proteomics, biophysics, genetic screen, functional assays in primary human and mouse cells), single lab with comprehensive evidence","pmids":["31436532"],"is_preprint":false},{"year":2022,"finding":"Loss of G6b-B impairs an early step of megakaryocyte differentiation: G6b-B-deficient megakaryocytes are smaller, have a less-developed demarcation membrane system, show globally reduced megakaryocyte-specific transcripts, decreased GATA-1 protein levels, and impaired thrombopoietin signaling.","method":"Spontaneous knock-in mutant mouse model (intronic SNV abolishing G6b-B expression), RNA sequencing, Western blot, confocal microscopy of demarcation membrane system","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function mouse model with RNA-seq plus protein-level validation and morphological readouts, single lab, multiple orthogonal methods","pmids":["35134123"],"is_preprint":false},{"year":2023,"finding":"In G6b-B knockout mice, elevated Syk kinase activity contributes to macrothrombocytopenia and loss of GPVI/α2β1; Syk loss-of-function (R41A) rescued macrothrombocytopenia and GPVI/α2β1 expression; romiplostim (thrombopoietin mimetic) rescued thrombocytopenia, GPVI expression, and collagen reactivity, suggesting G6b-B regulates a cell-intrinsic feedback mechanism controlling platelet reactivity.","method":"Genetic rescue (Syk R41A knock-in in G6b KO background), pharmacological treatment (Syk inhibitor BI1002494, dasatinib, romiplostim), flow cytometry, platelet aggregation assays","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological epistasis with multiple specific readouts, single lab, multiple orthogonal approaches","pmids":["36269841"],"is_preprint":false},{"year":2024,"finding":"Bispecific single-chain variable fragments (CAPRIs) that hetero-cluster G6b-B with GPVI-FcRγ or FcγRIIA (CD32A) inhibit collagen- or immune complex-induced platelet aggregation and thrombus formation under arterial shear, demonstrating that G6b-B's ITIM-mediated inhibitory signaling can be artificially engaged in trans to suppress ITAM-containing receptor activation.","method":"Bispecific scFv (bi-scFv) engineering, platelet aggregation assays, microfluidic thrombus formation assays under arterial shear, photochemical endothelial injury model","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional platelet and thrombus assays with engineered bispecific antibodies, preprint, single lab","pmids":["38798354"],"is_preprint":true}],"current_model":"G6b-B (MPIG6B) is a megakaryocyte- and platelet-specific ITIM/ITSM-containing inhibitory receptor whose extracellular Ig-like domain binds heparan sulfates (including perlecan HS chains and heparin, the latter inducing receptor dimerization), and whose cytoplasmic tyrosines Y212/Y238 are phosphorylated upon activation to recruit SHP-1 (requiring dual phosphorylation) and SHP-2 (requiring only single phosphorylation, with ~100-fold higher affinity than SHP-1); through these phosphatases, G6b-B suppresses constitutive and agonist-induced ITAM/hemi-ITAM signaling by GPVI-FcRγ and CLEC-2, restrains metalloproteinase-mediated receptor shedding, supports proplatelet formation and an early GATA-1-dependent step in megakaryocyte maturation including thrombopoietin signaling, and controls Syk activity to maintain normal GPVI and integrin α2β1 surface levels; loss of G6b-B or uncoupling from Shp1/Shp2 causes macrothrombocytopenia and myelofibrosis in mice and humans."},"narrative":{"mechanistic_narrative":"MPIG6B (G6b-B) is a megakaryocyte- and platelet-expressed inhibitory immunoreceptor that restrains ITAM/hemi-ITAM-driven activation to control platelet production and reactivity [PMID:17186946, PMID:23112346]. Its cytoplasmic tail carries two ITIM/ITSM tyrosines (Y212/Y238) that become phosphorylated upon platelet stimulation and serve as docking sites for the tyrosine phosphatases SHP-1 and SHP-2, with SHP-2 binding through its tandem SH2 domains at ~100-fold higher affinity and requiring only single-motif phosphorylation, whereas SHP-1 requires dual phosphorylation [PMID:11544253, PMID:17186946, PMID:23185356]. Through these phosphatases, G6b-B suppresses constitutive and agonist-induced signaling by the GPVI-FcRγ and CLEC-2 receptors and dampens platelet aggregation in response to collagen-related peptide and ADP [PMID:17311996, PMID:18955485, PMID:29891536]. The extracellular Ig-like domain engages heparan sulfate, binding heparin with high affinity in an electrostatic manner and recognizing the heparan sulfate chains of perlecan; multivalent