{"gene":"MYO1B","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":1999,"finding":"The 130-kDa myosin I (MI(130)), product of the myr-1 gene (MYO1B), was characterized biochemically and found to have very slow ATP-induced dissociation of the actin-MI complex (second-order rate constant of ATP binding ~1.7×10⁴ M⁻¹s⁻¹; maximal rate ~32 s⁻¹), slow ADP release from actin-MI (~2 s⁻¹), and high actin affinity (~15 nM), indicating it is kinetically adapted for maintenance of cortical tension rather than rapid motility. Ca²⁺ increased the rates of ATP-induced dissociation and ADP release 2–3-fold, indicating Ca²⁺-sensitivity of motor activity.","method":"Steady-state and stopped-flow kinetic analysis (transient kinetics) of purified MI(130) ATPase activity with actin","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — rigorous in vitro reconstitution with multiple kinetic assays and mutagenesis-equivalent parameter dissection","pmids":["10419463"],"is_preprint":false},{"year":2005,"finding":"Myo1b is alternatively spliced within the regulatory domain, yielding isoforms with six (myo1b-a), five (myo1b-b), or four (myo1b-c) IQ motifs. Calmodulin binds tightly (Kd <0.2 µM) to a subset of IQ motifs and very weakly (Kd >5 µM) to others, suggesting not all IQ motifs are calmodulin-bound under physiological conditions. In vitro motility rate depends on the isoform and calmodulin concentration, and Ca²⁺-dependent changes in ATPase activity are due to Ca²⁺ binding to the calmodulin closest to the motor domain. The regulatory domain acts as a rigid lever arm upon calmodulin binding.","method":"Recombinant expression with site-specific biotinylation, ATPase assays, in vitro motility assay, calmodulin-binding measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with multiple orthogonal methods (ATPase, motility, binding assays) in single study","pmids":["16254000"],"is_preprint":false},{"year":2008,"finding":"Myosin I (including Myo1b-class motors) acts as a molecular force sensor: single-molecule optical trap measurements showed that the rate of actin detachment decreases >75-fold under loads of ≤2 pN, causing the motor to transition from a low duty ratio (<0.2) to a high duty ratio (>0.9). This force-dependent gating supports a role for myosin I in sensing membrane tension.","method":"Single-molecule optical trap measurements of displacement and actin-attachment kinetics under defined mechanical loads","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — single-molecule reconstitution with quantitative force-clamp, landmark study with >100 citations","pmids":["18599791"],"is_preprint":false},{"year":1994,"finding":"MYO1B (myr-1 gene product) was identified as one of at least 11 unconventional myosin genes expressed in overlapping fashion across human cell types including epithelial cells, leukocytes, and liver, establishing it as a widely expressed class I myosin.","method":"PCR amplification from cDNA, hybridization screening, RNase protection assay, immunoblot","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — multiple complementary methods confirming expression and identity, foundational classification paper","pmids":["8022818"],"is_preprint":false},{"year":2019,"finding":"Splicing factor SRSF1 promotes gliomagenesis by switching alternative splicing of MYO1B to favor the full-length, membrane-localized oncogenic isoform (MYO1B-fl). This isoform switch increases tumorigenic potential of glioma cells through the PDK1/AKT and PAK/LIMK signaling pathways. Knockdown of MYO1B or reversal of the splice switch suppressed cell proliferation, survival, and invasion.","method":"RNA-seq, motif analysis, siRNA knockdown, overexpression, cell proliferation/invasion assays, pathway analysis (PDK1/AKT, PAK/LIMK)","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (RNA-seq, functional KD/OE, pathway validation) with defined molecular mechanism; >100 citations","pmids":["30481162"],"is_preprint":false},{"year":2021,"finding":"MYO1B promotes colorectal cancer metastasis by activating RhoA, which drives F-actin rearrangement through the ROCK2/LIMK/Cofilin axis and promotes assembly of focal adhesions. Co-immunoprecipitation confirmed MYO1B interaction with RhoA pathway components.","method":"Co-immunoprecipitation, western blotting, immunofluorescence, shRNA knockdown, in vitro and in vivo migration/invasion assays","journal":"Annals of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP plus functional KD with defined pathway readout in single lab","pmids":["34790749"],"is_preprint":false},{"year":2022,"finding":"Myo1b inhibits autophagosome-lysosome fusion, thereby blocking autophagic degradation of HIF-1α and leading to HIF-1α accumulation, enhanced VEGF secretion, and tumor angiogenesis in colorectal cancer. Silencing Myo1b restored autophagy flux and reduced VEGF/HIF-1α levels.","method":"siRNA knockdown, overexpression, autophagy flux assays, HIF-1α protein stability assays, VEGF secretion measurements, in vitro and in vivo tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2/3 — functional KD/OE with mechanistic readouts (autophagy flux, HIF-1α stability), single lab","pmids":["36347835"],"is_preprint":false},{"year":2023,"finding":"Myo1b interacts with LRRK2 via its tail domain, and this interaction promotes intracellular calcium elevation that impairs autophagosome-lysosome fusion, thereby suppressing autophagic flux and promoting endothelial cell senescence and vascular aging. Knockdown of Myo1b in senescent endothelial cells and in aged mice enhanced autophagy and ameliorated endothelial dysfunction.","method":"Co-immunoprecipitation, overexpression/knockdown, calcium imaging, autophagy flux assay, senescence markers (SA-β-gal, p21), in vivo aged mouse model","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP identifying LRRK2 interaction plus functional in vitro and in vivo validation","pmids":["36654782"],"is_preprint":false},{"year":2023,"finding":"MYO1B and MYO5B motor proteins, together with sorting nexin SNX27, regulate intracellular trafficking and apical targeting of membrane mucin MUC17 in enterocytes. MYO1B specifically controls MUC17 protein levels and its slow turnover at the brush border, while MYO5B governs MUC17 levels at the brush border. Loss of MYO1B-mediated trafficking renders enterocytes sensitive to bacterial invasion.","method":"Live imaging, knockdown/knockout, protein level quantification, brush border fractionation, bacterial challenge assays in enterocytes","journal":"bioRxiv / The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization and functional trafficking experiments with defined phenotypic consequence","pmids":["36945389","39661054"],"is_preprint":false},{"year":2022,"finding":"MYO1B activates the SNAI2/cyclin D1 signaling pathway in esophageal squamous cell carcinoma: MYO1B depletion downregulates SNAI2, which in turn inhibits cyclin D1, reducing tumorigenesis and increasing chemosensitivity to cisplatin.","method":"siRNA knockdown, overexpression, qPCR, western blot, CCK8/colony formation/Transwell assays, selective cyclin D1 inhibitor rescue experiment","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 3 — functional assays with pathway rescue, single lab","pmids":["35861939"],"is_preprint":false},{"year":2020,"finding":"Eucalyptal A, a phloroglucinol-terpene natural product, inhibits glioblastoma