{"gene":"MPP3","run_date":"2026-06-10T02:59:51","timeline":{"discoveries":[{"year":2003,"finding":"TSLC1 (CADM1) directly associates with MPP3 via a PDZ-binding motif at the carboxyl terminus of TSLC1; this interaction depends on the PDZ domain of MPP3, and both proteins colocalize at cell-cell attachment sites.","method":"Co-immunoprecipitation, PDZ-binding motif mutagenesis, colocalization imaging","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assay with domain-deletion mutant and colocalization, single lab","pmids":["13679854"],"is_preprint":false},{"year":2006,"finding":"MPP3 prevents desensitization of the serotonin 5-HT2C receptor Ca2+ response in heterologous cells and cortical neurons, and stabilizes cell-surface expression of the receptor, in contrast to PSD-95 which increases desensitization; both effects are mediated through PDZ-domain interaction with the receptor C-terminus.","method":"Calcium response assays in transfected cells and primary cortical neurons, Tat-peptide displacement of PDZ interactions, surface receptor quantification","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay with peptide inhibitor and receptor quantification in neurons, single lab, two orthogonal methods","pmids":["16914526"],"is_preprint":false},{"year":2006,"finding":"MPP3 is recruited to the MPP5 (PALS1) protein scaffold at the retinal outer limiting membrane (OLM), colocalizing with MPP5 and CRB1 at the subapical region; MPP3 also forms separate complexes with DLG1 at the outer plexiform layer, distinct from MPP4/DLG1 complexes.","method":"Immunofluorescence colocalization in human and mouse retina, in vivo co-immunoprecipitation","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo Co-IP and localization in retinal tissue, single lab, two orthogonal methods","pmids":["16519681"],"is_preprint":false},{"year":2013,"finding":"MPP3 is required for maintenance of the apical junctional complex and adherens junctions in cortical progenitor cells; conditional Mpp3 knockout in mouse cortex causes loss of apical complex proteins, randomized spindle orientation, ectopic mitoses, delayed neuronal migration, and defective cortical stratification without affecting cell division rate or cell-cycle exit.","method":"Conditional knockout mouse (Mpp3 cKO), immunostaining, spindle orientation analysis, BrdU/EdU cell-cycle analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with multiple specific cellular phenotype readouts (spindle orientation, migration, stratification) using orthogonal methods","pmids":["23658188"],"is_preprint":false},{"year":2013,"finding":"MPP3 is required for maintaining proper levels of PALS1 (MPP5) at the subapical region of the retina; loss of MPP3 in conditional knockout mice causes significant reduction of PALS1 at the OLM and accelerates retinal degeneration when combined with Pals1 knockdown.","method":"Conditional Mpp3 knockout mouse, immunostaining, electroretinography, genetic double-mutant epistasis with Pals1 conditional knockdown","journal":"Glia","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with protein-level phenotype and genetic epistasis (double mutant acceleration), single lab with multiple orthogonal approaches","pmids":["23893895"],"is_preprint":false},{"year":2014,"finding":"MPP3 and DLG form a multi-protein complex with CADM1 and the p85 regulatory subunit of PI3K at the cell periphery; trans-homophilic CADM1 interaction activates PI3K, leading to Akt and Rac1 activation and actin cytoskeleton reorganization for cell spreading.","method":"Cell-based spreading assay, chemical inhibitor screen (PI3K, Akt, Rac1 inhibitors), co-immunoprecipitation of CADM1/MPP3/Dlg/p85 complex","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of multi-protein complex with pharmacological pathway dissection, single lab; two PMIDs are duplicates of same study","pmids":["24503895","25268382"],"is_preprint":false},{"year":2023,"finding":"A distinct FcγR+/ERhigh secretory subset of myeloid-biased MPP3 hematopoietic progenitors directly amplifies myeloid (GMP) output through inflammation-triggered secretion of cytokines in the bone marrow microenvironment, acting as a self-reinforcing amplification compartment.","method":"Flow cytometry-based subset identification, lineage tracing, cytokine secretion assays, in vivo functional studies in inflammatory stress models","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo functional dissection with defined cellular and secretory phenotype, single lab; abstracts confirm secretion mechanism but full method detail not visible","pmids":["37115584"],"is_preprint":false}],"current_model":"MPP3 is a MAGUK-family scaffold protein that interacts via its PDZ domain with transmembrane proteins (CADM1/TSLC1, 5-HT2C receptor) and assembles multi-protein complexes (with MPP5/PALS1, DLG1, CRB1, and PI3K-p85) at cell-cell junctions and apical membranes, where it maintains apical complex integrity, stabilizes receptor surface expression, and links cell-adhesion signals to PI3K/Akt/Rac1 pathway activation; in the hematopoietic system, a secretory MPP3 subset amplifies myeloid output through cytokine secretion."