{"gene":"MMD","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2014,"finding":"MMD (monocyte to macrophage differentiation-associated) knockdown inhibits growth of lung cancer cells (A549 and LLC) in vitro and in vivo, and MMD is a direct functional target of miR-140-5p; the miR-140-5p/MMD axis regulates cell proliferation through ERK signaling.","method":"siRNA knockdown, xenograft tumor models, luciferase reporter assay (miRNA target validation), ERK signaling pathway analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — knockdown with defined cellular phenotype and pathway placement (ERK), direct miRNA target validated by luciferase assay; single lab","pmids":["24971538"],"is_preprint":false},{"year":2011,"finding":"MMD (PAQR family member) localizes to the endoplasmic reticulum, mitochondria, and Golgi apparatus (but not lysosomes or cytoplasm); overexpression in macrophages enhances ERK1/2 and Akt phosphorylation after LPS stimulation, leading to increased TNF-α and NO production; pharmacological blockade of ERK or Akt reduces TNF-α or NO production respectively in MMD-overexpressing macrophages.","method":"EGFP-MMD fusion protein live-cell colocalization, overexpression with pharmacological inhibitors, ELISA for TNF-α and NO","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — subcellular localization by direct imaging tied to functional consequence, overexpression with defined signaling readout; single lab, multiple methods","pmids":["22203480"],"is_preprint":false},{"year":2023,"finding":"MMD is a Golgi-resident scaffold protein that physically interacts with both ACSL4 and MBOAT7 (enzymes catalyzing sequential steps of arachidonic acid incorporation into phosphatidylinositol), increases flux of arachidonic acid into phosphatidylinositol lipids, elevates AA-PI and other AA-containing phospholipid species, and thereby promotes susceptibility to ferroptosis in ovarian and renal carcinoma cells.","method":"Co-immunoprecipitation (MMD with ACSL4 and MBOAT7), lipidomics, ferroptosis viability assays with knockdown, genetic epistasis (ACSL4- and MBOAT7-dependent rescue)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal Co-IP, lipidomics, epistasis with defined molecular mechanism; single lab with multiple orthogonal methods","pmids":["37691145"],"is_preprint":false},{"year":2022,"finding":"miR-140-5p delivered via microglia-derived extracellular vesicles downregulates MMD expression (validated by luciferase assay), reducing PI3K/AKT and Erk1/2 signaling, thereby attenuating microglia activation and inflammatory response (TNF-α, IL-1β) after subarachnoid hemorrhage in rats.","method":"Luciferase reporter assay (miR-140-5p targeting MMD 3'UTR), microglia-EV co-culture transfer, in vivo SAH rat model with EV treatment, immunofluorescence for microglial polarization","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct miRNA-target validation by luciferase, in vivo pathway placement; single lab","pmids":["36336031"],"is_preprint":false}],"current_model":"MMD is a Golgi-resident scaffold protein that physically associates with ACSL4 and MBOAT7 to promote arachidonic acid incorporation into phosphatidylinositol lipids, thereby sensitizing cells to ferroptosis; it also activates ERK and Akt signaling downstream of LPS stimulation in macrophages to drive TNF-α and NO production, and is post-transcriptionally repressed by miR-140-5p which dampens MMD-dependent ERK/Akt and PI3K/AKT activation."},"narrative":{"teleology":[{"year":2011,"claim":"Establishing where MMD resides and that it couples to inflammatory signaling resolved the basic question of how a differentiation-associated gene exerts cellular effects: MMD localizes to ER, mitochondria, and Golgi, and its overexpression in macrophages enhances LPS-triggered ERK1/2 and Akt phosphorylation to increase TNF-α and NO output.","evidence":"EGFP-MMD live-cell colocalization with organelle markers and overexpression with pharmacological ERK/Akt inhibitors in macrophage cell lines","pmids":["22203480"],"confidence":"Medium","gaps":["Overexpression-only design; endogenous loss-of-function not tested","Mechanism by which MMD activates ERK/Akt is unknown (direct kinase scaffolding vs. indirect)","No interacting proteins identified at this stage"]},{"year":2014,"claim":"Demonstrating that miR-140-5p directly targets MMD to restrain ERK-driven proliferation established both a post-transcriptional regulatory mechanism and a functional role for MMD in cancer cell growth.","evidence":"Luciferase reporter assay confirming miR-140-5p binding to MMD 3′UTR, siRNA knockdown reducing A549/LLC proliferation in vitro and xenograft growth in vivo","pmids":["24971538"],"confidence":"Medium","gaps":["Single cancer type (lung); generalizability unconfirmed","Whether MMD promotes proliferation through ERK alone or additional pathways is unresolved","No mechanistic connection to MMD's membrane/scaffold function"]},{"year":2022,"claim":"Extending