heparin induces receptor dimerization and triggers Shp1/Shp2-dependent inhibitory signaling [PMID:15848171, PMID:31436532]. Loss of G6b-B or uncoupling of its ITIMs from Shp1/Shp2 causes macrothrombocytopenia, megakaryocyte clustering and myelofibrosis driven by elevated metalloproteinase-mediated shedding of GPVI and GPIbα, defective proplatelet formation, and unrestrained Syk kinase activity, and additionally impairs an early GATA-1- and thrombopoietin-dependent step of megakaryocyte maturation [PMID:23112346, PMID:29891536, PMID:35134123, PMID:36269841].","teleology":[{"year":2001,"claim":"Established that G6b-B is an ITIM-bearing receptor whose phosphorylation recruits the SHP phosphatases, defining its candidate inhibitory wiring.","evidence":"Site-directed mutagenesis and co-immunoprecipitation of epitope-tagged protein in K562 and COS-7 cells","pmids":["11544253"],"confidence":"High","gaps":["Done in heterologous cell lines, not platelets","No physiological agonist or downstream functional output tested"]},{"year":2005,"claim":"Identified the extracellular ligand chemistry, showing the Ig-like domain binds sulfated glycans, pointing to heparin/heparan sulfate recognition.","evidence":"ELISA-based competitive heparin binding assay with recombinant extracellular domain","pmids":["15848171"],"confidence":"Medium","gaps":["Physiological ligand not yet identified","In vitro binding only, no cellular consequence"]},{"year":2006,"claim":"Placed G6b-B on the platelet surface and confirmed stimulation-dependent phosphorylation and SHP-1 association in primary cells.","evidence":"Platelet surface proteomics plus immunoprecipitation and Western blot from stimulated platelets","pmids":["17186946"],"confidence":"Medium","gaps":["Correlative association, no functional consequence shown","SHP-2 binding not assessed here"]},{"year":2007,"claim":"Demonstrated directly that engaging G6b-B inhibits platelet activation, establishing its function as an inhibitory receptor.","evidence":"Platelet aggregation and calcium flux assays with anti-G6B cross-linking against ADP and CRP","pmids":["17311996"],"confidence":"Medium","gaps":["Mechanism of inhibition not dissected","Antibody cross-linking is non-physiological engagement"]},{"year":2008,"claim":"Mapped the inhibitory target to ITAM/hemi-ITAM signaling by GPVI-FcRγ and CLEC-2 and showed ITIM-dependence, while finding it phosphatase-independent in this model.","evidence":"NFAT reporter assay in cell lines with ITIM mutagenesis and Src/Syk inhibitors","pmids":["18955485"],"confidence":"High","gaps":["Phosphatase-independence in cell line conflicts with platelet data","Cell line model may not reflect megakaryocyte context"]},{"year":2012,"claim":"Resolved the molecular basis of phosphatase recruitment, distinguishing high-affinity single-motif SHP-2 binding from dual-phosphorylation-dependent SHP-1 binding.","evidence":"Reciprocal co-IP from human platelets with quantitative SH2-domain affinity measurements","pmids":["23185356"],"confidence":"High","gaps":["Relative in vivo contribution of SHP-1 versus SHP-2 not resolved here","Functional readout of differential binding not tested"]},{"year":2012,"claim":"Defined the in vivo role through knockout, linking G6b-B loss to macrothrombocytopenia via receptor shedding and defective platelet production.","evidence":"G6b-B knockout mice with flow cytometry, metalloproteinase-inhibitor rescue, turnover and proplatelet assays","pmids":["23112346"],"confidence":"High","gaps":["Full knockout cannot separate signaling from structural roles","Ligand driving signaling in vivo unidentified at this stage"]},{"year":2018,"claim":"Showed that the ITIM/Shp coupling itself is required in vivo, as ITIM-to-phenylalanine knock-in phenocopies knockout including myelofibrosis.","evidence":"G6b-B diY/F knock-in mice compared with KO and MK-specific Shp2 KO, with aggregation assays","pmids":["29891536"],"confidence":"High","gaps":["Does not separate Shp1 from Shp2 contributions fully","Trigger for in vivo ITIM phosphorylation not defined here"]},{"year":2019,"claim":"Identified the physiological ligand as perlecan heparan sulfate and showed heparin-induced dimerization couples ligand engagement to Shp1/Shp2 inhibitory signaling.","evidence":"Affinity chromatography, proteomics, biophysics, genetic screen and functional assays in human platelets and mice","pmids":["31436532"],"confidence":"High","gaps":["Spatial source of perlecan HS engaging the receptor in vivo not mapped","Stoichiometry of physiological