by downregulating SRSF1 expression, thereby rectifying SRSF1-driven oncogenic alternative splicing of MYO1B mRNA. This correction of MYO1B splicing suppresses GBM cell proliferation, invasion, and tumor growth in vivo through the PDK1/AKT/c-Myc and PAK/Cofilin axes.","method":"RT-PCR splicing analysis, western blot, cell proliferation/invasion assays, xenograft tumor model, survival analysis","journal":"European journal of pharmacology","confidence":"Medium","confidence_rationale":"Tier 2/3 — pharmacological intervention plus in vivo validation confirming MYO1B splice isoform as effector","pmids":["33098832"],"is_preprint":false},{"year":2024,"finding":"MYO1B was functionally validated as a mediator of pancreatic ductal adenocarcinoma (PDAC) metastasis in a functional screen linking pre-metastatic cell state to in vivo metastatic potential. Myo1b knockdown reduced metastatic capacity of PDAC subclones with high metastatic potential.","method":"DNA barcode lineage tracing, ATAC-seq, RNA-seq, functional metastasis screen (in vivo)","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — functional screen validation, preprint, single study","pmids":["bio_10.1101_2024.08.14.607813"],"is_preprint":true},{"year":2024,"finding":"MYO1B interacts with the classical swine fever virus (CSFV) Core (C) protein, and this interaction is mediated by specific N-terminal sites on the C protein. MYO1B knockdown significantly reduced C protein and viral genome content in exosomes and decreased CSFV titers, establishing MYO1B as required for transport of the viral nucleocapsid into exosomes during CSFV infection.","method":"Co-immunoprecipitation, co-localization, C protein point mutations and truncation variants, siRNA knockdown, exosome isolation and quantification, viral titer assays","journal":"Veterinary microbiology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with mutagenesis mapping interaction sites plus functional KD phenotype","pmids":["39603013"],"is_preprint":false}],"current_model":"MYO1B is a widely expressed class I myosin that binds actin with high affinity and is kinetically tuned for tension maintenance rather than rapid motility, functioning as a molecular force sensor whose actin-detachment rate decreases >75-fold under piconewton loads; its regulatory domain contains multiple calmodulin-binding IQ motifs whose occupancy controls lever-arm mechanics and ATPase activity in an isoform- and Ca²⁺-dependent manner; in cells it promotes membrane trafficking (including apical targeting of MUC17 in enterocytes), drives cytoskeletal remodeling via RhoA/ROCK2/LIMK/Cofilin and PAK/LIMK pathways, suppresses autophagosome-lysosome fusion (through a LRRK2-tail-domain interaction that elevates intracellular Ca²⁺), and stabilizes HIF-1α to promote VEGF-driven angiogenesis; oncogenic alternative splicing of MYO1B driven by SRSF1 produces a membrane-localized full-length isoform that activates PDK1/AKT signaling and contributes to glioma progression."},"narrative":{"teleology":[{"year":1994,"claim":"Establishing MYO1B as a widely expressed unconventional myosin resolved whether this class I myosin was tissue-restricted or ubiquitous, setting the stage for functional studies across cell types.","evidence":"PCR, hybridization screening, RNase protection, and immunoblot across human cell types","pmids":["8022818"],"confidence":"Medium","gaps":["No functional characterization beyond expression profiling","Subcellular localization not resolved"]},{"year":1999,"claim":"Detailed transient kinetic analysis revealed that MYO1B is kinetically tuned for tension maintenance rather than rapid motility, establishing a biochemical framework for its cellular role as a cortical force-bearing motor.","evidence":"Steady-state and stopped-flow kinetic analysis of purified MI(130) ATPase activity with actin","pmids":["10419463"],"confidence":"High","gaps":["Force-dependent kinetic behavior not yet measured","In vivo relevance of slow kinetics not demonstrated"]},{"year":2005,"claim":"Characterization of alternatively spliced IQ-motif isoforms and their differential calmodulin binding explained how MYO1B lever-arm mechanics and Ca²⁺ sensitivity are diversified post-transcriptionally.","evidence":"Recombinant isoform expression, calmodulin-binding Kd measurements, ATPase assays, and in vitro motility assays","pmids":["16254000"],"confidence":"High","gaps":["Physiological consequences of isoform-specific motility differences unknown","Identity of the light chain at weakly bound IQ motifs unresolved"]},{"year":2008,"claim":"Single-molecule force measurements demonstrated that myosin I transitions from low to high duty ratio under piconewton loads, establishing MYO1B-class motors as bona fide molecular force sensors capable of detecting membrane tension.","evidence":"Single-molecule optical trap with force-clamp on individual myosin I molecules","pmids":["18599791"],"confidence":"High","gaps":["Direct demonstration of force-sensing in a cellular membrane-tension context not provided","Structural basis of force-dependent ADP release not resolved"]},{"year":2019,"claim":"Discovery that SRSF1 drives oncogenic alternative splicing of MYO1B to produce a membrane-localized full-length isoform that activates PDK1/AKT and PAK/LIMK signaling linked MYO1B isoform regulation to glioma progression.","evidence":"RNA-seq, splice-switching, siRNA knockdown and overexpression in glioma cells with pathway readouts","pmids":["30481162"],"confidence":"High","gaps":["Direct structural or biochemical basis for isoform-specific PDK1/AKT activation not defined","Whether the splicing switch operates in non-glioma tumors not established"]},{"year":2020,"claim":"Pharmacological correction of SRSF1-driven MYO1B splicing by Eucalyptal A validated the MYO1B splice isoform as a druggable effector in glioblastoma, confirming the PDK1/AKT and PAK/Cofilin axes in vivo.","evidence":"RT-PCR splicing analysis, cell assays, and xenograft tumor model with survival analysis","pmids":["33098832"],"confidence":"Medium","gaps":["Eucalyptal A target specificity not fully characterized; off-target effects possible","No direct binding assay between compound and SRSF1/MYO1B mRNA"]},{"year":2021,"claim":"Identification of MYO1B as an activator of RhoA/ROCK2/LIMK/Cofilin signaling in colorectal cancer connected its motor function to cytoskeletal remodeling and focal adhesion dynamics in metastasis.","evidence":"Co-immunoprecipitation, shRNA knockdown, immunofluorescence, in vitro and in vivo migration/invasion assays","pmids":["34790749"],"confidence":"Medium","gaps":["Reciprocal IP or direct binding assay for MYO1B–RhoA interaction not shown","Mechanism by which a myosin I activates RhoA not elucidated"]},{"year":2022,"claim":"Demonstration that MYO1B inhibits autophagosome–lysosome fusion, stabilizing HIF-1α and promoting VEGF-dependent angiogenesis, revealed a non-canonical trafficking function with direct consequences for tumor vascularization.","evidence":"siRNA/overexpression with autophagy flux, HIF-1α stability, and VEGF secretion assays in colorectal cancer models","pmids":["36347835"],"confidence":"Medium","gaps":["Molecular mechanism by which MYO1B blocks autophagosome–lysosome fusion not defined","Whether HIF-1α stabilization requires the motor domain or tail domain unclear"]},{"year":2023,"claim":"The finding that MYO1B