miR-140-5p–MMD regulation to neuroinflammation showed that extracellular-vesicle-delivered miR-140-5p suppresses MMD in microglia, dampening both PI3K/AKT and ERK1/2 signaling and reducing inflammatory cytokine release after brain injury.","evidence":"Microglia-derived EV transfer of miR-140-5p, luciferase target validation, subarachnoid hemorrhage rat model with immunofluorescence for microglial polarization","pmids":["36336031"],"confidence":"Medium","gaps":["Single in vivo model (SAH in rats); relevance to other neuroinflammatory contexts untested","Whether MMD's scaffold function at the Golgi is involved in microglia signaling is unknown","Endogenous stoichiometry of miR-140-5p–MMD regulation not quantified"]},{"year":2023,"claim":"Identifying MMD as a Golgi-resident scaffold that bridges ACSL4 and MBOAT7 to channel arachidonic acid into phosphatidylinositol revealed the first direct molecular mechanism for MMD, explaining how it sensitizes cells to ferroptosis through lipid remodeling.","evidence":"Reciprocal co-immunoprecipitation of MMD with ACSL4 and MBOAT7, lipidomics profiling of AA-PI species, ferroptosis viability assays with genetic epistasis in ovarian and renal carcinoma cells","pmids":["37691145"],"confidence":"High","gaps":["Structural basis of the MMD–ACSL4–MBOAT7 complex is unresolved","Whether the scaffolding role is relevant to MMD's ERK/Akt signaling function is unknown","In vivo physiological relevance of MMD-dependent ferroptosis sensitization not yet tested"]},{"year":null,"claim":"It remains unknown how MMD's lipid-remodeling scaffold function at the Golgi relates mechanistically to its amplification of ERK/Akt inflammatory signaling, and whether these represent independent or coupled activities.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of MMD or its complexes exists","Endogenous knockout phenotype in primary macrophages or in vivo immune models has not been reported","Whether MMD's PAQR-family topology confers any receptor-like or channel-like activity is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[2]}],"complexes":[],"partners":["ACSL4","MBOAT7"],"other_free_text":[]},"mechanistic_narrative":"MMD is a multi-pass membrane protein that localizes to the Golgi apparatus (and also the endoplasmic reticulum and mitochondria) and functions as a scaffold linking lipid-remodeling enzymes and inflammatory signaling pathways [PMID:22203480, PMID:37691145]. At the Golgi, MMD physically associates with ACSL4 and MBOAT7, promoting arachidonic acid incorporation into phosphatidylinositol species and thereby sensitizing cells to ferroptosis [PMID:37691145]. In macrophages and microglia, MMD amplifies LPS-stimulated ERK1/2 and Akt phosphorylation, driving TNF-α and nitric oxide production; this signaling axis is post-transcriptionally repressed by miR-140-5p, which directly targets the MMD 3′UTR [PMID:22203480, PMID:24971538, PMID:36336031]."},"prefetch_data":{"uniprot":{"accession":"Q15546","full_name":"Monocyte to macrophage differentiation factor","aliases":["Progestin and adipoQ receptor family member 11","Progestin and adipoQ receptor family member XI"],"length_aa":238,"mass_kda":27.7,"function":"Involved in the dynamics of lysosomal membranes associated with microglial activation following brain lesion","subcellular_location":"Late endosome membrane; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q15546/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MMD","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MMD","total_profiled":1310},"omim":[{"mim_id":"620687","title":"MOYAMOYA DISEASE 7; MYMY7","url":"https://www.omim.org/entry/620687"},{"mim_id":"614581","title":"MONOCYTE-TO-MACROPHAGE DIFFERENTIATION-ASSOCIATED PROTEIN 2; MMD2","url":"https://www.omim.org/entry/614581"},{"mim_id":"604467","title":"MONOCYTE-TO-MACROPHAGE DIFFERENTIATION-ASSOCIATED PROTEIN; MMD","url":"https://www.omim.org/entry/604467"},{"mim_id":"602771","title":"CONGENITAL MYOPATHY 3 WITH RIGID SPINE; CMYO3","url":"https://www.omim.org/entry/602771"},{"mim_id":"255320","title":"CONGENITAL MYOPATHY 1B, AUTOSOMAL RECESSIVE; CMYO1B","url":"https://www.omim.org/entry/255320"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"adipose tissue","ntpm":142.9},{"tissue":"brain","ntpm":101.7}],"url":"https://www.proteinatlas.org/search/MMD"},"hgnc":{"alias_symbol":["MMA","PAQR11"],"prev_symbol":[]},"alphafold":{"accession":"Q15546","domains":[{"cath_id":"1.20.1070","chopping":"23-230","consensus_level":"medium","plddt":95.1171,"start":23,"end":230}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15546","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15546-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15546-F1-predicted_aligned_error_v6.png","plddt_mean":92.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MMD","jax_strain_url":"https://www.jax.org/strain/search?query=MMD"},"sequence":{"accession":"Q15546","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15546.