clustering unresolved"]},{"year":2022,"claim":"Extended the role beyond signaling restraint to megakaryocyte maturation, implicating GATA-1 and thrombopoietin signaling in an early differentiation step.","evidence":"Spontaneous loss-of-function knock-in mouse with RNA-seq, Western blot and confocal imaging of the demarcation membrane system","pmids":["35134123"],"confidence":"High","gaps":["Mechanism linking G6b-B to GATA-1 levels not established","Whether maturation defect is cell-intrinsic to the receptor or secondary unresolved"]},{"year":2023,"claim":"Identified elevated Syk activity as a driver of the knockout phenotype and showed thrombopoietin-mimetic rescue, framing G6b-B as a cell-intrinsic feedback regulator of platelet reactivity.","evidence":"Syk R41A genetic rescue in G6b KO, Syk inhibitors and romiplostim, with flow cytometry and aggregation assays","pmids":["36269841"],"confidence":"High","gaps":["Direct biochemical link between G6b-B and Syk regulation not detailed","Relationship between Syk control and maturation defect not integrated"]},{"year":2024,"claim":"Demonstrated that G6b-B inhibitory signaling can be engaged in trans to suppress GPVI- and FcγRIIA-driven thrombosis, establishing therapeutic targetability.","evidence":"Bispecific scFv hetero-clustering with aggregation and microfluidic thrombus assays under arterial shear (preprint)","pmids":["38798354"],"confidence":"Medium","gaps":["Preprint, single lab, not peer-reviewed","In vivo efficacy and safety not established"]},{"year":null,"claim":"How heparan sulfate ligand engagement is spatially and temporally controlled in the marrow niche, and how G6b-B mechanistically couples to GATA-1 and Syk during maturation, remain open.","evidence":"No timeline discovery resolves these questions","pmids":[],"confidence":"Low","gaps":["No mechanism linking receptor signaling to GATA-1 regulation","Physiological source and geometry of perlecan-HS ligand undefined","Direct mode of Syk activity control not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,5,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,6,5]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,3]}],"pathway":[{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[3,7,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,6,9]}],"complexes":[],"partners":["PTPN6","PTPN11","SYK","PLCG2","HSPG2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O95866","full_name":"Megakaryocyte and platelet inhibitory receptor G6b","aliases":["Protein G6b"],"length_aa":241,"mass_kda":26.2,"function":"Inhibitory receptor that acts as a critical regulator of hematopoietic lineage differentiation, megakaryocyte function and platelet production (PubMed:12665801, PubMed:17311996, PubMed:27743390). Inhibits platelet aggregation and activation by agonists such as ADP and collagen-related peptide (PubMed:12665801). This regulation of megakaryocate function as well as platelet production ann activation is done through the inhibition (via the 2 ITIM motifs) of the receptors CLEC1B and GP6:FcRgamma signaling (PubMed:17311996). Appears to operate in a calcium-independent manner (PubMed:12665801) Isoform B, displayed in this entry, is the only isoform to contain both a transmembrane region and 2 immunoreceptor tyrosine-based inhibitor motifs (ITIMs) and, thus, the only one which probably has a role of inhibitory receptor. Isoform A may be the activating counterpart of isoform B","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/O95866/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MPIG6B","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MPIG6B","total_profiled":1310},"omim":[{"mim_id":"617441","title":"THROMBOCYTOPENIA, ANEMIA, AND MYELOFIBROSIS; THAMY","url":"https://www.omim.org/entry/617441"},{"mim_id":"611822","title":"MITOCHONDRIAL RIBOSOMAL PROTEIN L2; MRPL2","url":"https://www.omim.org/entry/611822"},{"mim_id":"606520","title":"MEGAKARYOCYTE AND PLATELET INHIBITORY RECEPTOR G6B; MPIG6B","url":"https://www.omim.org/entry/606520"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Endoplasmic reticulum","reliability":"Additional"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":4.5},{"tissue":"skin 1","ntpm":7.7}],"url":"https://www.proteinatlas.org/search/MPIG6B"},"hgnc":{"alias_symbol":["G6b","NG31","G6b-B"],"prev_symbol":["C6orf25"]},"alphafold":{"accession":"O95866","domains":[{"cath_id":"2.60.40.10","chopping":"23-123","consensus_level":"high","plddt":92.2502,"start":23,"end":123}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O95866","model_url":"https://alphafold.ebi.ac.uk/files/AF-O95866-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O95866-F1-predicted_aligned_error_v6.png","plddt_mean":73.