interacts with LRRK2 via its tail domain and elevates intracellular Ca²⁺ to suppress autophagy provided a molecular mechanism for the autophagy-inhibitory activity and extended its relevance to endothelial senescence and vascular aging.","evidence":"Co-immunoprecipitation, calcium imaging, autophagy flux assay, senescence markers, aged mouse model","pmids":["36654782"],"confidence":"Medium","gaps":["Whether LRRK2 kinase activity is required for the MYO1B-dependent Ca²⁺ elevation unknown","Source of Ca²⁺ (ER release vs. channel opening) not identified"]},{"year":2023,"claim":"Functional trafficking studies showed MYO1B controls MUC17 protein levels and apical brush-border targeting in enterocytes, establishing a direct physiological role in intestinal barrier defense against bacterial invasion.","evidence":"Live imaging, knockdown/knockout, brush border fractionation, bacterial challenge in enterocytes","pmids":["36945389","39661054"],"confidence":"Medium","gaps":["Cargo-recognition mechanism between MYO1B and MUC17-containing vesicles not defined","Whether other brush-border cargoes depend on MYO1B trafficking unclear"]},{"year":2024,"claim":"MYO1B was shown to interact with CSFV Core protein and to be required for nucleocapsid loading into exosomes, extending its trafficking roles to viral exploitation of the exosomal pathway.","evidence":"Co-immunoprecipitation with C-protein truncation/point mutants, siRNA knockdown, exosome isolation, viral titer assays","pmids":["39603013"],"confidence":"Medium","gaps":["Generalizability to other viruses not tested","Whether MYO1B motor activity or tail-mediated binding is the critical determinant not resolved"]},{"year":null,"claim":"Key unresolved questions include the structural basis for MYO1B force-dependent gating, the mechanism by which the tail domain inhibits autophagosome–lysosome fusion, and whether distinct isoforms have non-overlapping trafficking versus signaling roles in vivo.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of MYO1B in a force-bearing state","No genetic model cleanly separating isoform-specific functions","Tail-domain interaction network beyond LRRK2 largely unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,8]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[8,12]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,7]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[8,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,5,6,9,10]}],"complexes":[],"partners":["CALM1","LRRK2","RHOA","SRSF1","SNX27","MYO5B","MUC17"],"other_free_text":[]},"mechanistic_narrative":"MYO1B is a widely expressed class I unconventional myosin that functions as a molecular force sensor and tension-maintenance motor, with kinetics characterized by very slow ATP-induced actin dissociation, slow ADP release, and high actin affinity (~15 nM Kd), and whose actin-detachment rate decreases >75-fold under piconewton loads, transitioning it from low to high duty ratio [PMID:10419463, PMID:18599791]. Its regulatory domain is alternatively spliced to yield isoforms with four to six calmodulin-binding IQ motifs, and differential calmodulin occupancy and Ca²⁺ sensitivity tune lever-arm rigidity, ATPase activity, and motility rate in an isoform-dependent manner [PMID:16254000]. In cells, MYO1B regulates membrane trafficking—including apical targeting of MUC17 in enterocytes and exosomal cargo transport—and drives cytoskeletal remodeling through RhoA/ROCK2/LIMK/Cofilin signaling, while also suppressing autophagosome–lysosome fusion via a LRRK2-tail-domain interaction that elevates intracellular Ca²⁺, thereby stabilizing HIF-1α and promoting VEGF-driven angiogenesis [PMID:39661054, PMID:34790749, PMID:36347835, PMID:36654782]. Oncogenic alternative splicing driven by SRSF1 produces a membrane-localized full-length isoform that activates PDK1/AKT signaling and contributes to glioma progression [PMID:30481162]."},"prefetch_data":{"uniprot":{"accession":"O43795","full_name":"Unconventional myosin-Ib","aliases":["MYH-1c","Myosin I alpha","MMI-alpha","MMIa"],"length_aa":1136,"mass_kda":132.0,"function":"Motor protein that may participate in process critical to neuronal development and function such as cell migration, neurite outgrowth and vesicular transport","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/O43795/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYO1B","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000128641","cell_line_id":"CID001440","localizations":[{"compartment":"membrane","grade":3},{"compartment":"cell_contact","grade":2}],"interactors":[{"gene":"ACTN4","stoichiometry":0.2},{"gene":"CALD1","stoichiometry":0.2},{"gene":"CALM1","stoichiometry":0.2},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CHMP2A","stoichiometry":0.2},{"gene":"COPG1","stoichiometry":0.2},{"gene":"CTTN","stoichiometry":0.2},{"gene":"NAP1L1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001440","total_profiled":1310},"omim":[{"mim_id":"606537","title":"MYOSIN IB; MYO1B","url":"https://www.omim.org/entry/606537"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Plasma membrane","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":238.9}],"url":"https://www.proteinatlas.org/search/MYO1B"},"hgnc":{"alias_symbol":["myr1"],"prev_symbol":[]},"alphafold":{"accession":"O43795","domains":[{"cath_id":"3.40.850.10","chopping":"19-265_361-404_591-629","consensus_level":"medium","plddt":90.6515,"start":19,"end":629},{"cath_id":"1.20.120.720","chopping":"274-358_530-575","consensus_level":"medium","plddt":87.8987,"start":274,"end":575},{"cath_id":"3.30.70.1590","chopping":"633-688","consensus_level":"medium","plddt":93.1166,"start":633,"end":688},{"cath_id":"-","chopping":"862-929","consensus_level":"medium","plddt":83.119,"start":862,"end":929},{"cath_id":"2.30.29.30","chopping":"931-1133","consensus_level":"high","plddt":86.7562,"start":931,"end":1133}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O43795","model_url":"https://alphafold.ebi.ac.uk/files/AF-O43795-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O43795-F1-predicted_aligned_error_v6.png","plddt_mean":85.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYO1B","jax_strain_url":"https://www.jax.org/strain/search?query=MYO1B"},"sequence":{"accession":"O43795","fasta_url":"https://rest.uniprot.org/uniprotkb/O43795.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O43795/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O43795"}},"corpus_meta":[{"pmid":"26838724","id":"PMC_26838724","title":"A Novel Secreted Protein, MYR1, Is Central to Toxoplasma's Manipulation of Host Cells.","date":"2016","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/26838724","citation_count":130,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30481162","id":"PMC_30481162","title":"Splicing factor SRSF1 promotes gliomagenesis via oncogenic splice-switching of MYO1B.","date":"2019","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/30481162","citation_count":121,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10419463","id":"PMC_10419463","title":"Transient kinetic analysis of the 130-kDa myosin I (MYR-1 gene product) from rat liver. A myosin I designed for maintenance of tension?","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10419463","citation_count":86,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29115582","id":"PMC_29115582","title":"Passenger strand of miR-145-3p acts as a tumor-suppressor by targeting MYO1B in head and neck squamous cell carcinoma.","date":"2017","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29115582","citation_count":61,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32075880","id":"PMC_32075880","title":"Coimmunoprecipitation with MYR1 Identifies Three Additional Proteins within the Toxoplasma gondii Parasitophorous Vacuole Required for Translocation of Dense Granule Effectors into Host 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Ca²⁺ increases these rates 2–3 fold, revealing Ca²⁺-sensitivity of motor activity.