{"gene":"MYO1E","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2002,"finding":"Myo1e (human myosin-IC) has a defined ATPase kinetic mechanism: it has low K(ATPase) (~1 µM) for actin, weak actin affinity in the presence of ATP, rapid phosphate release while dissociated from actin, and actin activation of ADP release as the primary mechanism of actin-stimulated ATPase activation. ADP release from actomyo1e is >10-fold faster than other vertebrate myosin-I isoforms, suggesting subclass-1 myosin-Is are tuned for rapid sliding.","method":"In vitro kinetic analysis (stopped-flow, ATPase assays) of truncated myo1e motor+IQ construct with bound calmodulin","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — rigorous in vitro reconstitution with multiple kinetic measurements (rate and equilibrium constants for all key ATPase cycle steps), single comprehensive study","pmids":["11940582"],"is_preprint":false},{"year":2010,"finding":"The myo1e C-terminal tail domain binds anionic phospholipids (PtdIns(4,5)P2 and phosphatidylserine) with high affinity through nonspecific electrostatic interactions rather than stereospecific protein-phosphoinositide interaction. The rate of attachment to lipid vesicles nears the diffusion limit, and the calculated dissociation rate is slow (≤0.4 s⁻¹). Mutation of conserved PH-domain residues has little effect on lipid binding in vitro or membrane localization in vivo. The basic region of the tail (not the PH domain per se) is required for localization to clathrin-coated vesicles.","method":"Sedimentation assays, stopped-flow fluorescence, fluorescence microscopy with recombinant myo1e-tail constructs and site-directed mutagenesis of PH domain residues","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding assays with mutagenesis plus in vivo localization, multiple orthogonal methods in single study","pmids":["20860408"],"is_preprint":false},{"year":2011,"finding":"Two MYO1E mutations identified in familial FSGS have distinct functional consequences: the A159P motor-domain mutation causes abnormal subcellular localization of Myo1e in transfected cells, while the Y695X mutation causes loss of calmodulin binding and loss of the tail domains of Myo1e. Both mutations segregate with autosomal recessive FSGS, establishing Myo1e as required for podocyte function and glomerular filtration barrier integrity.","method":"Whole-genome linkage analysis, high-throughput sequencing, transfection/expression studies in cultured cells, immunohistochemistry on kidney biopsies, electron microscopy","journal":"The New England journal of medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic, cell biological, structural) in well-controlled study, replicated in two independent pedigrees","pmids":["21756023"],"is_preprint":false},{"year":2013,"finding":"Knockdown of Myo1e in cultured podocytes induces actin cytoskeleton rearrangement, morphological changes, and defects in cell proliferation, migration, endocytosis, and adhesion to the glomerular basement membrane. In zebrafish, Myo1e knockdown causes pericardial edema and pronephric cysts consistent with proteinuria, establishing Myo1e as a key component of podocyte cytoskeletal organization.","method":"Myo1e-specific knockdown in zebrafish (morpholino) and conditionally immortalized podocyte cell line; actin staining, migration assay, endocytosis assay, adhesion assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in two model systems (zebrafish and cultured cells) with defined cellular phenotypes, single lab","pmids":["23977349"],"is_preprint":false},{"year":2014,"finding":"Myo1e overexpression in mouse podocytes enhances endocytosis (FITC-transferrin internalization), cell migration, and cell adhesion to substrate, and inhibits puromycin aminonucleoside-induced podocyte detachment, establishing Myo1e as a positive regulator of these cellular processes in podocytes.","method":"Overexpression of Myo1e in MPC5 podocyte cell line; transwell migration assay, FITC-transferrin endocytosis assay, detachment assay","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain-of-function with multiple cellular readouts, single lab, no in vitro reconstitution","pmids":["24339252"],"is_preprint":false},{"year":2014,"finding":"Myo1e (and Myo1f) are required for LPS-triggered macrophage spreading. Loss of Myo1e leads to selectively increased CCL2 chemokine secretion and reduced MHC class