{"gene":"MALL","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2001,"finding":"MALL (BENE) is a proteolipid protein predominantly present in glycolipid- and cholesterol-enriched membrane (GEM) rafts in endothelial ECV304 cells, and co-immunoprecipitation experiments revealed that BENE/MALL interacts with caveolin-1. Confocal immunofluorescence and electron microscopy showed BENE mainly accumulates in intracellular vesicular/tubular structures that partially colocalize with internal caveolin-1. In response to cell surface cholesterol oxidation, BENE redistributes to dilated vesicular structures concentrating caveolin-1, and after cessation of cholesterol oxidation, a fraction of BENE migrates to the plasmalemma accompanying caveolin-1, establishing BENE/MALL as an element of the raft-mediated trafficking machinery in endothelial cells.","method":"Co-immunoprecipitation, confocal immunofluorescence, electron microscopy, cholesterol oxidation functional assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus two orthogonal imaging methods (confocal and EM) with functional cholesterol perturbation experiment, single lab","pmids":["11294831"],"is_preprint":false},{"year":2022,"finding":"MALL, a membrane-tetra-spanning proteolipid, distributes in membranes outside the nucleus and within the nucleus localizes to membrane-less, liquid-like PML body biomolecular condensates. The acquisition of the condensate-compatible conformation requires PML expression. Excess MALL perturbed the distribution of inner nuclear membrane proteins emerin and LAP2β and the DNA-binding protein BAF, leading to formation of aberrant nuclei. Detection in one or other environment was strictly dependent on the method of cell fixation, suggesting MALL adopts different conformations depending on its physical environment (lipidic vs. aqueous).","method":"Differential cell fixation methods, immunofluorescence, live-cell imaging, overexpression loss-of-function analysis with defined nuclear morphology phenotype","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (fixation-dependent detection, imaging of condensates, OE phenotype on nuclear proteins), single lab","pmids":["35399121"],"is_preprint":false},{"year":2026,"finding":"In pancreatic cancer cells, sphingosine-1-phosphate (S1P) secreted by cancer-associated fibroblasts activates S1PR3/JNK/JUN signaling to transcriptionally induce MALL. MALL binds syndecan-4 (SDC4) and promotes its recycling to the plasma membrane, increasing surface SDC4 abundance. This MALL-SDC4 program promotes RhoA/phosphorylated myosin light chain 2 (p-MLC2)-dependent amoeboid motility and sensitizes cancer cells to Schwann cell-derived pleiotrophin, strengthening directed perineural invasion. Genetic perturbation of MALL or SDC4 in cancer cells, or AAV-mediated knockdown in KPC mice, significantly reduced perineural invasion and tumor burden.","method":"Co-immunoprecipitation/binding assay (MALL-SDC4 interaction), genetic knockdown/perturbation, KPC mouse model, functional motility assays, multiplex immunofluorescence, single-cell transcriptomics","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (binding assay, KO phenotype in vitro and in vivo), single lab, not yet replicated","pmids":["42017444"],"is_preprint":false},{"year":2016,"finding":"Overexpression of MALL in HCT116 and SW480 colorectal cancer cell lines suppressed cell proliferation and inhibited HCT116 cell migration, establishing a direct functional role for MALL in suppressing cancer cell growth and motility.","method":"Overexpression of MALL in cancer cell lines with proliferation and migration assays","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single overexpression approach, no pathway placement beyond phenotypic readout","pmids":["26992238"],"is_preprint":false}],"current_model":"MALL (BENE) is a membrane-tetra-spanning proteolipid that resides in GEM rafts and interacts with caveolin-1 to participate in raft-mediated vesicular trafficking in endothelial cells; within the nucleus it adopts an alternative conformation and localizes to PML body biomolecular condensates where excess MALL disrupts inner nuclear membrane protein distribution; in pancreatic cancer, CAF-derived S1P transcriptionally induces MALL, which then binds syndecan-4 and promotes its plasma membrane recycling to drive RhoA/p-MLC2-dependent amoeboid motility and perineural invasion."