\",\n      \"method\": \"Steady-state and stopped-flow transient kinetic analysis of purified MI(130) in vitro\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted enzymatic assays with multiple kinetic parameters measured\",\n      \"pmids\": [\"10419463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Myo1b is alternatively spliced within the regulatory domain, yielding isoforms with six (myo1b-a), five (myo1b-b), or four (myo1b-c) IQ motifs. Calmodulin binds tightly to a subset of IQ motifs (Kd <0.2 µM) and weakly to others (Kd >5 µM). In vitro motility rate depends on isoform identity and calmodulin concentration, and the regulatory domain acts as a rigid lever arm upon calmodulin binding. Ca²⁺-dependent ATPase changes are due to Ca²⁺ binding to the calmodulin closest to the motor domain.\",\n      \"method\": \"Recombinant expression of biotinylated isoforms, ATPase assays, in vitro motility assays, calmodulin-binding measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with multiple orthogonal assays; mutagenesis-level isoform dissection\",\n      \"pmids\": [\"16254000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SRSF1-mediated alternative splicing switches MYO1B to its full-length membrane-localized isoform (MYO1B-fl) in glioma, promoting cell proliferation, survival, and invasion through the PDK1/AKT and PAK/LIMK pathways.\",\n      \"method\": \"RNA-Seq splicing analysis, SRSF1 knockdown/overexpression, functional assays (proliferation, invasion), pathway western blotting in glioma cells\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (RNA-Seq, functional assays, pathway analysis) in a single study with strong controls\",\n      \"pmids\": [\"30481162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYO1B promotes colorectal cancer metastasis by activating RhoA, which drives F-actin rearrangement through the ROCK2/LIMK/Cofilin axis and promotes focal adhesion assembly.\",\n      \"method\": \"Co-immunoprecipitation, western blotting, immunofluorescence, shRNA knockdown and lentiviral overexpression in CRC cells, in vitro migration/invasion assays\",\n      \"journal\": \"Annals of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — co-IP with functional knockdown and pathway readouts, single lab\",\n      \"pmids\": [\"34790749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Myo1b inhibits autophagosome-lysosome fusion in colorectal cancer cells, blocking autophagic degradation of HIF-1α and leading to HIF-1α accumulation, enhanced VEGF secretion, and tumor angiogenesis.\",\n      \"method\": \"Myo1b knockdown/overexpression, autophagy flux assays, co-localization of autophagosome and lysosome markers, VEGF ELISA, in vitro and in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway defined with functional readouts in vitro and in vivo, single lab\",\n      \"pmids\": [\"36347835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MYO1B activates the SNAI2/cyclin D1 pathway in esophageal squamous cell carcinoma; suppression of MYO1B downregulates SNAI2, thereby inhibiting cyclin D1 and reducing tumorigenesis and chemoresistance.\",\n      \"method\": \"siRNA knockdown, qPCR, western blot, functional assays (CCK8, colony formation, wound healing, Transwell), pharmacological reversal with cyclin D1 inhibitor\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — mechanistic pathway established with rescue experiment, single lab\",\n      \"pmids\": [\"35861939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Myo1b interacts with LRRK2 through its tail domain, promoting intracellular calcium elevation, which impairs autophagosome-lysosome fusion (autophagic flux) and drives endothelial cell senescence and vascular aging.\",\n      \"method\": \"Co-immunoprecipitation (Myo1b–LRRK2 interaction), domain mapping, calcium measurement, autophagy flux assays, siRNA knockdown in senescent ECs and in vivo aged mouse model\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with domain mapping plus in vitro/in vivo functional validation, single lab\",\n      \"pmids\": [\"36654782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MYO1B regulates intracellular trafficking and protein levels of the membrane mucin MUC17 in enterocytes, controlling its slow turnover at the apical brush border; loss of MYO1B renders enterocytes sensitive to bacterial invasion.\",\n      \"method\": \"MYO1B knockdown/KO in enterocytes, live-cell imaging of MUC17 trafficking, brush border fractionation, bacterial challenge assay\",\n      \"journal\": \"The Biochemical journal / bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization and trafficking experiments with functional consequence (bacterial susceptibility), two publications (preprint + peer-reviewed)\",\n      \"pmids\": [\"36945389\", \"39661054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYO1B interacts with the classical swine fever virus core (C) protein; specific N-terminal sites on C are critical for this interaction, and MYO1B knockdown reduces C protein and viral genome content in exosomes, decreasing CSFV titers.\",\n      \"method\": \"Co-immunoprecipitation, co-localization, C protein point mutations and truncation variants, MYO1B knockdown with exosome isolation and titer measurement\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with domain mapping and functional knockdown readout, single lab\",\n      \"pmids\": [\"39603013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MYO1B knockdown in head and neck squamous cell carcinoma inhibits the PI3K/AKT signaling pathway, reducing stemness markers (SOX2, OCT4), EMT-related proteins, and ATM phosphorylation, thereby enhancing radiosensitivity; AKT activator rescues these effects.\",\n      \"method\": \"siRNA knockdown, western blot, AKT activator rescue, in vitro functional assays, xenograft in vivo model\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway with pharmacological rescue and in vivo confirmation, single lab\",\n      \"pmids\": [\"40604770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2029,\n      \"finding\": \"MYO1B activates the PI3K-AKT signaling pathway in breast cancer cells to promote proliferation, inhibit apoptosis, and confer resistance to tamoxifen and palbociclib.