},"narrative":{"mechanistic_narrative":"MPP3 is a PDZ-domain scaffold protein that organizes membrane-associated multi-protein complexes at cell-cell junctions and apical membranes to maintain epithelial/neuroepithelial architecture and to couple adhesion to intracellular signaling [PMID:13679854, PMID:23658188]. Through its PDZ domain it binds the C-terminal PDZ-binding motifs of transmembrane partners, directly associating with the adhesion molecule CADM1/TSLC1 at cell-cell attachment sites [PMID:13679854] and with the serotonin 5-HT2C receptor, where it stabilizes receptor surface expression and prevents desensitization of the receptor Ca2+ response [PMID:16914526]. In neuroepithelia, MPP3 is recruited into the MPP5/PALS1 apical scaffold alongside CRB1 and forms separate complexes with DLG1, and it is required to maintain PALS1 levels at the retinal subapical region and the integrity of the apical junctional complex; its loss randomizes spindle orientation, produces ectopic mitoses, and disrupts cortical stratification and retinal organization [PMID:16519681, PMID:23658188, PMID:23893895]. MPP3 also nucleates a CADM1–DLG–p85(PI3K) complex in which trans-homophilic CADM1 engagement activates PI3K, Akt and Rac1 to drive actin reorganization and cell spreading [PMID:24503895, PMID:25268382]. In the hematopoietic system, a secretory FcγR+/ERhigh subset of myeloid-biased MPP3 progenitors amplifies myeloid output through inflammation-triggered cytokine secretion [PMID:37115584].","teleology":[{"year":2003,"claim":"Established that MPP3 functions as a junctional scaffold by identifying its first direct transmembrane binding partner, defining the PDZ-domain mode of interaction.","evidence":"Co-immunoprecipitation, PDZ-binding motif mutagenesis and colocalization of CADM1/TSLC1 with MPP3","pmids":["13679854"],"confidence":"Medium","gaps":["Functional consequence of the CADM1-MPP3 interaction not addressed","Single lab, no in vivo validation"]},{"year":2006,"claim":"Showed MPP3 has a receptor-stabilizing function distinct from other MAGUKs, regulating surface expression and signaling kinetics of a GPCR via PDZ binding.","evidence":"Calcium response and surface receptor assays in transfected cells and cortical neurons with Tat-peptide PDZ displacement","pmids":["16914526"],"confidence":"Medium","gaps":["Structural basis of differential effect versus PSD-95 not defined","Physiological relevance of 5-HT2C regulation in vivo not tested"]},{"year":2006,"claim":"Placed MPP3 within the apical CRB/PALS1 scaffold and showed it forms compartment-specific complexes, locating it within the apical polarity machinery.","evidence":"Immunofluorescence colocalization and in vivo Co-IP in human and mouse retina","pmids":["16519681"],"confidence":"Medium","gaps":["Hierarchy of complex assembly not resolved","Functional requirement not tested in this study"]},{"year":2013,"claim":"Demonstrated MPP3 is functionally required to maintain apical junctional and adherens complexes, linking the scaffold to spindle orientation and cortical development.","evidence":"Conditional Mpp3 knockout mouse cortex with immunostaining, spindle orientation and cell-cycle analyses","pmids":["23658188"],"confidence":"High","gaps":["Direct molecular mechanism connecting MPP3 to spindle positioning not established","Which partner loss drives each phenotype unresolved"]},{"year":2013,"claim":"Established MPP3 as a stabilizer of PALS1 at the apical membrane through genetic epistasis, defining a hierarchical scaffold dependency in retinal maintenance.","evidence":"Conditional Mpp3 KO with immunostaining, electroretinography and Pals1 double-mutant epistasis","pmids":["23893895"],"confidence":"High","gaps":["Mechanism by which MPP3 stabilizes PALS1 (protection from degradation vs recruitment) not defined"]},{"year":2014,"claim":"Connected MPP3-anchored adhesion complexes to downstream signaling, showing CADM1 engagement drives PI3K/Akt/Rac1 activation and cytoskeletal remodeling.","evidence":"Cell spreading assays with PI3K/Akt/Rac1 inhibitors and Co-IP of CADM1/MPP3/DLG/p85 complex","pmids":["24503895","25268382"],"confidence":"Medium","gaps":["Direct