},"narrative":{"mechanistic_narrative":"MALL (BENE) is a membrane-tetra-spanning proteolipid that operates in raft-based membrane organization and vesicular trafficking [PMID:11294831]. In endothelial cells it partitions into glycolipid- and cholesterol-enriched membrane (GEM) rafts, accumulates in intracellular vesicular/tubular structures, and physically interacts with caveolin-1; upon cholesterol oxidation it redistributes with caveolin-1 between dilated vesicular compartments and the plasmalemma, marking it as a component of the raft-mediated trafficking machinery [PMID:11294831]. MALL is conformationally plastic: detection depends on fixation conditions, and within the nucleus it adopts a condensate-compatible conformation that requires PML expression and targets it to liquid-like PML body condensates, where excess MALL disrupts the distribution of the inner nuclear membrane proteins emerin and LAP2β and the DNA-binding protein BAF to generate aberrant nuclei [PMID:35399121]. In pancreatic cancer, MALL is transcriptionally induced by cancer-associated-fibroblast-derived sphingosine-1-phosphate acting through S1PR3/JNK/JUN signaling; induced MALL binds syndecan-4 and promotes its recycling to the plasma membrane, driving RhoA/p-MLC2-dependent amoeboid motility and perineural invasion in vitro and in KPC mice [PMID:42017444].","teleology":[{"year":2001,"claim":"Established the basic molecular identity and cellular role of MALL by placing it in cholesterol-rich membrane rafts and tying it to caveolin-1-dependent trafficking, answering where the protein resides and what machinery it belongs to.","evidence":"Co-immunoprecipitation, confocal and electron microscopy, and cholesterol-oxidation perturbation in endothelial ECV304 cells","pmids":["11294831"],"confidence":"Medium","gaps":["Direct interaction interface with caveolin-1 not mapped","Cargo transported by MALL-containing vesicles not identified","Single cell line and single lab"]},{"year":2016,"claim":"Provided an initial functional readout that MALL can restrain cancer cell behavior, raising the question of whether MALL is growth/motility-suppressive.","evidence":"Overexpression in HCT116 and SW480 colorectal cancer lines with proliferation and migration assays","pmids":["26992238"],"confidence":"Low","gaps":["Single overexpression approach with no loss-of-function counterpart","No molecular mechanism or pathway placement","Apparent contrast with later pro-invasive role in pancreatic cancer not reconciled"]},{"year":2022,"claim":"Revealed an unanticipated conformationally plastic, nuclear behavior of MALL, showing it can localize to PML body condensates and influence nuclear envelope protein organization, extending its role beyond cytoplasmic membranes.","evidence":"Fixation-dependent immunofluorescence, live-cell imaging of condensates, and overexpression phenotyping of nuclear envelope proteins","pmids":["35399121"],"confidence":"Medium","gaps":["Structural basis of the lipidic-vs-aqueous conformational switch undefined","Whether nuclear MALL has a physiological (non-overexpression) function unclear","Mechanism by which PML enables the condensate-compatible conformation unknown"]},{"year":2026,"claim":"Connected MALL to a defined signaling-to-motility axis in cancer, identifying its transcriptional induction, a direct binding partner, and a downstream contractility program driving perineural invasion.","evidence":"Binding assays, genetic perturbation, motility assays, single-cell transcriptomics, and AAV knockdown in KPC mice","pmids":["42017444"],"confidence":"Medium","gaps":["MALL-SDC4 interaction shown by binding assay without structural detail","Reconciliation with the earlier tumor-suppressive phenotype in colorectal cells not addressed","Single lab, not independently replicated"]},{"year":null,"claim":"How MALL's raft/caveolin trafficking role, its nuclear condensate localization, and its SDC4 recycling function mechanistically relate within a single protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying structural model linking membrane and nuclear conformations","Endogenous physiological function in normal tissues not established","Context dependence of pro- versus anti-tumor activity unexplained"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2]}],"complexes":[],"partners":["CAV1","SDC4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13021","full_name":"MAL-like protein","aliases":["Protein BENE"],"length_aa":153,"mass_kda":17.4,"function":"","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q13021/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MALL","classification":"Not Classified","n_dependent_lines":32,"n_total_lines":1208,"dependency_fraction":0.026490066225165563},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MALL","total_profiled":1310},"omim":[{"mim_id":"616837","title":"HUMAN PLURIPOTENCY-ASSOCIATED TRANSCRIPT 5, NONCODING","url":"https://www.omim.org/entry/616837"},{"mim_id":"616062","title":"ANKYRIN REPEAT- AND LEM DOMAIN-CONTAINING PROTEIN 2; ANKLE2","url":"https://www.omim.org/entry/616062"},{"mim_id":"615031","title":"NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IX, WITH DEVELOPMENTAL DELAY; HSAN9","url":"https://www.omim.org/entry/615031"},{"mim_id":"615000","title":"TECTONIN BETA-PROPELLER REPEAT-CONTAINING PROTEIN 2; TECPR2","url":"https://www.omim.org/entry/615000"},{"mim_id":"613084","title":"MYELIN TRANSCRIPTION FACTOR 1-LIKE; MYT1L","url":"https://www.omim.org/entry/613084"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":482.8},{"tissue":"intestine","ntpm":221.6},{"tissue":"vagina","ntpm":189.9}],"url":"https://www.proteinatlas.org/search/MALL"},"hgnc":{"alias_symbol":["BENE"],"prev_symbol":[]},"alphafold":{"accession":"Q13021","domains":[{"cath_id":"-","chopping":"26-153","consensus_level":"high","plddt":94.7344,"start":26,"end":153}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13021","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13021-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13021-F1-predicted_aligned_error_v6.png","plddt_mean":89.