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MPIG6B","jax_strain_url":"https://www.jax.org/strain/search?query=MPIG6B"},"sequence":{"accession":"O95866","fasta_url":"https://rest.uniprot.org/uniprotkb/O95866.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O95866/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O95866"}},"corpus_meta":[{"pmid":"17186946","id":"PMC_17186946","title":"A comprehensive proteomics and genomics analysis reveals novel transmembrane proteins in human platelets and mouse megakaryocytes including G6b-B, a novel immunoreceptor tyrosine-based inhibitory motif protein.","date":"2006","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/17186946","citation_count":122,"is_preprint":false},{"pmid":"23112346","id":"PMC_23112346","title":"Mice lacking the ITIM-containing receptor G6b-B exhibit macrothrombocytopenia and aberrant platelet function.","date":"2012","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/23112346","citation_count":66,"is_preprint":false},{"pmid":"17311996","id":"PMC_17311996","title":"The novel inhibitory receptor G6B is expressed on the surface of platelets and attenuates platelet function in vitro.","date":"2007","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/17311996","citation_count":53,"is_preprint":false},{"pmid":"31436532","id":"PMC_31436532","title":"Heparan sulfates are critical regulators of the inhibitory megakaryocyte-platelet receptor G6b-B.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31436532","citation_count":52,"is_preprint":false},{"pmid":"18955485","id":"PMC_18955485","title":"G6b-B inhibits constitutive and agonist-induced signaling by glycoprotein VI and CLEC-2.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18955485","citation_count":47,"is_preprint":false},{"pmid":"11544253","id":"PMC_11544253","title":"G6b, a novel immunoglobulin superfamily member encoded in the human major histocompatibility complex, interacts with SHP-1 and SHP-2.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11544253","citation_count":46,"is_preprint":false},{"pmid":"29898956","id":"PMC_29898956","title":"Congenital macrothrombocytopenia with focal myelofibrosis due to mutations in human G6b-B is rescued in humanized 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expression.","date":"2025","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/40643151","citation_count":2,"is_preprint":false},{"pmid":"38798354","id":"PMC_38798354","title":"G6b-B antibody-based cis-acting platelet receptor inhibitors (CAPRIs) as a new family of anti-thrombotic therapeutics.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38798354","citation_count":2,"is_preprint":false},{"pmid":"38481905","id":"PMC_38481905","title":"A Rare MPIG6B Gene Mutation in a Saudi Adolescent Male With Thrombocytopenia, Anemia, and Myelofibrosis: A Case Report.","date":"2024","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/38481905","citation_count":2,"is_preprint":false},{"pmid":"38694137","id":"PMC_38694137","title":"MPIG6B Gene-Related Myelofibrosis: A Rare Inherited Disease That Is Frequently Described in Arab Population.","date":"2024","source":"Avicenna journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38694137","citation_count":2,"is_preprint":false},{"pmid":"41838173","id":"PMC_41838173","title":"MPIG6B-related thrombocytopenia and myelofibrosis: A case report.","date":"2026","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/41838173","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13594,"output_tokens":3466,"usd":0.046386,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10989,"output_tokens":3677,"usd":0.073435,"stage2_stop_reason":"end_turn"},"total_usd":0.119821,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"G6b-B (MPIG6B) contains two ITIMs in its cytoplasmic tail and undergoes tyrosine phosphorylation upon pervanadate treatment; phosphorylation of tyrosine 211 is critical for interaction with SHP-1 and SHP-2, as shown by mutagenesis.\",\n      \"method\": \"Site-directed mutagenesis, co-immunoprecipitation, epitope-tagged recombinant protein expression in K562 and COS-7 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct mutagenesis identifying critical tyrosine residue, with co-immunoprecipitation in multiple cell lines by single lab\",\n      \"pmids\": [\"11544253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The extracellular Ig-like domain of G6b-B binds heparin with high affinity in a predominantly electrostatic, salt-dependent manner, with an IC50 of ~0.5 µg/ml; other sulfated glycans showed weaker or no competition.