II surface expression without transcriptional changes in these genes, indicating Myo1e regulates intracellular transport of CCL2 and MHC-II. Myo1e-deficient macrophages and DCs have impaired capacity to stimulate antigen-specific CD4+ T-cell proliferation, and Myo1e-deficient DCs show increased proteolytic cleavage of endocytosed antigen.","method":"Bone marrow-derived macrophages and DCs from Myo1e knockout mice; spreading assay, ELISA for chemokines, flow cytometry for surface MHC-II, T-cell proliferation assay, antigen proteolysis assay","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with multiple defined cellular phenotypes, single lab","pmids":["25263281"],"is_preprint":false},{"year":2020,"finding":"Myo1e overexpression promotes albumin endocytosis in podocytes via a Dynamin-dependent mechanism: inhibition of Dynamin GTPase activity (Dynasore) attenuates the Myo1e-overexpression-induced increase in FITC-BSA endocytosis, suggesting a Myo1e–Dynamin–Albumin pathway for podocyte albumin internalization.","method":"Myo1e overexpression and knockdown in MPC5 podocytes; FITC-BSA endocytosis measured by flow cytometry; Dynasore pharmacological inhibition","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological epistasis plus gain/loss-of-function, single lab","pmids":["32211226"],"is_preprint":false},{"year":2020,"finding":"Myo1e is required for efficient adhesion and inclusion of activated B cells into high endothelial venules in vivo, and for B-cell migration in vitro. Myo1e-deficient B cells show reduced integrin and F-actin levels in membrane protrusions, reduced phosphorylation of FAK, AKT, and RAC-1, indicating Myo1e acts upstream of the FAK–PI3K–RAC-1 signaling pathway to regulate B-cell adhesion and migration.","method":"Intravital microscopy in Myo1e-deficient mice; in vitro adhesion and migration assays; flow cytometry for integrin expression; phosphorylation assays for FAK, AKT, RAC-1","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro experiments in KO model with pathway epistasis, single lab","pmids":["31964710"],"is_preprint":false},{"year":2022,"finding":"Two SRNS-associated MYO1E motor domain mutations, T119I and D388H, have distinct functional consequences: T119I disrupts Myo1e enrichment at cell junctions and clathrin-coated vesicles (CCVs); D388H localizes similarly to WT but shows decreased rate of dissociation from junctions and CCVs (suggesting altered interaction with binding partners) and has drastically reduced ATPase activity and actin filament translocation ability in vitro.","method":"EGFP-Myo1e expression in Myo1e-KO mouse podocyte cells; localization and FRAP analysis; clathrin-dependent endocytosis assay; in vitro ATPase assay and actin gliding assay using baculovirus-expressed truncated constructs","journal":"Journal of the American Society of Nephrology : JASN","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of motor activity plus mutagenesis plus cell-based localization and functional assays in single study, multiple orthogonal methods","pmids":["36316095"],"is_preprint":false},{"year":2022,"finding":"Pathogenic MYO1E variants (including compound heterozygous variants and exon 19 deletion) cause mislocalization of Myo1e protein in kidney sections. Pathogenic variants predominantly map to the motor and neck domains, consistent with disruption of Myo1e function in regulating podocyte actin cytoskeleton dynamics and cell adhesion.","method":"DNA/RNA sequencing; immunolocalization of Myo1e in kidney sections; computer modeling of variant effects","journal":"Pediatric nephrology (Berlin, Germany)","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment on patient tissue, computational modeling, single lab","pmids":["35723736"],"is_preprint":false},{"year":2025,"finding":"Myo1e (and Myo1f) localize to a specific region underneath the podosome core near the ventral plasma membrane (the podosome 'base'), with localization primarily mediated by the Myo1e/f TH2 domains. Knockout/knockdown of Myo1e/f increases podosome size, alters podosome turnover and lateral mobility, and reduces 3D and 2D macrophage migration, indicating that Myo1e/f regulate attachment of core actin filaments to the plasma membrane at podosomes.","method":"Fluorescence microscopy and TIRF of Myo1e/f-GFP fusions; siRNA knockdown and CRISPR knockout in macrophages; podosome size/turnover/mobility measurements; 3D and 2D migration