vs indirect role of MPP3 in PI3K recruitment not separated","In vivo significance of the signaling axis not tested"]},{"year":2023,"claim":"Identified a functionally distinct secretory subset of MPP3 progenitors that amplifies myeloid output, extending MPP3-associated biology to hematopoiesis.","evidence":"Flow cytometry subset identification, lineage tracing and cytokine secretion assays in inflammatory stress models","pmids":["37115584"],"confidence":"Medium","gaps":["Role of the MPP3 scaffold protein itself versus the MPP3 progenitor population not disambiguated","Molecular link between scaffold function and secretory phenotype not established"]},{"year":null,"claim":"How MPP3 mechanistically stabilizes its partners (PALS1, surface receptors) and whether its junctional scaffolding role connects to the secretory hematopoietic progenitor biology remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of MPP3 PDZ-partner complexes","No reconstitution of the CADM1/MPP3/DLG/p85 signaling module","Whether 'MPP3 progenitor' biology involves the scaffold gene product is unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,4]}],"complexes":["CRB1-PALS1(MPP5) apical complex","CADM1-MPP3-DLG-p85(PI3K) complex"],"partners":["CADM1","MPP5","CRB1","DLG1","HTR2C","PIK3R1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13368","full_name":"MAGUK p55 subfamily member 3","aliases":["Discs large homolog 3","Protein MPP3"],"length_aa":585,"mass_kda":66.2,"function":"Participates in cell spreading through the phosphoinositide-3-kinase (PI3K) pathway by connecting CADM1 to DLG1 and the regulatory subunit of phosphoinositide-3-kinase (PI3K) (PubMed:24503895). Stabilizes HTR2C at the plasma membrane and prevents its desensitization. May participates in the maintenance of adherens junctions (By similarity)","subcellular_location":"Cell membrane; Apical cell membrane; Cell junction, adherens junction","url":"https://www.uniprot.org/uniprotkb/Q13368/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MPP3","classification":"Not Classified","n_dependent_lines":51,"n_total_lines":1208,"dependency_fraction":0.042218543046357616},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MPP3","total_profiled":1310},"omim":[{"mim_id":"610973","title":"MEMBRANE PROTEIN, PALMITOYLATED 7; MPP7","url":"https://www.omim.org/entry/610973"},{"mim_id":"606575","title":"MEMBRANE PROTEIN, PALMITOYLATED 4; MPP4","url":"https://www.omim.org/entry/606575"},{"mim_id":"601114","title":"MEMBRANE PROTEIN, PALMITOYLATED 3; MPP3","url":"https://www.omim.org/entry/601114"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":28.2},{"tissue":"heart muscle","ntpm":14.5}],"url":"https://www.proteinatlas.org/search/MPP3"},"hgnc":{"alias_symbol":[],"prev_symbol":["DLG3"]},"alphafold":{"accession":"Q13368","domains":[{"cath_id":"-","chopping":"11-59","consensus_level":"medium","plddt":74.6157,"start":11,"end":59},{"cath_id":"-","chopping":"69-113","consensus_level":"medium","plddt":87.9511,"start":69,"end":113},{"cath_id":"2.30.42.10","chopping":"137-216","consensus_level":"high","plddt":88.5095,"start":137,"end":216},{"cath_id":"2.30.30.40","chopping":"230-303","consensus_level":"high","plddt":91.3323,"start":230,"end":303},{"cath_id":"3.40.50.300","chopping":"381-413_478-509_529-585","consensus_level":"medium","plddt":90.2621,"start":381,"end":585}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13368","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13368-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13368-F1-predicted_aligned_error_v6.png","plddt_mean":78.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MPP3","jax_strain_url":"https://www.jax.org/strain/search?query=MPP3"},"sequence":{"accession":"Q13368","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13368.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13368/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13368"}},"corpus_meta":[{"pmid":"13679854","id":"PMC_13679854","title":"Association of a lung tumor suppressor TSLC1 with MPP3, a human homologue of Drosophila tumor suppressor Dlg.","date":"2003","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/13679854","citation_count":69,"is_preprint":false},{"pmid":"16914526","id":"PMC_16914526","title":"Opposite effects of PSD-95 and MPP3 PDZ proteins on serotonin 5-hydroxytryptamine2C receptor desensitization and membrane stability.","date":"2006","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/16914526","citation_count":57,"is_preprint":false},{"pmid":"24503895","id":"PMC_24503895","title":"Trans-homophilic interaction of CADM1 activates PI3K by forming a complex with MAGuK-family proteins MPP3 and Dlg.