\",\n      \"method\": \"Functional assays (proliferation, apoptosis), western blot for PI3K/AKT pathway components, drug sensitivity assays in BRCA cell lines\",\n      \"journal\": \"In vitro cellular & developmental biology. Animal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single method type, no direct interaction assay\",\n      \"pmids\": [\"41986768\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYO1B is a class I myosin mechanochemical motor kinetically tuned for tension maintenance (slow ADP release, slow actin dissociation, Ca²⁺-regulated activity) whose alternatively spliced isoforms differ in calmodulin binding and motility; in cells it localizes to endosomal and ruffling membranes where its tail domain mediates interactions with partners such as LRRK2, coupling to regulation of autophagosome-lysosome fusion, intracellular membrane/mucin trafficking (MUC17), and actin remodeling via RhoA/ROCK/LIMK and PAK/LIMK pathways, while its oncogenic splice isoform (promoted by SRSF1) activates PDK1/AKT signaling to drive tumor cell proliferation and invasion.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"The 130-kDa myosin I (MI(130)), product of the myr-1 gene (MYO1B), was characterized biochemically and found to have very slow ATP-induced dissociation of the actin-MI complex (second-order rate constant of ATP binding ~1.7×10⁴ M⁻¹s⁻¹; maximal rate ~32 s⁻¹), slow ADP release from actin-MI (~2 s⁻¹), and high actin affinity (~15 nM), indicating it is kinetically adapted for maintenance of cortical tension rather than rapid motility. Ca²⁺ increased the rates of ATP-induced dissociation and ADP release 2–3-fold, indicating Ca²⁺-sensitivity of motor activity.\",\n      \"method\": \"Steady-state and stopped-flow kinetic analysis (transient kinetics) of purified MI(130) ATPase activity with actin\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — rigorous in vitro reconstitution with multiple kinetic assays and mutagenesis-equivalent parameter dissection\",\n      \"pmids\": [\"10419463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Myo1b is alternatively spliced within the regulatory domain, yielding isoforms with six (myo1b-a), five (myo1b-b), or four (myo1b-c) IQ motifs. Calmodulin binds tightly (Kd <0.2 µM) to a subset of IQ motifs and very weakly (Kd >5 µM) to others, suggesting not all IQ motifs are calmodulin-bound under physiological conditions. In vitro motility rate depends on the isoform and calmodulin concentration, and Ca²⁺-dependent changes in ATPase activity are due to Ca²⁺ binding to the calmodulin closest to the motor domain. The regulatory domain acts as a rigid lever arm upon calmodulin binding.\",\n      \"method\": \"Recombinant expression with site-specific biotinylation, ATPase assays, in vitro motility assay, calmodulin-binding measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with multiple orthogonal methods (ATPase, motility, binding assays) in single study\",\n      \"pmids\": [\"16254000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Myosin I (including Myo1b-class motors) acts as a molecular force sensor: single-molecule optical trap measurements showed that the rate of actin detachment decreases >75-fold under loads of ≤2 pN, causing the motor to transition from a low duty ratio (<0.2) to a high duty ratio (>0.9). This force-dependent gating supports a role for myosin I in sensing membrane tension.\",\n      \"method\": \"Single-molecule optical trap measurements of displacement and actin-attachment kinetics under defined mechanical loads\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — single-molecule reconstitution with quantitative force-clamp, landmark study with >100 citations\",\n      \"pmids\": [\"18599791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"MYO1B (myr-1 gene product) was identified as one of at least 11 unconventional myosin genes expressed in overlapping fashion across human cell types including epithelial cells, leukocytes, and liver, establishing it as a widely expressed class I myosin.\",\n      \"method\": \"PCR amplification from cDNA, hybridization screening, RNase protection assay, immunoblot\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple complementary methods confirming expression and identity, foundational classification paper\",\n      \"pmids\": [\"8022818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Splicing factor SRSF1 promotes gliomagenesis by switching alternative splicing of MYO1B to favor the full-length, membrane-localized oncogenic isoform (MYO1B-fl). This isoform switch increases tumorigenic potential of glioma cells through the PDK1/AKT and PAK/LIMK signaling pathways. Knockdown of MYO1B or reversal of the splice switch suppressed cell proliferation, survival, and invasion.\",\n      \"method\": \"RNA-seq, motif analysis, siRNA knockdown, overexpression, cell proliferation/invasion assays, pathway analysis (PDK1/AKT, PAK/LIMK)\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (RNA-seq, functional KD/OE, pathway validation) with defined molecular mechanism; >100 citations\",\n      \"pmids\": [\"30481162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYO1B promotes colorectal cancer metastasis by activating RhoA, which drives F-actin rearrangement through the ROCK2/LIMK/Cofilin axis and promotes assembly of focal adhesions. Co-immunoprecipitation confirmed MYO1B interaction with RhoA pathway components.\",\n      \"method\": \"Co-immunoprecipitation, western blotting, immunofluorescence, shRNA knockdown, in vitro and in vivo migration/invasion assays\",\n      \"journal\": \"Annals of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP plus functional KD with defined pathway readout in single lab\",\n      \"pmids\": [\"34790749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Myo1b inhibits autophagosome-lysosome fusion, thereby blocking autophagic degradation of HIF-1α and leading to HIF-1α accumulation, enhanced VEGF secretion, and tumor angiogenesis in colorectal cancer. Silencing Myo1b restored autophagy flux and reduced VEGF/HIF-1α levels.\",\n      \"method\": \"siRNA knockdown, overexpression, autophagy flux assays, HIF-1α protein stability assays, VEGF secretion measurements, in vitro and in vivo tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — functional KD/OE with mechanistic readouts (autophagy flux, HIF-1α stability), single lab\",\n      \"pmids\": [\"36347835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Myo1b interacts with LRRK2 via its tail domain, and this interaction promotes intracellular calcium elevation that impairs autophagosome-lysosome fusion, thereby suppressing autophagic flux and promoting endothelial cell senescence and vascular aging. Knockdown of Myo1b in senescent endothelial cells and in aged mice enhanced autophagy and ameliorated endothelial dysfunction.\",\n      \"method\": \"Co-immunoprecipitation, overexpression/knockdown, calcium imaging, autophagy flux assay, senescence markers (SA-β-gal, p21), in vivo aged mouse model\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP identifying LRRK2 interaction plus functional in vitro and in vivo validation\",\n      \"pmids\": [\"36654782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MYO1B and MYO5B motor proteins, together with sorting nexin SNX27, regulate intracellular trafficking and apical targeting of membrane mucin MUC17 in enterocytes. MYO1B specifically controls MUC17 protein levels and its slow turnover at the brush border, while MYO5B governs MUC17 levels at the brush border. Loss of MYO1B-mediated trafficking renders enterocytes sensitive to bacterial invasion.