assays; domain deletion constructs for TH2 domain localization","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — preprint, CRISPR KO with multiple cellular phenotypes and domain dissection, single lab","pmids":["bio_10.1101_2025.04.28.651090"],"is_preprint":true},{"year":2026,"finding":"Myo1e and Myo1f are required for efficient phagocytic cup closure in macrophages via Fc-receptor-mediated phagocytosis. In double-KO macrophages, podosome formation during phagocytosis is diminished, actin 'teeth' structures are absent, the contractile phagocytic ring forms prematurely, cup progression stalls, and trogocytosis (partial target ingestion) increases. Myo1e/f localize to phagocytic podosomes and the inner surface of the phagocytic ring; their absence correlates with diffuse distribution of non-muscle myosin II (NM2) at the ring outer surface.","method":"CRISPR-edited Myo1e/f double-KO RAW 264.7 macrophages; bead uptake assay; lattice-light-sheet and confocal imaging of F-actin architectures; rescue by re-expression; trogocytosis assay","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — preprint, CRISPR KO with multiple mechanistic readouts and rescue experiment, single lab","pmids":["42094351"],"is_preprint":true},{"year":2025,"finding":"In human iPSCs, Myo1e is recruited to clathrin-mediated endocytosis (CME) sites that stall due to increased membrane tension. Under normal tension, Myo1e recruitment is rare; as membrane tension increases, Myo1e is recruited to more CME sites. Loss of Myo1e results in increased Arp2/3 complex lifetime at CME sites under normal conditions and failure to recruit sufficient Arp2/3 at high membrane tension, indicating Myo1e promotes branched actin network assembly via Arp2/3 to rescue stalled CME sites.","method":"Live-cell imaging and super-resolution microscopy of genome-edited hiPSCs expressing endogenous tagged proteins; Myo1e knockout; manipulation of membrane tension; measurement of CME dynamics and Arp2/3 lifetime","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — preprint, genome-edited cells with live imaging and KO, multiple orthogonal approaches, single lab","pmids":["bio_10.1101_2025.11.12.688091"],"is_preprint":true}],"current_model":"Myo1e is a single-headed class I myosin motor that links the plasma membrane to the actin cytoskeleton via electrostatic binding of its tail domain to anionic phospholipids (PtdIns(4,5)P2 and PS), with a kinetic mechanism tuned for rapid actin sliding (fast ADP release, actin-activated ADP release as the primary regulatory step); in podocytes it is enriched at cell junctions and clathrin-coated vesicles where it regulates actin dynamics, endocytosis, adhesion, and migration, and disease-associated motor-domain mutations (e.g. A159P, T119I, D388H) impair its localization and/or ATPase/translocation activity; in immune cells (macrophages, B cells, DCs) it localizes to the podosome base and phagocytic cup where it coordinates protrusive/contractile actin transitions required for podosome dynamics, phagocytic cup closure, macrophage migration, B-cell adhesion via the FAK–PI3K–RAC-1 pathway, and MHC-II surface trafficking."},"narrative":{"mechanistic_narrative":"MYO1E encodes a single-headed class I myosin motor that couples the plasma membrane to the actin cytoskeleton to regulate endocytosis, adhesion, and migration across podocytes and immune cells [PMID:23977349, PMID:36316095]. Its motor domain has a defined ATPase cycle in which actin activates ADP release as the primary regulatory step, with ADP release more than tenfold faster than other vertebrate myosin-I isoforms, kinetically tuning Myo1e for rapid actin sliding [PMID:11940582]. The C-terminal tail anchors the motor to membranes by binding anionic phospholipids (PtdIns(4,5)P2 and phosphatidylserine) through nonspecific electrostatic interactions of its basic region rather than a stereospecific PH-domain contact, and this basic region directs localization to clathrin-coated vesicles [PMID:20860408]. Through this membrane-actin linkage Myo1e promotes clathrin-mediated and dynamin-dependent endocytosis, cell adhesion, and migration in podocytes [PMID:23977349, PMID:24339252, PMID:32211226], and is recruited to clathrin-mediated endocytosis sites stalled by elevated membrane tension where it promotes Arp2/3-dependent branched actin assembly to rescue them [PMID:bio_10.1101_2025.11.12.688091]. In immune