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24503895","citation_count":36,"is_preprint":false},{"pmid":"16519681","id":"PMC_16519681","title":"MPP3 is recruited to the MPP5 protein scaffold at the retinal outer limiting membrane.","date":"2006","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/16519681","citation_count":32,"is_preprint":false},{"pmid":"37115584","id":"PMC_37115584","title":"Secretory MPP3 reinforce myeloid differentiation trajectory and amplify myeloid cell production.","date":"2023","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37115584","citation_count":21,"is_preprint":false},{"pmid":"25268382","id":"PMC_25268382","title":"Trans-homophilic interaction of CADM1 activates PI3K by forming a complex with MAGuK-family proteins MPP3 and Dlg.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25268382","citation_count":16,"is_preprint":false},{"pmid":"23658188","id":"PMC_23658188","title":"MPP3 is required for maintenance of the apical junctional complex, neuronal migration, and stratification in the developing cortex.","date":"2013","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23658188","citation_count":13,"is_preprint":false},{"pmid":"23893895","id":"PMC_23893895","title":"MPP3 regulates levels of PALS1 and adhesion between photoreceptors and Müller cells.","date":"2013","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/23893895","citation_count":12,"is_preprint":false},{"pmid":"23011156","id":"PMC_23011156","title":"MPP3 inactivation by promoter CpG islands hypermethylation in colorectal carcinogenesis.","date":"2012","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/23011156","citation_count":5,"is_preprint":false},{"pmid":"41286351","id":"PMC_41286351","title":"Extracellular vesicle-mediated transfer of MIR22HG inhibits the colonization of enteric neural crest cells in the colon by decreasing MPP3 expression.","date":"2025","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/41286351","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.07.674755","title":"Unfolded protein response signaling promotes myeloid cell production and cooperates with oncogenic mutation","date":"2025-09-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.07.674755","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.08.05.668600","title":"A conserved upstream element in the mouse  <i>Csf1r</i>  locus contributes to transcription in hematopoietic and trophoblast cells","date":"2025-08-05","source":"bioRxiv","url":"https://doi.org/10.1101/2025.08.05.668600","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8127,"output_tokens":1765,"usd":0.025428,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8614,"output_tokens":2649,"usd":0.054648,"stage2_stop_reason":"end_turn"},"total_usd":0.080076,"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\": 2003,\n      \"finding\": \"TSLC1 (CADM1) directly associates with MPP3 via a PDZ-binding motif at the carboxyl terminus of TSLC1; this interaction depends on the PDZ domain of MPP3, and both proteins colocalize at cell-cell attachment sites.\",\n      \"method\": \"Co-immunoprecipitation, PDZ-binding motif mutagenesis, colocalization imaging\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assay with domain-deletion mutant and colocalization, single lab\",\n      \"pmids\": [\"13679854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MPP3 prevents desensitization of the serotonin 5-HT2C receptor Ca2+ response in heterologous cells and cortical neurons, and stabilizes cell-surface expression of the receptor, in contrast to PSD-95 which increases desensitization; both effects are mediated through PDZ-domain interaction with the receptor C-terminus.\",\n      \"method\": \"Calcium response assays in transfected cells and primary cortical neurons, Tat-peptide displacement of PDZ interactions, surface receptor quantification\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay with peptide inhibitor and receptor quantification in neurons, single lab, two orthogonal methods\",\n      \"pmids\": [\"16914526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"MPP3 is recruited to the MPP5 (PALS1) protein scaffold at the retinal outer limiting membrane (OLM), colocalizing with MPP5 and CRB1 at the subapical region; MPP3 also forms separate complexes with DLG1 at the outer plexiform layer, distinct from MPP4/DLG1 complexes.