\",\n      \"method\": \"ELISA-based heparin binding assay with competitive displacement using soluble heparin and other sulfated glycans\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro binding assay with recombinant extracellular domain, single lab, single method\",\n      \"pmids\": [\"15848171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"G6b-B is expressed on the platelet surface, undergoes tyrosine phosphorylation upon platelet stimulation, and associates with SHP-1 in stimulated platelets.\",\n      \"method\": \"Proteomics (LC-MS/MS of enriched platelet surface proteins), specific antibody immunoprecipitation, Western blot\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein identification by proteomics plus co-immunoprecipitation of SHP-1 from stimulated platelets, single lab, two orthogonal methods\",\n      \"pmids\": [\"17186946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cross-linking of G6b-B on platelet surfaces significantly inhibits platelet aggregation and activation by ADP and collagen-related peptide (CRP) in a calcium-independent manner, demonstrating its function as an inhibitory receptor.\",\n      \"method\": \"Platelet aggregation assay using polyclonal anti-G6B antisera for cross-linking; calcium flux measurements\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional platelet aggregation assay with receptor cross-linking, single lab, single method\",\n      \"pmids\": [\"17311996\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"G6b-B expression in CD4+ T cells is upregulated by interleukin-4 via a STAT6-binding cis-acting element in the 5'-flanking region of the gene.\",\n      \"method\": \"Luciferase reporter gene assay, electrophoretic mobility shift assay (EMSA), real-time PCR\",\n      \"journal\": \"Human immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — luciferase reporter and EMSA identifying STAT6 site, single lab, two orthogonal methods\",\n      \"pmids\": [\"17678728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"G6b-B inhibits both constitutive and agonist-induced ITAM/hemi-ITAM signaling by GPVI-FcRγ and CLEC-2 in a cell line model; this inhibition requires the conserved ITIM tyrosines of G6b-B but is independent of SHP-1, SHP-2, and SHIP.\",\n      \"method\": \"NFAT transcriptional reporter assay in cell lines, ITIM tyrosine mutagenesis, pharmacological inhibitors of Src/Syk family kinases\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis combined with functional reporter assay and pharmacological dissection in cell line model, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"18955485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"G6b-B associates with both SHP-1 and SHP-2 in human platelets; the tandem SH2 domains of SHP-2 bind G6b-B with ~100-fold higher affinity than SHP-1; SHP-2 can bind when only one ITIM/ITSM motif is phosphorylated (N-terminal SH2 domain with ITIM being most important), whereas SHP-1 requires dual phosphorylation; Syk and PLCγ2 also demonstrate specificity for phosphorylated G6b-B motifs.\",\n      \"method\": \"Co-immunoprecipitation from human platelets, direct in vitro binding assays (surface plasmon resonance / affinity measurements), SH2 domain specificity profiling\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct binding assays with quantitative affinity measurements combined with reciprocal co-IP from platelets, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23185356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"G6b-B-deficient mice exhibit macrothrombocytopenia due to increased platelet turnover, enhanced metalloproteinase-mediated shedding of GPVI and GPIbα from megakaryocyte surfaces, reduced integrin-mediated functions, and defective proplatelet formation, establishing G6b-B as a major inhibitory receptor regulating megakaryocyte activation and platelet production.\",\n      \"method\": \"G6b-B knockout mouse model, flow cytometry, metalloproteinase inhibitor rescue experiments, platelet turnover assays, proplatelet formation assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with multiple specific cellular phenotypic readouts and pharmacological rescue, replicated across multiple assays in a single rigorous study\",\n      \"pmids\": [\"23112346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Mutation of the two ITIM/ITSM tyrosines (Y212 and Y238) of G6b-B to phenylalanine (uncoupling from Shp1/Shp2) in mice causes macrothrombocytopenia, megakaryocyte clusters, and myelofibrosis similar to full G6b-B knockout; G6b-B inhibits CLEC-2-mediated platelet activation through Shp2.