\",\n      \"method\": \"Live imaging, knockdown/knockout, protein level quantification, brush border fractionation, bacterial challenge assays in enterocytes\",\n      \"journal\": \"bioRxiv / The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization and functional trafficking experiments with defined phenotypic consequence\",\n      \"pmids\": [\"36945389\", \"39661054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MYO1B activates the SNAI2/cyclin D1 signaling pathway in esophageal squamous cell carcinoma: MYO1B depletion downregulates SNAI2, which in turn inhibits cyclin D1, reducing tumorigenesis and increasing chemosensitivity to cisplatin.\",\n      \"method\": \"siRNA knockdown, overexpression, qPCR, western blot, CCK8/colony formation/Transwell assays, selective cyclin D1 inhibitor rescue experiment\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional assays with pathway rescue, single lab\",\n      \"pmids\": [\"35861939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Eucalyptal A, a phloroglucinol-terpene natural product, inhibits glioblastoma by downregulating SRSF1 expression, thereby rectifying SRSF1-driven oncogenic alternative splicing of MYO1B mRNA. This correction of MYO1B splicing suppresses GBM cell proliferation, invasion, and tumor growth in vivo through the PDK1/AKT/c-Myc and PAK/Cofilin axes.\",\n      \"method\": \"RT-PCR splicing analysis, western blot, cell proliferation/invasion assays, xenograft tumor model, survival analysis\",\n      \"journal\": \"European journal of pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — pharmacological intervention plus in vivo validation confirming MYO1B splice isoform as effector\",\n      \"pmids\": [\"33098832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYO1B was functionally validated as a mediator of pancreatic ductal adenocarcinoma (PDAC) metastasis in a functional screen linking pre-metastatic cell state to in vivo metastatic potential. Myo1b knockdown reduced metastatic capacity of PDAC subclones with high metastatic potential.\",\n      \"method\": \"DNA barcode lineage tracing, ATAC-seq, RNA-seq, functional metastasis screen (in vivo)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — functional screen validation, preprint, single study\",\n      \"pmids\": [\"bio_10.1101_2024.08.14.607813\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYO1B interacts with the classical swine fever virus (CSFV) Core (C) protein, and this interaction is mediated by specific N-terminal sites on the C protein. MYO1B knockdown significantly reduced C protein and viral genome content in exosomes and decreased CSFV titers, establishing MYO1B as required for transport of the viral nucleocapsid into exosomes during CSFV infection.\",\n      \"method\": \"Co-immunoprecipitation, co-localization, C protein point mutations and truncation variants, siRNA knockdown, exosome isolation and quantification, viral titer assays\",\n      \"journal\": \"Veterinary microbiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with mutagenesis mapping interaction sites plus functional KD phenotype\",\n      \"pmids\": [\"39603013\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYO1B is a widely expressed class I myosin that binds actin with high affinity and is kinetically tuned for tension maintenance rather than rapid motility, functioning as a molecular force sensor whose actin-detachment rate decreases >75-fold under piconewton loads; its regulatory domain contains multiple calmodulin-binding IQ motifs whose occupancy controls lever-arm mechanics and ATPase activity in an isoform- and Ca²⁺-dependent manner; in cells it promotes membrane trafficking (including apical targeting of MUC17 in enterocytes), drives cytoskeletal remodeling via RhoA/ROCK2/LIMK/Cofilin and PAK/LIMK pathways, suppresses autophagosome-lysosome fusion (through a LRRK2-tail-domain interaction that elevates intracellular Ca²⁺), and stabilizes HIF-1α to promote VEGF-driven angiogenesis; oncogenic alternative splicing of MYO1B driven by SRSF1 produces a membrane-localized full-length isoform that activates PDK1/AKT signaling and contributes to glioma progression.\"\n}\n```","stage2_raw":"\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"MYO1B is a widely expressed class I unconventional myosin that functions as a molecular force sensor and tension-maintenance motor, with kinetics characterized by very slow ATP-induced actin dissociation, slow ADP release, and high actin affinity (~15 nM Kd), and whose actin-detachment rate decreases >75-fold under piconewton loads, transitioning it from low to high duty ratio [PMID:10419463, PMID:18599791]. Its regulatory domain is alternatively spliced to yield isoforms with four to six calmodulin-binding IQ motifs, and differential calmodulin occupancy and Ca²⁺ sensitivity tune lever-arm rigidity, ATPase activity, and motility rate in an isoform-dependent manner [PMID:16254000]. In cells, MYO1B regulates membrane trafficking—including apical targeting of MUC17 in enterocytes and exosomal cargo transport—and drives cytoskeletal remodeling through RhoA/ROCK2/LIMK/Cofilin signaling, while also suppressing autophagosome–lysosome fusion via a LRRK2-tail-domain interaction that elevates intracellular Ca²⁺, thereby stabilizing HIF-1α and promoting VEGF-driven angiogenesis [PMID:39661054, PMID:34790749, PMID:36347835, PMID:36654782]. Oncogenic alternative splicing driven by SRSF1 produces a membrane-localized full-length isoform that activates PDK1/AKT signaling and contributes to glioma progression [PMID:30481162].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing MYO1B as a widely expressed unconventional myosin resolved whether this class I myosin was tissue-restricted or ubiquitous, setting the stage for functional studies across cell types.\",\n      \"evidence\": \"PCR, hybridization screening, RNase protection, and immunoblot across human cell types\",\n      \"pmids\": [\"8022818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional characterization beyond expression profiling\", \"Subcellular localization not resolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Detailed transient kinetic analysis revealed that MYO1B is kinetically tuned for tension maintenance rather than rapid motility, establishing a biochemical framework for its cellular role as a cortical force-bearing motor.\",\n      \"evidence\": \"Steady-state and stopped-flow kinetic analysis of purified MI(130) ATPase activity with actin\",\n      \"pmids\": [\"10419463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Force-dependent kinetic behavior not yet measured\", \"In vivo relevance of slow kinetics not demonstrated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Characterization of alternatively spliced IQ-motif isoforms and their differential calmodulin binding explained how MYO1B lever-arm mechanics and Ca²⁺ sensitivity are diversified post-transcriptionally.\",\n      \"evidence\": \"Recombinant isoform expression, calmodulin-binding Kd measurements, ATPase assays, and in vitro motility assays\",\n      \"pmids\": [\"16254000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequences of isoform-specific motility differences unknown\", \"Identity of the light chain at weakly bound IQ motifs unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Single-molecule force measurements demonstrated that myosin I transitions from low to high duty ratio under piconewton loads, establishing MYO1B-class motors as bona fide molecular force sensors capable of detecting membrane tension.