\",\n      \"method\": \"Immunofluorescence colocalization in human and mouse retina, in vivo co-immunoprecipitation\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo Co-IP and localization in retinal tissue, single lab, two orthogonal methods\",\n      \"pmids\": [\"16519681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MPP3 is required for maintenance of the apical junctional complex and adherens junctions in cortical progenitor cells; conditional Mpp3 knockout in mouse cortex causes loss of apical complex proteins, randomized spindle orientation, ectopic mitoses, delayed neuronal migration, and defective cortical stratification without affecting cell division rate or cell-cycle exit.\",\n      \"method\": \"Conditional knockout mouse (Mpp3 cKO), immunostaining, spindle orientation analysis, BrdU/EdU cell-cycle analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with multiple specific cellular phenotype readouts (spindle orientation, migration, stratification) using orthogonal methods\",\n      \"pmids\": [\"23658188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MPP3 is required for maintaining proper levels of PALS1 (MPP5) at the subapical region of the retina; loss of MPP3 in conditional knockout mice causes significant reduction of PALS1 at the OLM and accelerates retinal degeneration when combined with Pals1 knockdown.\",\n      \"method\": \"Conditional Mpp3 knockout mouse, immunostaining, electroretinography, genetic double-mutant epistasis with Pals1 conditional knockdown\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with protein-level phenotype and genetic epistasis (double mutant acceleration), single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"23893895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MPP3 and DLG form a multi-protein complex with CADM1 and the p85 regulatory subunit of PI3K at the cell periphery; trans-homophilic CADM1 interaction activates PI3K, leading to Akt and Rac1 activation and actin cytoskeleton reorganization for cell spreading.\",\n      \"method\": \"Cell-based spreading assay, chemical inhibitor screen (PI3K, Akt, Rac1 inhibitors), co-immunoprecipitation of CADM1/MPP3/Dlg/p85 complex\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of multi-protein complex with pharmacological pathway dissection, single lab; two PMIDs are duplicates of same study\",\n      \"pmids\": [\"24503895\", \"25268382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A distinct FcγR+/ERhigh secretory subset of myeloid-biased MPP3 hematopoietic progenitors directly amplifies myeloid (GMP) output through inflammation-triggered secretion of cytokines in the bone marrow microenvironment, acting as a self-reinforcing amplification compartment.\",\n      \"method\": \"Flow cytometry-based subset identification, lineage tracing, cytokine secretion assays, in vivo functional studies in inflammatory stress models\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo functional dissection with defined cellular and secretory phenotype, single lab; abstracts confirm secretion mechanism but full method detail not visible\",\n      \"pmids\": [\"37115584\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MPP3 is a MAGUK-family scaffold protein that interacts via its PDZ domain with transmembrane proteins (CADM1/TSLC1, 5-HT2C receptor) and assembles multi-protein complexes (with MPP5/PALS1, DLG1, CRB1, and PI3K-p85) at cell-cell junctions and apical membranes, where it maintains apical complex integrity, stabilizes receptor surface expression, and links cell-adhesion signals to PI3K/Akt/Rac1 pathway activation; in the hematopoietic system, a secretory MPP3 subset amplifies myeloid output through cytokine secretion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MPP3 is a PDZ-domain scaffold protein that organizes membrane-associated multi-protein complexes at cell-cell junctions and apical membranes to maintain epithelial/neuroepithelial architecture and to couple adhesion to intracellular signaling [#0, #3]. Through its PDZ domain it binds the C-terminal PDZ-binding motifs of transmembrane partners, directly associating with the adhesion molecule CADM1/TSLC1 at cell-cell attachment sites [#0] and with the serotonin 5-HT2C receptor, where it stabilizes receptor surface expression and prevents desensitization of the receptor Ca2+ response [#1]. In neuroepithelia, MPP3 is recruited into the MPP5/PALS1 apical scaffold alongside CRB1 and forms separate complexes with DLG1, and it is required to maintain PALS1 levels at the retinal subapical region and the integrity of the apical junctional complex; its loss randomizes spindle orientation, produces ectopic mitoses, and disrupts cortical stratification and retinal organization [#2, #3, #4]. MPP3 also nucleates a CADM1–DLG–p85(PI3K) complex in which trans-homophilic CADM1 engagement activates PI3K, Akt and Rac1 to drive actin reorganization and cell spreading [#5]. In the hematopoietic system, a secretory FcγR+/ERhigh subset of myeloid-biased MPP3 progenitors amplifies myeloid output through inflammation-triggered cytokine secretion [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that MPP3 functions as a junctional scaffold by identifying its first direct transmembrane binding partner, defining the PDZ-domain mode of interaction.