cells Myo1e localizes to the podosome base via its TH2 domain to control podosome size, turnover, and macrophage migration [PMID:bio_10.1101_2025.04.28.651090], is required for phagocytic cup closure during Fc-receptor phagocytosis [PMID:42094351], and acts upstream of the FAK–PI3K–RAC-1 pathway to govern B-cell adhesion and migration while also directing intracellular transport of CCL2 and MHC-II [PMID:25263281, PMID:31964710]. Biallelic MYO1E mutations cause autosomal recessive focal segmental glomerulosclerosis and steroid-resistant nephrotic syndrome, with pathogenic variants clustered in the motor and neck domains that disrupt subcellular localization and/or ATPase and actin-translocation activity [PMID:21756023, PMID:36316095, PMID:35723736].","teleology":[{"year":2002,"claim":"Established the kinetic identity of the motor, answering whether Myo1e is built for force-holding or for fast movement along actin.","evidence":"In vitro stopped-flow and ATPase analysis of a truncated motor+IQ construct with calmodulin","pmids":["11940582"],"confidence":"High","gaps":["Kinetics measured on a truncated construct, not full-length protein","Does not address how the tail or membrane binding modulates motor output"]},{"year":2010,"claim":"Defined how the motor is tethered to membranes, showing the tail uses electrostatic phospholipid binding rather than a stereospecific PH-domain interaction.","evidence":"Sedimentation and stopped-flow lipid-binding assays plus PH-domain mutagenesis and in vivo localization of recombinant tail constructs","pmids":["20860408"],"confidence":"High","gaps":["Does not identify the protein partners at clathrin-coated vesicles","Binding studied on tail fragments outside the context of the intact motor"]},{"year":2011,"claim":"Linked MYO1E to human disease, establishing it as required for glomerular filtration barrier integrity via two functionally distinct FSGS mutations.","evidence":"Linkage analysis, sequencing, and expression/localization studies in two autosomal-recessive FSGS pedigrees","pmids":["21756023"],"confidence":"High","gaps":["Cellular mechanism connecting mislocalization to podocyte failure not resolved here","Motor-domain mutation effect on ATPase activity not measured"]},{"year":2013,"claim":"Connected the genetic disease phenotype to defined cellular roles, showing Myo1e is needed for podocyte actin organization, migration, endocytosis, and adhesion.","evidence":"Morpholino knockdown in zebrafish and knockdown in conditionally immortalized podocytes with actin, migration, endocytosis, and adhesion assays","pmids":["23977349"],"confidence":"Medium","gaps":["Single lab","Does not separate direct motor function from indirect actin reorganization effects"]},{"year":2014,"claim":"Showed Myo1e is a positive, dose-sensitive regulator of podocyte endocytosis, migration, and adhesion through gain-of-function.","evidence":"Overexpression in MPC5 podocytes with transferrin endocytosis, transwell migration, and detachment assays","pmids":["24339252"],"confidence":"Medium","gaps":["Overexpression may not reflect physiological stoichiometry","No in vitro reconstitution"]},{"year":2014,"claim":"Extended Myo1e function to immune cells, implicating it in intracellular transport of CCL2 and MHC-II and in antigen presentation independent of transcription.","evidence":"Knockout bone marrow-derived macrophages and DCs with spreading, chemokine ELISA, surface MHC-II flow cytometry, T-cell proliferation, and antigen proteolysis assays","pmids":["25263281"],"confidence":"Medium","gaps":["Direct cargo/transport mechanism not defined","Redundancy with Myo1f not fully separated"]},{"year":2020,"claim":"Placed Myo1e in a dynamin-dependent albumin internalization pathway in podocytes.","evidence":"Gain/loss-of-function in MPC5 podocytes with FITC-BSA endocytosis and Dynasore epistasis","pmids":["32211226"],"confidence":"Medium","gaps":["Pharmacological dynamin inhibition lacks genetic confirmation","Direct Myo1e-dynamin physical link not shown"]},{"year":2020,"claim":"Positioned Myo1e upstream of FAK–PI3K–RAC-1 signaling to drive B-cell adhesion and migration in vivo.","evidence":"Intravital microscopy in Myo1e-deficient mice plus in vitro adhesion/migration and FAK/AKT/RAC-1 phosphorylation assays","pmids":["31964710"],"confidence":"Medium","gaps":["Whether Myo1e acts directly or via altered actin/integrin geometry on the pathway is