\",\n      \"method\": \"Transgenic knock-in mouse model (G6b-B diY/F), flow cytometry, platelet aggregation assays, comparison with G6b KO and MK-specific Shp2 KO mice\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous knock-in mutagenesis in vivo with multiple orthogonal readouts and genetic epistasis comparison across three mouse models\",\n      \"pmids\": [\"29891536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The heparan sulfate proteoglycan perlecan is a G6b-B extracellular binding partner; the interaction is specifically mediated by heparan sulfate (HS) chains (not the protein core); heparin forms a high-affinity complex with G6b-B and mediates dimerization; binding to HS/multivalent heparin induces downstream signaling via Shp1 and Shp2 to inhibit platelet and megakaryocyte function.\",\n      \"method\": \"Immunohistochemistry, affinity chromatography, proteomics, in vitro biochemical binding assays, cell-based genetic screen, biophysical analysis (dimerization), functional assays with human platelets and genetically modified mice\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (affinity chromatography, proteomics, biophysics, genetic screen, functional assays in primary human and mouse cells), single lab with comprehensive evidence\",\n      \"pmids\": [\"31436532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of G6b-B impairs an early step of megakaryocyte differentiation: G6b-B-deficient megakaryocytes are smaller, have a less-developed demarcation membrane system, show globally reduced megakaryocyte-specific transcripts, decreased GATA-1 protein levels, and impaired thrombopoietin signaling.\",\n      \"method\": \"Spontaneous knock-in mutant mouse model (intronic SNV abolishing G6b-B expression), RNA sequencing, Western blot, confocal microscopy of demarcation membrane system\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function mouse model with RNA-seq plus protein-level validation and morphological readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35134123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In G6b-B knockout mice, elevated Syk kinase activity contributes to macrothrombocytopenia and loss of GPVI/α2β1; Syk loss-of-function (R41A) rescued macrothrombocytopenia and GPVI/α2β1 expression; romiplostim (thrombopoietin mimetic) rescued thrombocytopenia, GPVI expression, and collagen reactivity, suggesting G6b-B regulates a cell-intrinsic feedback mechanism controlling platelet reactivity.\",\n      \"method\": \"Genetic rescue (Syk R41A knock-in in G6b KO background), pharmacological treatment (Syk inhibitor BI1002494, dasatinib, romiplostim), flow cytometry, platelet aggregation assays\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological epistasis with multiple specific readouts, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"36269841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Bispecific single-chain variable fragments (CAPRIs) that hetero-cluster G6b-B with GPVI-FcRγ or FcγRIIA (CD32A) inhibit collagen- or immune complex-induced platelet aggregation and thrombus formation under arterial shear, demonstrating that G6b-B's ITIM-mediated inhibitory signaling can be artificially engaged in trans to suppress ITAM-containing receptor activation.\",\n      \"method\": \"Bispecific scFv (bi-scFv) engineering, platelet aggregation assays, microfluidic thrombus formation assays under arterial shear, photochemical endothelial injury model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional platelet and thrombus assays with engineered bispecific antibodies, preprint, single lab\",\n      \"pmids\": [\"38798354\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"G6b-B (MPIG6B) is a megakaryocyte- and platelet-specific ITIM/ITSM-containing inhibitory receptor whose extracellular Ig-like domain binds heparan sulfates (including perlecan HS chains and heparin, the latter inducing receptor dimerization), and whose cytoplasmic tyrosines Y212/Y238 are phosphorylated upon activation to recruit SHP-1 (requiring dual phosphorylation) and SHP-2 (requiring only single phosphorylation, with ~100-fold higher affinity than SHP-1); through these phosphatases, G6b-B suppresses constitutive and agonist-induced ITAM/hemi-ITAM signaling by GPVI-FcRγ and CLEC-2, restrains metalloproteinase-mediated receptor shedding, supports proplatelet formation and an early GATA-1-dependent step in megakaryocyte maturation including thrombopoietin signaling, and controls Syk activity to maintain normal GPVI and integrin α2β1 surface levels; loss of G6b-B or uncoupling from Shp1/Shp2 causes macrothrombocytopenia and myelofibrosis in mice and humans.