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MALL","jax_strain_url":"https://www.jax.org/strain/search?query=MALL"},"sequence":{"accession":"Q13021","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13021.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13021/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13021"}},"corpus_meta":[{"pmid":"9573215","id":"PMC_9573215","title":"Identification and enzymatic characterization of the maltose-inducible alpha-glucosidase MalL (sucrase-isomaltase-maltase) of Bacillus subtilis.","date":"1998","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/9573215","citation_count":44,"is_preprint":false},{"pmid":"11294831","id":"PMC_11294831","title":"BENE, a novel raft-associated protein of the MAL proteolipid family, interacts with caveolin-1 in human endothelial-like ECV304 cells.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11294831","citation_count":42,"is_preprint":false},{"pmid":"14718022","id":"PMC_14718022","title":"Down-regulation of members of glycolipid-enriched membrane raft gene family, MAL and BENE, in cervical squamous cell cancers.","date":"2004","source":"The journal of obstetrics and gynaecology research","url":"https://pubmed.ncbi.nlm.nih.gov/14718022","citation_count":34,"is_preprint":false},{"pmid":"10229946","id":"PMC_10229946","title":"Properties of maltose-inducible alpha-glucosidase MalL (sucrase-isomaltase-maltase) in Bacillus subtilis: evidence for its contribution to maltodextrin utilization.","date":"1999","source":"Research in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/10229946","citation_count":26,"is_preprint":false},{"pmid":"9886734","id":"PMC_9886734","title":"Arg124Cys mutation of the betaig-h3 bene in a Japanese family with lattice corneal dystrophy type I.","date":"1998","source":"Japanese journal of ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/9886734","citation_count":24,"is_preprint":false},{"pmid":"27010569","id":"PMC_27010569","title":"The Genetics of Bene Israel from India Reveals Both Substantial Jewish and Indian Ancestry.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27010569","citation_count":13,"is_preprint":false},{"pmid":"20716330","id":"PMC_20716330","title":"\"Mi voglio bene\": a pediatrician-based randomized controlled trial for the prevention of obesity in Italian preschool children.","date":"2010","source":"Italian journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/20716330","citation_count":13,"is_preprint":false},{"pmid":"26992238","id":"PMC_26992238","title":"Decreased MALL expression negatively impacts colorectal cancer patient survival.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26992238","citation_count":12,"is_preprint":false},{"pmid":"28092484","id":"PMC_28092484","title":"An amended history of tissue culture: Concerning Harrison, Burrows, Mall, and Carrel.","date":"2017","source":"Journal of medical biography","url":"https://pubmed.ncbi.nlm.nih.gov/28092484","citation_count":10,"is_preprint":false},{"pmid":"18245325","id":"PMC_18245325","title":"Mutations in the Drosophila mitochondrial tRNA amidotransferase, bene/gatA, cause growth defects in mitotic and endoreplicating tissues.","date":"2008","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18245325","citation_count":8,"is_preprint":false},{"pmid":"38428775","id":"PMC_38428775","title":"In vitro release modeling of beta-carotene from Bene oleosome and electrosprayed Quince seed hydrocolloids loaded with oleosomes containing beta-carotene.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/38428775","citation_count":5,"is_preprint":false},{"pmid":"16249950","id":"PMC_16249950","title":"Genetics, history, and identity: the case of the Bene Israel and the Lemba.","date":"2005","source":"Culture, medicine and psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/16249950","citation_count":3,"is_preprint":false},{"pmid":"9179327","id":"PMC_9179327","title":"Adolescents and adults at the mall: dyadic interactions.","date":"1997","source":"Adolescence","url":"https://pubmed.ncbi.nlm.nih.gov/9179327","citation_count":3,"is_preprint":false},{"pmid":"35399121","id":"PMC_35399121","title":"MALL, a membrane-tetra-spanning proteolipid overexpressed in cancer, is present in membraneless nuclear biomolecular condensates.","date":"2022","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/35399121","citation_count":2,"is_preprint":false},{"pmid":"36427971","id":"PMC_36427971","title":"Prenatal diagnosis and molecular cytogenetic characterization of a de novo duplication of 2q12.2→q13 encompassing MALL, NPHP1, RGPD6 and BUB1.","date":"2022","source":"Taiwanese journal of obstetrics & gynecology","url":"https://pubmed.ncbi.nlm.nih.gov/36427971","citation_count":1,"is_preprint":false},{"pmid":"41233680","id":"PMC_41233680","title":"Integrating circular economy in food waste management: insights from Thailand's shopping mall and community.","date":"2025","source":"Environmental science and