\",\n      \"evidence\": \"Single-molecule optical trap with force-clamp on individual myosin I molecules\",\n      \"pmids\": [\"18599791\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of force-sensing in a cellular membrane-tension context not provided\", \"Structural basis of force-dependent ADP release not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery that SRSF1 drives oncogenic alternative splicing of MYO1B to produce a membrane-localized full-length isoform that activates PDK1/AKT and PAK/LIMK signaling linked MYO1B isoform regulation to glioma progression.\",\n      \"evidence\": \"RNA-seq, splice-switching, siRNA knockdown and overexpression in glioma cells with pathway readouts\",\n      \"pmids\": [\"30481162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural or biochemical basis for isoform-specific PDK1/AKT activation not defined\", \"Whether the splicing switch operates in non-glioma tumors not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Pharmacological correction of SRSF1-driven MYO1B splicing by Eucalyptal A validated the MYO1B splice isoform as a druggable effector in glioblastoma, confirming the PDK1/AKT and PAK/Cofilin axes in vivo.\",\n      \"evidence\": \"RT-PCR splicing analysis, cell assays, and xenograft tumor model with survival analysis\",\n      \"pmids\": [\"33098832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Eucalyptal A target specificity not fully characterized; off-target effects possible\", \"No direct binding assay between compound and SRSF1/MYO1B mRNA\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of MYO1B as an activator of RhoA/ROCK2/LIMK/Cofilin signaling in colorectal cancer connected its motor function to cytoskeletal remodeling and focal adhesion dynamics in metastasis.\",\n      \"evidence\": \"Co-immunoprecipitation, shRNA knockdown, immunofluorescence, in vitro and in vivo migration/invasion assays\",\n      \"pmids\": [\"34790749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal IP or direct binding assay for MYO1B–RhoA interaction not shown\", \"Mechanism by which a myosin I activates RhoA not elucidated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstration that MYO1B inhibits autophagosome–lysosome fusion, stabilizing HIF-1α and promoting VEGF-dependent angiogenesis, revealed a non-canonical trafficking function with direct consequences for tumor vascularization.\",\n      \"evidence\": \"siRNA/overexpression with autophagy flux, HIF-1α stability, and VEGF secretion assays in colorectal cancer models\",\n      \"pmids\": [\"36347835\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which MYO1B blocks autophagosome–lysosome fusion not defined\", \"Whether HIF-1α stabilization requires the motor domain or tail domain unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The finding that MYO1B interacts with LRRK2 via its tail domain and elevates intracellular Ca²⁺ to suppress autophagy provided a molecular mechanism for the autophagy-inhibitory activity and extended its relevance to endothelial senescence and vascular aging.\",\n      \"evidence\": \"Co-immunoprecipitation, calcium imaging, autophagy flux assay, senescence markers, aged mouse model\",\n      \"pmids\": [\"36654782\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether LRRK2 kinase activity is required for the MYO1B-dependent Ca²⁺ elevation unknown\", \"Source of Ca²⁺ (ER release vs. channel opening) not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Functional trafficking studies showed MYO1B controls MUC17 protein levels and apical brush-border targeting in enterocytes, establishing a direct physiological role in intestinal barrier defense against bacterial invasion.\",\n      \"evidence\": \"Live imaging, knockdown/knockout, brush border fractionation, bacterial challenge in enterocytes\",\n      \"pmids\": [\"36945389\", \"39661054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cargo-recognition mechanism between MYO1B and MUC17-containing vesicles not defined\", \"Whether other brush-border cargoes depend on MYO1B trafficking unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"MYO1B was shown to interact with CSFV Core protein and to be required for nucleocapsid loading into exosomes, extending its trafficking roles to viral exploitation of the exosomal pathway.\",\n      \"evidence\": \"Co-immunoprecipitation with C-protein truncation/point mutants, siRNA knockdown, exosome isolation, viral titer assays\",\n      \"pmids\": [\"39603013\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalizability to other viruses not tested\", \"Whether MYO1B motor activity or tail-mediated binding is the critical determinant not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for MYO1B force-dependent gating, the mechanism by which the tail domain inhibits autophagosome–lysosome fusion, and whether distinct isoforms have non-overlapping trafficking versus signaling roles in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of MYO1B in a force-bearing state\", \"No genetic model cleanly separating isoform-specific functions\", \"Tail-domain interaction network beyond LRRK2 largely unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [8, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [4, 5, 10]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5, 6, 9, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CALM1\",\n      \"LRRK2\",\n      \"RHOA\",\n      \"SRSF1\",\n      \"SNX27\",\n      \"MYO5B\",\n      \"MUC17\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I need to fix the pathway term_ids. I accidentally used \"GO:0162582\" which isn't valid. Let me correct:\n\n```json\n{\n  \"mechanistic_narrative\": \"MYO1B is a widely expressed class I unconventional myosin that functions as a molecular force sensor and tension-maintenance motor, with kinetics characterized by very slow ATP-induced actin dissociation, slow ADP release, and high actin affinity (~15 nM Kd), and whose actin-detachment rate decreases >75-fold under piconewton loads, transitioning it from low to high duty ratio [PMID:10419463, PMID:18599791]. Its regulatory domain is alternatively spliced to yield isoforms with four to six calmodulin-binding IQ motifs, and differential calmodulin occupancy and Ca²⁺ sensitivity tune lever-arm rigidity, ATPase activity, and motility rate in an isoform-dependent manner [PMID:16254000]. In cells, MYO1B regulates membrane trafficking—including apical targeting of MUC17 in enterocytes and exosomal cargo transport—and drives cytoskeletal remodeling through RhoA/ROCK2/LIMK/Cofilin signaling, while also suppressing autophagosome–lysosome fusion via a LRRK2-tail-domain interaction that elevates intracellular Ca²⁺, thereby stabilizing HIF-1α and promoting VEGF-driven angiogenesis [PMID:39661054, PMID:34790749, PMID:36347835, PMID:36654782]. Oncogenic alternative splicing driven by SRSF1 produces a membrane-localized full-length isoform that activates PDK1/AKT signaling and contributes to glioma progression [PMID:30481162].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing MYO1B as a widely expressed unconventional myosin resolved whether this class I myosin was tissue-restricted or ubiquitous, setting the stage for functional studies across cell types.