unresolved","Single lab"]},{"year":2022,"claim":"Resolved how disease mutations act mechanistically, distinguishing localization defects from ATPase/translocation defects within the motor domain.","evidence":"EGFP-Myo1e localization and FRAP in Myo1e-KO podocytes plus in vitro ATPase and actin-gliding assays of mutant constructs","pmids":["36316095"],"confidence":"High","gaps":["The altered binding partners implied by D388H FRAP behavior not identified","Effects measured on truncated motor constructs"]},{"year":2022,"claim":"Confirmed across additional patients that pathogenic variants cluster in motor and neck domains and cause Myo1e protein mislocalization in kidney.","evidence":"Sequencing, immunolocalization in patient kidney sections, and computational variant modeling","pmids":["35723736"],"confidence":"Medium","gaps":["Functional consequences inferred computationally for most variants","Single lab"]},{"year":2025,"claim":"Defined the sub-podosome localization and its determinant, showing Myo1e/f attach core actin filaments to the membrane at the podosome base to control podosome dynamics and migration.","evidence":"TIRF/fluorescence imaging of Myo1e/f-GFP, siRNA/CRISPR depletion, and TH2 domain-deletion constructs in macrophages (preprint)","pmids":["bio_10.1101_2025.04.28.651090"],"confidence":"Medium","gaps":["Preprint, single lab","Myo1e versus Myo1f individual contributions not fully separated"]},{"year":2025,"claim":"Identified Myo1e as a membrane-tension-sensing rescue factor at clathrin-mediated endocytosis sites acting through Arp2/3-dependent branched actin.","evidence":"Live-cell and super-resolution imaging of genome-edited hiPSCs with endogenous tagging, Myo1e knockout, and membrane tension manipulation (preprint)","pmids":["bio_10.1101_2025.11.12.688091"],"confidence":"Medium","gaps":["Preprint, single lab","Direct Myo1e-Arp2/3 interaction versus indirect recruitment not distinguished"]},{"year":2026,"claim":"Established a role in phagocytic cup closure, showing Myo1e/f organize actin teeth and the contractile ring during Fc-receptor phagocytosis to prevent premature ring constriction and trogocytosis.","evidence":"CRISPR double-KO RAW 264.7 macrophages with bead uptake, lattice-light-sheet imaging, rescue, and trogocytosis assays (preprint)","pmids":["42094351"],"confidence":"Medium","gaps":["Preprint, single lab","Mechanism coupling Myo1e/f to NM2 ring organization not defined"]},{"year":null,"claim":"How Myo1e's fast-sliding motor kinetics, electrostatic membrane tethering, and Arp2/3-based actin assembly are integrated and which physical partners recruit it to distinct sites (CCVs, podosomes, phagocytic cup) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified direct protein partner explaining junction/CCV recruitment","No structure of full-length motor on membrane","Relationship between motor activity and tension sensing not mechanistically reconciled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,8]},{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[0,8]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,10]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,10]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,8,12]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3,10]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[6,8,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,7,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,8,9]}],"complexes":[],"partners":["MYO1F","CALM1","DNM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q12965","full_name":"Unconventional myosin-Ie","aliases":["Myosin-Ic","Unconventional myosin 1E"],"length_aa":1108,"mass_kda":127.1,"function":"Actin-based motor molecule with ATPase activity (PubMed:11940582, PubMed:36316095). Unconventional myosins serve in intracellular movements. Their highly divergent tails bind to membranous compartments, which are then moved relative to actin filaments. Binds to membranes containing anionic phospholipids via its tail domain. Involved in clathrin-mediated endocytosis and intracellular movement of clathrin-coated vesicles (PubMed:36316095). Required for normal morphology of the glomerular basement membrane, normal development of foot processes by kidney podocytes and normal kidney function. In dendritic cells, may control the movement of class II-containing cytoplasmic vesicles along the actin cytoskeleton by connecting