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15546/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15546"}},"corpus_meta":[{"pmid":"10698679","id":"PMC_10698679","title":"Monomethylarsonous acid (MMA(III)) is more toxic than arsenite in Chang human hepatocytes.","date":"2000","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/10698679","citation_count":496,"is_preprint":false},{"pmid":"11511179","id":"PMC_11511179","title":"Human monomethylarsonic acid (MMA(V)) reductase is a member of the glutathione-S-transferase superfamily.","date":"2001","source":"Chemical research in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/11511179","citation_count":181,"is_preprint":false},{"pmid":"10604879","id":"PMC_10604879","title":"Enzymatic reduction of arsenic compounds in mammalian systems: the rate-limiting enzyme of rabbit liver arsenic biotransformation is MMA(V) reductase.","date":"1999","source":"Chemical research in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/10604879","citation_count":100,"is_preprint":false},{"pmid":"27869652","id":"PMC_27869652","title":"Epithelial-to-mesenchymal transition drives a pro-metastatic Golgi compaction process through scaffolding protein PAQR11.","date":"2016","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/27869652","citation_count":91,"is_preprint":false},{"pmid":"14680363","id":"PMC_14680363","title":"Polymorphisms in the human monomethylarsonic acid (MMA V) reductase/hGSTO1 gene and changes in urinary arsenic profiles.","date":"2003","source":"Chemical research in toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/14680363","citation_count":86,"is_preprint":false},{"pmid":"10387927","id":"PMC_10387927","title":"Enzymatic methylation of arsenic compounds. 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the miR-140-5p/MMD axis regulates cell proliferation through ERK signaling.\",\n      \"method\": \"siRNA knockdown, xenograft tumor models, luciferase reporter assay (miRNA target validation), ERK signaling pathway analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — knockdown with defined cellular phenotype and pathway placement (ERK), direct miRNA target validated by luciferase assay; single lab\",\n      \"pmids\": [\"24971538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MMD (PAQR family member) localizes to the endoplasmic reticulum, mitochondria, and Golgi apparatus (but not lysosomes or cytoplasm); overexpression in macrophages enhances ERK1/2 and Akt phosphorylation after LPS stimulation, leading to increased TNF-α and NO production; pharmacological blockade of ERK or Akt reduces TNF-α or NO production respectively in MMD-overexpressing macrophages.\",\n      \"method\": \"EGFP-MMD fusion protein live-cell colocalization, overexpression with pharmacological inhibitors, ELISA for TNF-α and NO\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — subcellular localization by direct imaging tied to functional consequence, overexpression with defined signaling readout; single lab, multiple methods\",\n      \"pmids\": [\"22203480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MMD is a Golgi-resident scaffold protein that physically interacts with both ACSL4 and MBOAT7 (enzymes catalyzing sequential steps of arachidonic acid incorporation into phosphatidylinositol), increases flux of arachidonic acid into phosphatidylinositol lipids, elevates AA-PI and other AA-containing phospholipid species, and thereby promotes susceptibility to ferroptosis in ovarian and renal carcinoma cells.\",\n      \"method\": \"Co-immunoprecipitation (MMD with ACSL4 and MBOAT7), lipidomics, ferroptosis viability assays with knockdown, genetic epistasis (ACSL4- and MBOAT7-dependent rescue)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal Co-IP, lipidomics, epistasis with defined molecular mechanism; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37691145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-140-5p delivered via microglia-derived extracellular vesicles downregulates MMD expression (validated by luciferase assay), reducing PI3K/AKT and Erk1/2 signaling, thereby attenuating microglia activation and inflammatory response (TNF-α, IL-1β) after subarachnoid hemorrhage in rats.