\",\n      \"evidence\": \"PCR, hybridization screening, RNase protection, and immunoblot across human cell types\",\n      \"pmids\": [\"8022818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional characterization beyond expression profiling\", \"Subcellular localization not resolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Detailed transient kinetic analysis revealed that MYO1B is kinetically tuned for tension maintenance rather than rapid motility, establishing a biochemical framework for its cellular role as a cortical force-bearing motor.\",\n      \"evidence\": \"Steady-state and stopped-flow kinetic analysis of purified MI(130) ATPase activity with actin\",\n      \"pmids\": [\"10419463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Force-dependent kinetic behavior not yet measured\", \"In vivo relevance of slow kinetics not demonstrated\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Characterization of alternatively spliced IQ-motif isoforms and their differential calmodulin binding explained how MYO1B lever-arm mechanics and Ca²⁺ sensitivity are diversified post-transcriptionally.\",\n      \"evidence\": \"Recombinant isoform expression, calmodulin-binding Kd measurements, ATPase assays, and in vitro motility assays\",\n      \"pmids\": [\"16254000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological consequences of isoform-specific motility differences unknown\", \"Identity of the light chain at weakly bound IQ motifs unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Single-molecule force measurements demonstrated that myosin I transitions from low to high duty ratio under piconewton loads, establishing MYO1B-class motors as bona fide molecular force sensors capable of detecting membrane tension.\",\n      \"evidence\": \"Single-molecule optical trap with force-clamp on individual myosin I molecules\",\n      \"pmids\": [\"18599791\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of force-sensing in a cellular membrane-tension context not provided\", \"Structural basis of force-dependent ADP release not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery that SRSF1 drives oncogenic alternative splicing of MYO1B to produce a membrane-localized full-length isoform that activates PDK1/AKT and PAK/LIMK signaling linked MYO1B isoform regulation to glioma progression.\",\n      \"evidence\": \"RNA-seq, splice-switching, siRNA knockdown and overexpression in glioma cells with pathway readouts\",\n      \"pmids\": [\"30481162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct structural or biochemical basis for isoform-specific PDK1/AKT activation not defined\", \"Whether the splicing switch operates in non-glioma tumors not established\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Pharmacological correction of SRSF1-driven MYO1B splicing by Eucalyptal A validated the MYO1B splice isoform as a druggable effector in glioblastoma, confirming the PDK1/AKT and PAK/Cofilin axes in vivo.\",\n      \"evidence\": \"RT-PCR splicing analysis, cell assays, and xenograft tumor model with survival analysis\",\n      \"pmids\": [\"33098832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Eucalyptal A target specificity not fully characterized; off-target effects possible\", \"No direct binding assay between compound and SRSF1/MYO1B mRNA\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of MYO1B as an activator of RhoA/ROCK2/LIMK/Cofilin signaling in colorectal cancer connected its motor function to cytoskeletal remodeling and focal adhesion dynamics in metastasis.\",\n      \"evidence\": \"Co-immunoprecipitation, shRNA knockdown, immunofluorescence, in vitro and in vivo migration/invasion assays\",\n      \"pmids\": [\"34790749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal IP or direct binding assay for MYO1B–RhoA interaction not shown\", \"Mechanism by which a myosin I activates RhoA not elucidated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstration that MYO1B inhibits autophagosome–lysosome fusion, stabilizing HIF-1α and promoting VEGF-dependent angiogenesis, revealed a non-canonical trafficking function with direct consequences for tumor vascularization.\",\n      \"evidence\": \"siRNA/overexpression with autophagy flux, HIF-1α stability, and VEGF secretion assays in colorectal cancer models\",\n      \"pmids\": [\"36347835\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which MYO1B blocks autophagosome–lysosome fusion not defined\", \"Whether HIF-1α stabilization requires the motor domain or tail domain unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The finding that MYO1B interacts with LRRK2 via its tail domain and elevates intracellular Ca²⁺ to suppress autophagy provided a molecular mechanism for the autophagy-inhibitory activity and extended its relevance to endothelial senescence and vascular aging.\",\n      \"evidence\": \"Co-immunoprecipitation, calcium imaging, autophagy flux assay, senescence markers, aged mouse model\",\n      \"pmids\": [\"36654782\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether LRRK2 kinase activity is required for the MYO1B-dependent Ca²⁺ elevation unknown\", \"Source of Ca²⁺ (ER release vs. channel opening) not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Functional trafficking studies showed MYO1B controls MUC17 protein levels and apical brush-border targeting in enterocytes, establishing a direct physiological role in intestinal barrier defense against bacterial invasion.\",\n      \"evidence\": \"Live imaging, knockdown/knockout, brush border fractionation, bacterial challenge in enterocytes\",\n      \"pmids\": [\"36945389\", \"39661054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cargo-recognition mechanism between MYO1B and MUC17-containing vesicles not defined\", \"Whether other brush-border cargoes depend on MYO1B trafficking unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"MYO1B was shown to interact with CSFV Core protein and to be required for nucleocapsid loading into exosomes, extending its trafficking roles to viral exploitation of the exosomal pathway.\",\n      \"evidence\": \"Co-immunoprecipitation with C-protein truncation/point mutants, siRNA knockdown, exosome isolation, viral titer assays\",\n      \"pmids\": [\"39603013\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalizability to other viruses not tested\", \"Whether MYO1B motor activity or tail-mediated binding is the critical determinant not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for MYO1B force-dependent gating, the mechanism by which the tail domain inhibits autophagosome–lysosome fusion, and whether distinct isoforms have non-overlapping trafficking versus signaling roles in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution structure of MYO1B in a force-bearing state\", \"No genetic model cleanly separating isoform-specific functions\", \"Tail-domain interaction network beyond LRRK2 largely unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 8]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [8, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 10]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [8, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5, 6, 9, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CALM1\",\n      \"LRRK2\",\n      \"RHOA\",\n      \"SRSF1\",\n      \"SNX27\",\n      \"MYO5B\",\n      \"MUC17\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}