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MPIG6B (G6b-B) is a megakaryocyte- and platelet-expressed inhibitory immunoreceptor that restrains ITAM/hemi-ITAM-driven activation to control platelet production and reactivity [#2, #7]. Its cytoplasmic tail carries two ITIM/ITSM tyrosines (Y212/Y238) that become phosphorylated upon platelet stimulation and serve as docking sites for the tyrosine phosphatases SHP-1 and SHP-2, with SHP-2 binding through its tandem SH2 domains at ~100-fold higher affinity and requiring only single-motif phosphorylation, whereas SHP-1 requires dual phosphorylation [#0, #2, #6]. Through these phosphatases, G6b-B suppresses constitutive and agonist-induced signaling by the GPVI-FcRγ and CLEC-2 receptors and dampens platelet aggregation in response to collagen-related peptide and ADP [#3, #5, #8]. The extracellular Ig-like domain engages heparan sulfate, binding heparin with high affinity in an electrostatic manner and recognizing the heparan sulfate chains of perlecan; multivalent heparin induces receptor dimerization and triggers Shp1/Shp2-dependent inhibitory signaling [#1, #9]. Loss of G6b-B or uncoupling of its ITIMs from Shp1/Shp2 causes macrothrombocytopenia, megakaryocyte clustering and myelofibrosis driven by elevated metalloproteinase-mediated shedding of GPVI and GPIbα, defective proplatelet formation, and unrestrained Syk kinase activity, and additionally impairs an early GATA-1- and thrombopoietin-dependent step of megakaryocyte maturation [#7, #8, #10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established that G6b-B is an ITIM-bearing receptor whose phosphorylation recruits the SHP phosphatases, defining its candidate inhibitory wiring.\",\n      \"evidence\": \"Site-directed mutagenesis and co-immunoprecipitation of epitope-tagged protein in K562 and COS-7 cells\",\n      \"pmids\": [\"11544253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Done in heterologous cell lines, not platelets\", \"No physiological agonist or downstream functional output tested\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified the extracellular ligand chemistry, showing the Ig-like domain binds sulfated glycans, pointing to heparin/heparan sulfate recognition.\",\n      \"evidence\": \"ELISA-based competitive heparin binding assay with recombinant extracellular domain\",\n      \"pmids\": [\"15848171\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological ligand not yet identified\", \"In vitro binding only, no cellular consequence\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed G6b-B on the platelet surface and confirmed stimulation-dependent phosphorylation and SHP-1 association in primary cells.\",\n      \"evidence\": \"Platelet surface proteomics plus immunoprecipitation and Western blot from stimulated platelets\",\n      \"pmids\": [\"17186946\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative association, no functional consequence shown\", \"SHP-2 binding not assessed here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated directly that engaging G6b-B inhibits platelet activation, establishing its function as an inhibitory receptor.\",\n      \"evidence\": \"Platelet aggregation and calcium flux assays with anti-G6B cross-linking against ADP and CRP\",\n      \"pmids\": [\"17311996\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of inhibition not dissected\", \"Antibody cross-linking is non-physiological engagement\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapped the inhibitory target to ITAM/hemi-ITAM signaling by GPVI-FcRγ and CLEC-2 and showed ITIM-dependence, while finding it phosphatase-independent in this model.\",\n      \"evidence\": \"NFAT reporter assay in cell lines with ITIM mutagenesis and Src/Syk inhibitors\",\n      \"pmids\": [\"18955485\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase-independence in cell line conflicts with platelet data\", \"Cell line model may not reflect megakaryocyte context\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Resolved the molecular basis of phosphatase recruitment, distinguishing high-affinity single-motif SHP-2 binding from dual-phosphorylation-dependent SHP-1 binding.