\",\n      \"method\": \"Luciferase reporter assay (miR-140-5p targeting MMD 3'UTR), microglia-EV co-culture transfer, in vivo SAH rat model with EV treatment, immunofluorescence for microglial polarization\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct miRNA-target validation by luciferase, in vivo pathway placement; single lab\",\n      \"pmids\": [\"36336031\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MMD is a Golgi-resident scaffold protein that physically associates with ACSL4 and MBOAT7 to promote arachidonic acid incorporation into phosphatidylinositol lipids, thereby sensitizing cells to ferroptosis; it also activates ERK and Akt signaling downstream of LPS stimulation in macrophages to drive TNF-α and NO production, and is post-transcriptionally repressed by miR-140-5p which dampens MMD-dependent ERK/Akt and PI3K/AKT activation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MMD is a multi-pass membrane protein that localizes to the Golgi apparatus (and also the endoplasmic reticulum and mitochondria) and functions as a scaffold linking lipid-remodeling enzymes and inflammatory signaling pathways [PMID:22203480, PMID:37691145]. At the Golgi, MMD physically associates with ACSL4 and MBOAT7, promoting arachidonic acid incorporation into phosphatidylinositol species and thereby sensitizing cells to ferroptosis [PMID:37691145]. In macrophages and microglia, MMD amplifies LPS-stimulated ERK1/2 and Akt phosphorylation, driving TNF-α and nitric oxide production; this signaling axis is post-transcriptionally repressed by miR-140-5p, which directly targets the MMD 3′UTR [PMID:22203480, PMID:24971538, PMID:36336031].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing where MMD resides and that it couples to inflammatory signaling resolved the basic question of how a differentiation-associated gene exerts cellular effects: MMD localizes to ER, mitochondria, and Golgi, and its overexpression in macrophages enhances LPS-triggered ERK1/2 and Akt phosphorylation to increase TNF-α and NO output.\",\n      \"evidence\": \"EGFP-MMD live-cell colocalization with organelle markers and overexpression with pharmacological ERK/Akt inhibitors in macrophage cell lines\",\n      \"pmids\": [\"22203480\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Overexpression-only design; endogenous loss-of-function not tested\",\n        \"Mechanism by which MMD activates ERK/Akt is unknown (direct kinase scaffolding vs. indirect)\",\n        \"No interacting proteins identified at this stage\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that miR-140-5p directly targets MMD to restrain ERK-driven proliferation established both a post-transcriptional regulatory mechanism and a functional role for MMD in cancer cell growth.\",\n      \"evidence\": \"Luciferase reporter assay confirming miR-140-5p binding to MMD 3′UTR, siRNA knockdown reducing A549/LLC proliferation in vitro and xenograft growth in vivo\",\n      \"pmids\": [\"24971538\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single cancer type (lung); generalizability unconfirmed\",\n        \"Whether MMD promotes proliferation through ERK alone or additional pathways is unresolved\",\n        \"No mechanistic connection to MMD's membrane/scaffold function\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extending miR-140-5p–MMD regulation to neuroinflammation showed that extracellular-vesicle-delivered miR-140-5p suppresses MMD in microglia, dampening both PI3K/AKT and ERK1/2 signaling and reducing inflammatory cytokine release after brain injury.\",\n      \"evidence\": \"Microglia-derived EV transfer of miR-140-5p, luciferase target validation, subarachnoid hemorrhage rat model with immunofluorescence for microglial polarization\",\n      \"pmids\": [\"36336031\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single in vivo model (SAH in rats); relevance to other neuroinflammatory contexts untested\",\n        \"Whether MMD's scaffold function at the Golgi is involved in microglia signaling is unknown\",\n        \"Endogenous stoichiometry of miR-140-5p–MMD regulation not quantified\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying MMD as a Golgi-resident scaffold that bridges ACSL4 and MBOAT7 to channel arachidonic acid into phosphatidylinositol revealed the first direct molecular mechanism for MMD, explaining how it sensitizes cells to ferroptosis through lipid remodeling.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation of MMD with ACSL4 and MBOAT7, lipidomics profiling of AA-PI species, ferroptosis viability assays with genetic epistasis in ovarian and renal carcinoma cells\",\n      \"pmids\": [\"37691145\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the MMD–ACSL4–MBOAT7 complex is unresolved\",\n        \"Whether the scaffolding role is relevant to MMD's ERK/Akt signaling function is unknown\",\n        \"In vivo physiological relevance of MMD-dependent ferroptosis sensitization not yet tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how MMD's lipid-remodeling scaffold function at the Golgi relates mechanistically to its amplification of ERK/Akt inflammatory signaling, and whether these represent independent or coupled activities.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of MMD or its complexes exists\",\n        \"Endogenous knockout phenotype in primary macrophages or in vivo immune models has not been reported\",\n        \"Whether MMD's PAQR-family topology confers any receptor-like or channel-like activity is untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ACSL4\",\n      \"MBOAT7\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}