pollution research international","url":"https://pubmed.ncbi.nlm.nih.gov/41233680","citation_count":0,"is_preprint":false},{"pmid":"37203120","id":"PMC_37203120","title":"Two rare copy number variants involving loss of NPHP1, MALL, and MTLN genes contribute to nephronophthisis-induced nephropathy progression in a family: A case report.","date":"2023","source":"Nigerian journal of clinical practice","url":"https://pubmed.ncbi.nlm.nih.gov/37203120","citation_count":0,"is_preprint":false},{"pmid":"42017444","id":"PMC_42017444","title":"Cancer-Associated Fibroblast-Derived Sphingosine-1-Phosphate Activates a MALL-SDC4 Axis to Facilitate Perineural Invasion in Pancreatic 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responses","date":"2025-09-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.18.677123","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12901,"output_tokens":1379,"usd":0.029694,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8119,"output_tokens":1968,"usd":0.044897,"stage2_stop_reason":"end_turn"},"total_usd":0.074591,"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\": \"MALL (BENE) is a proteolipid protein predominantly present in glycolipid- and cholesterol-enriched membrane (GEM) rafts in endothelial ECV304 cells, and co-immunoprecipitation experiments revealed that BENE/MALL interacts with caveolin-1. Confocal immunofluorescence and electron microscopy showed BENE mainly accumulates in intracellular vesicular/tubular structures that partially colocalize with internal caveolin-1. In response to cell surface cholesterol oxidation, BENE redistributes to dilated vesicular structures concentrating caveolin-1, and after cessation of cholesterol oxidation, a fraction of BENE migrates to the plasmalemma accompanying caveolin-1, establishing BENE/MALL as an element of the raft-mediated trafficking machinery in endothelial cells.\",\n      \"method\": \"Co-immunoprecipitation, confocal immunofluorescence, electron microscopy, cholesterol oxidation functional assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus two orthogonal imaging methods (confocal and EM) with functional cholesterol perturbation experiment, single lab\",\n      \"pmids\": [\"11294831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MALL, a membrane-tetra-spanning proteolipid, distributes in membranes outside the nucleus and within the nucleus localizes to membrane-less, liquid-like PML body biomolecular condensates. The acquisition of the condensate-compatible conformation requires PML expression. Excess MALL perturbed the distribution of inner nuclear membrane proteins emerin and LAP2β and the DNA-binding protein BAF, leading to formation of aberrant nuclei. Detection in one or other environment was strictly dependent on the method of cell fixation, suggesting MALL adopts different conformations depending on its physical environment (lipidic vs. aqueous).\",\n      \"method\": \"Differential cell fixation methods, immunofluorescence, live-cell imaging, overexpression loss-of-function analysis with defined nuclear morphology phenotype\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (fixation-dependent detection, imaging of condensates, OE phenotype on nuclear proteins), single lab\",\n      \"pmids\": [\"35399121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In pancreatic cancer cells, sphingosine-1-phosphate (S1P) secreted by cancer-associated fibroblasts activates S1PR3/JNK/JUN signaling to transcriptionally induce MALL. MALL binds syndecan-4 (SDC4) and promotes its recycling to the plasma membrane, increasing surface SDC4 abundance. This MALL-SDC4 program promotes RhoA/phosphorylated myosin light chain 2 (p-MLC2)-dependent amoeboid motility and sensitizes cancer cells to Schwann cell-derived pleiotrophin, strengthening directed perineural invasion. Genetic perturbation of MALL or SDC4 in cancer cells, or AAV-mediated knockdown in KPC mice, significantly reduced perineural invasion and tumor burden.\",\n      \"method\": \"Co-immunoprecipitation/binding assay (MALL-SDC4 interaction), genetic knockdown/perturbation, KPC mouse model, functional motility assays, multiplex immunofluorescence, single-cell transcriptomics\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (binding assay, KO phenotype in vitro and in vivo), single lab, not yet replicated\",\n      \"pmids\": [\"42017444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Overexpression of MALL in HCT116 and SW480 colorectal cancer cell lines suppressed cell proliferation and inhibited HCT116 cell migration, establishing a direct functional role for MALL in suppressing cancer cell growth and motility.