\",\n      \"evidence\": \"Reciprocal co-IP from human platelets with quantitative SH2-domain affinity measurements\",\n      \"pmids\": [\"23185356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative in vivo contribution of SHP-1 versus SHP-2 not resolved here\", \"Functional readout of differential binding not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined the in vivo role through knockout, linking G6b-B loss to macrothrombocytopenia via receptor shedding and defective platelet production.\",\n      \"evidence\": \"G6b-B knockout mice with flow cytometry, metalloproteinase-inhibitor rescue, turnover and proplatelet assays\",\n      \"pmids\": [\"23112346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full knockout cannot separate signaling from structural roles\", \"Ligand driving signaling in vivo unidentified at this stage\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed that the ITIM/Shp coupling itself is required in vivo, as ITIM-to-phenylalanine knock-in phenocopies knockout including myelofibrosis.\",\n      \"evidence\": \"G6b-B diY/F knock-in mice compared with KO and MK-specific Shp2 KO, with aggregation assays\",\n      \"pmids\": [\"29891536\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not separate Shp1 from Shp2 contributions fully\", \"Trigger for in vivo ITIM phosphorylation not defined here\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified the physiological ligand as perlecan heparan sulfate and showed heparin-induced dimerization couples ligand engagement to Shp1/Shp2 inhibitory signaling.\",\n      \"evidence\": \"Affinity chromatography, proteomics, biophysics, genetic screen and functional assays in human platelets and mice\",\n      \"pmids\": [\"31436532\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Spatial source of perlecan HS engaging the receptor in vivo not mapped\", \"Stoichiometry of physiological clustering unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended the role beyond signaling restraint to megakaryocyte maturation, implicating GATA-1 and thrombopoietin signaling in an early differentiation step.\",\n      \"evidence\": \"Spontaneous loss-of-function knock-in mouse with RNA-seq, Western blot and confocal imaging of the demarcation membrane system\",\n      \"pmids\": [\"35134123\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking G6b-B to GATA-1 levels not established\", \"Whether maturation defect is cell-intrinsic to the receptor or secondary unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified elevated Syk activity as a driver of the knockout phenotype and showed thrombopoietin-mimetic rescue, framing G6b-B as a cell-intrinsic feedback regulator of platelet reactivity.\",\n      \"evidence\": \"Syk R41A genetic rescue in G6b KO, Syk inhibitors and romiplostim, with flow cytometry and aggregation assays\",\n      \"pmids\": [\"36269841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between G6b-B and Syk regulation not detailed\", \"Relationship between Syk control and maturation defect not integrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that G6b-B inhibitory signaling can be engaged in trans to suppress GPVI- and FcγRIIA-driven thrombosis, establishing therapeutic targetability.\",\n      \"evidence\": \"Bispecific scFv hetero-clustering with aggregation and microfluidic thrombus assays under arterial shear (preprint)\",\n      \"pmids\": [\"38798354\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab, not peer-reviewed\", \"In vivo efficacy and safety not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How heparan sulfate ligand engagement is spatially and temporally controlled in the marrow niche, and how G6b-B mechanistically couples to GATA-1 and Syk during maturation, remain open.\",\n      \"evidence\": \"No timeline discovery resolves these questions\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No mechanism linking receptor signaling to GATA-1 regulation\", \"Physiological source and geometry of perlecan-HS ligand undefined\", \"Direct mode of Syk activity control not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 5, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 6, 5]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [3, 7, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 6, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PTPN6\", \"PTPN11\", \"SYK\", \"PLCG2\", \"HSPG2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}