\",\n      \"evidence\": \"Co-immunoprecipitation, PDZ-binding motif mutagenesis and colocalization of CADM1/TSLC1 with MPP3\",\n      \"pmids\": [\"13679854\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the CADM1-MPP3 interaction not addressed\", \"Single lab, no in vivo validation\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed MPP3 has a receptor-stabilizing function distinct from other MAGUKs, regulating surface expression and signaling kinetics of a GPCR via PDZ binding.\",\n      \"evidence\": \"Calcium response and surface receptor assays in transfected cells and cortical neurons with Tat-peptide PDZ displacement\",\n      \"pmids\": [\"16914526\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of differential effect versus PSD-95 not defined\", \"Physiological relevance of 5-HT2C regulation in vivo not tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Placed MPP3 within the apical CRB/PALS1 scaffold and showed it forms compartment-specific complexes, locating it within the apical polarity machinery.\",\n      \"evidence\": \"Immunofluorescence colocalization and in vivo Co-IP in human and mouse retina\",\n      \"pmids\": [\"16519681\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Hierarchy of complex assembly not resolved\", \"Functional requirement not tested in this study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated MPP3 is functionally required to maintain apical junctional and adherens complexes, linking the scaffold to spindle orientation and cortical development.\",\n      \"evidence\": \"Conditional Mpp3 knockout mouse cortex with immunostaining, spindle orientation and cell-cycle analyses\",\n      \"pmids\": [\"23658188\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular mechanism connecting MPP3 to spindle positioning not established\", \"Which partner loss drives each phenotype unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established MPP3 as a stabilizer of PALS1 at the apical membrane through genetic epistasis, defining a hierarchical scaffold dependency in retinal maintenance.\",\n      \"evidence\": \"Conditional Mpp3 KO with immunostaining, electroretinography and Pals1 double-mutant epistasis\",\n      \"pmids\": [\"23893895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which MPP3 stabilizes PALS1 (protection from degradation vs recruitment) not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected MPP3-anchored adhesion complexes to downstream signaling, showing CADM1 engagement drives PI3K/Akt/Rac1 activation and cytoskeletal remodeling.\",\n      \"evidence\": \"Cell spreading assays with PI3K/Akt/Rac1 inhibitors and Co-IP of CADM1/MPP3/DLG/p85 complex\",\n      \"pmids\": [\"24503895\", \"25268382\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect role of MPP3 in PI3K recruitment not separated\", \"In vivo significance of the signaling axis not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a functionally distinct secretory subset of MPP3 progenitors that amplifies myeloid output, extending MPP3-associated biology to hematopoiesis.\",\n      \"evidence\": \"Flow cytometry subset identification, lineage tracing and cytokine secretion assays in inflammatory stress models\",\n      \"pmids\": [\"37115584\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Role of the MPP3 scaffold protein itself versus the MPP3 progenitor population not disambiguated\", \"Molecular link between scaffold function and secretory phenotype not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MPP3 mechanistically stabilizes its partners (PALS1, surface receptors) and whether its junctional scaffolding role connects to the secretory hematopoietic progenitor biology remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of MPP3 PDZ-partner complexes\", \"No reconstitution of the CADM1/MPP3/DLG/p85 signaling module\", \"Whether 'MPP3 progenitor' biology involves the scaffold gene product is unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [\"CRB1-PALS1(MPP5) apical complex\", \"CADM1-MPP3-DLG-p85(PI3K) complex\"],\n    \"partners\": [\"CADM1\", \"MPP5\", \"CRB1\", \"DLG1\", \"HTR2C\", \"PIK3R1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}