\",\n      \"method\": \"Overexpression of MALL in cancer cell lines with proliferation and migration assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single overexpression approach, no pathway placement beyond phenotypic readout\",\n      \"pmids\": [\"26992238\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MALL (BENE) is a membrane-tetra-spanning proteolipid that resides in GEM rafts and interacts with caveolin-1 to participate in raft-mediated vesicular trafficking in endothelial cells; within the nucleus it adopts an alternative conformation and localizes to PML body biomolecular condensates where excess MALL disrupts inner nuclear membrane protein distribution; in pancreatic cancer, CAF-derived S1P transcriptionally induces MALL, which then binds syndecan-4 and promotes its plasma membrane recycling to drive RhoA/p-MLC2-dependent amoeboid motility and perineural invasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MALL (BENE) is a membrane-tetra-spanning proteolipid that operates in raft-based membrane organization and vesicular trafficking [#0]. In endothelial cells it partitions into glycolipid- and cholesterol-enriched membrane (GEM) rafts, accumulates in intracellular vesicular/tubular structures, and physically interacts with caveolin-1; upon cholesterol oxidation it redistributes with caveolin-1 between dilated vesicular compartments and the plasmalemma, marking it as a component of the raft-mediated trafficking machinery [#0]. MALL is conformationally plastic: detection depends on fixation conditions, and within the nucleus it adopts a condensate-compatible conformation that requires PML expression and targets it to liquid-like PML body condensates, where excess MALL disrupts the distribution of the inner nuclear membrane proteins emerin and LAP2\\u03b2 and the DNA-binding protein BAF to generate aberrant nuclei [#1]. In pancreatic cancer, MALL is transcriptionally induced by cancer-associated-fibroblast-derived sphingosine-1-phosphate acting through S1PR3/JNK/JUN signaling; induced MALL binds syndecan-4 and promotes its recycling to the plasma membrane, driving RhoA/p-MLC2-dependent amoeboid motility and perineural invasion in vitro and in KPC mice [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the basic molecular identity and cellular role of MALL by placing it in cholesterol-rich membrane rafts and tying it to caveolin-1-dependent trafficking, answering where the protein resides and what machinery it belongs to.\",\n      \"evidence\": \"Co-immunoprecipitation, confocal and electron microscopy, and cholesterol-oxidation perturbation in endothelial ECV304 cells\",\n      \"pmids\": [\"11294831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct interaction interface with caveolin-1 not mapped\",\n        \"Cargo transported by MALL-containing vesicles not identified\",\n        \"Single cell line and single lab\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided an initial functional readout that MALL can restrain cancer cell behavior, raising the question of whether MALL is growth/motility-suppressive.\",\n      \"evidence\": \"Overexpression in HCT116 and SW480 colorectal cancer lines with proliferation and migration assays\",\n      \"pmids\": [\"26992238\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single overexpression approach with no loss-of-function counterpart\",\n        \"No molecular mechanism or pathway placement\",\n        \"Apparent contrast with later pro-invasive role in pancreatic cancer not reconciled\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed an unanticipated conformationally plastic, nuclear behavior of MALL, showing it can localize to PML body condensates and influence nuclear envelope protein organization, extending its role beyond cytoplasmic membranes.\",\n      \"evidence\": \"Fixation-dependent immunofluorescence, live-cell imaging of condensates, and overexpression phenotyping of nuclear envelope proteins\",\n      \"pmids\": [\"35399121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of the lipidic-vs-aqueous conformational switch undefined\",\n        \"Whether nuclear MALL has a physiological (non-overexpression) function unclear\",\n        \"Mechanism by which PML enables the condensate-compatible conformation unknown\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Connected MALL to a defined signaling-to-motility axis in cancer, identifying its transcriptional induction, a direct binding partner, and a downstream contractility program driving perineural invasion.\",\n      \"evidence\": \"Binding assays, genetic perturbation, motility assays, single-cell transcriptomics, and AAV knockdown in KPC mice\",\n      \"pmids\": [\"42017444\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"MALL-SDC4 interaction shown by binding assay without structural detail\",\n        \"Reconciliation with the earlier tumor-suppressive phenotype in colorectal cells not addressed\",\n        \"Single lab, not independently replicated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MALL's raft/caveolin trafficking role, its nuclear condensate localization, and its SDC4 recycling function mechanistically relate within a single protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No unifying structural model linking membrane and nuclear conformations\",\n        \"Endogenous physiological function in normal tissues not established\",\n        \"Context dependence of pro- versus anti-tumor activity unexplained\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CAV1\", \"SDC4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":4,"faith_total":4,"faith_pct":100.0}}