them with the actin network via ARL14EP and ARL14","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton; Cytoplasmic vesicle; Cytoplasmic vesicle, clathrin-coated vesicle; Cell junction","url":"https://www.uniprot.org/uniprotkb/Q12965/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYO1E","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000157483","cell_line_id":"CID000535","localizations":[{"compartment":"cytoplasmic","grade":3}],"interactors":[{"gene":"HIST1H1D","stoichiometry":10.0},{"gene":"H1FX","stoichiometry":10.0},{"gene":"OSTF1","stoichiometry":10.0},{"gene":"SMARCA5","stoichiometry":4.0},{"gene":"H1F0","stoichiometry":4.0},{"gene":"NUMA1","stoichiometry":4.0},{"gene":"CALM1","stoichiometry":0.2},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"WHSC1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000535","total_profiled":1310},"omim":[{"mim_id":"614442","title":"PLECKSTRIN AND SEC7 DOMAINS-CONTAINING PROTEIN 4; PSD4","url":"https://www.omim.org/entry/614442"},{"mim_id":"614439","title":"ADP-RIBOSYLATION FACTOR-LIKE GTPase 14; ARL14","url":"https://www.omim.org/entry/614439"},{"mim_id":"614131","title":"FOCAL SEGMENTAL GLOMERULOSCLEROSIS 6; FSGS6","url":"https://www.omim.org/entry/614131"},{"mim_id":"612295","title":"ADP-RIBOSYLATION FACTOR-LIKE GTPase 14 EFFECTOR PROTEIN; ARL14EP","url":"https://www.omim.org/entry/612295"},{"mim_id":"609791","title":"LEUCINE-RICH REPEAT- AND Ig DOMAIN-CONTAINING NOGO RECEPTOR-INTERACTING PROTEIN 1; LINGO1","url":"https://www.omim.org/entry/609791"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MYO1E"},"hgnc":{"alias_symbol":["MYO1C","HuncM-IC","MGC104638"],"prev_symbol":[]},"alphafold":{"accession":"Q12965","domains":[{"cath_id":"3.30.70.1590","chopping":"623-684","consensus_level":"high","plddt":86.5692,"start":623,"end":684},{"cath_id":"2.30.29.30","chopping":"726-882_892-919","consensus_level":"high","plddt":89.7929,"start":726,"end":919},{"cath_id":"2.30.30.40","chopping":"1054-1106","consensus_level":"high","plddt":90.1808,"start":1054,"end":1106}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12965","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q12965-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q12965-F1-predicted_aligned_error_v6.png","plddt_mean":80.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYO1E","jax_strain_url":"https://www.jax.org/strain/search?query=MYO1E"},"sequence":{"accession":"Q12965","fasta_url":"https://rest.uniprot.org/uniprotkb/Q12965.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q12965/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q12965"}},"corpus_meta":[{"pmid":"21756023","id":"PMC_21756023","title":"MYO1E mutations and childhood familial focal segmental glomerulosclerosis.","date":"2011","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21756023","citation_count":195,"is_preprint":false},{"pmid":"11940582","id":"PMC_11940582","title":"The kinetic mechanism of Myo1e (human myosin-IC).","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11940582","citation_count":60,"is_preprint":false},{"pmid":"21697813","id":"PMC_21697813","title":"Exome sequencing identified MYO1E and NEIL1 as candidate genes for human autosomal recessive steroid-resistant nephrotic syndrome.","date":"2011","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/21697813","citation_count":54,"is_preprint":false},{"pmid":"20860408","id":"PMC_20860408","title":"Myo1e binds anionic phospholipids with high affinity.","date":"2010","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20860408","citation_count":51,"is_preprint":false},{"pmid":"25739341","id":"PMC_25739341","title":"Coinheritance of COL4A5 and MYO1E mutations accentuate the severity of kidney disease.","date":"2015","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/25739341","citation_count":37,"is_preprint":false},{"pmid":"16137664","id":"PMC_16137664","title":"Differential expression and molecular characterisation of Lmo7, Myo1e, Sash1, and Mcoln2 genes in Btk-defective B-cells.","date":"2005","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/16137664","citation_count":36,"is_preprint":false},{"pmid":"25263281","id":"PMC_25263281","title":"Class I myosin Myo1e regulates TLR4-triggered macrophage spreading, chemokine release, and antigen presentation via MHC class II.","date":"2014","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25263281","citation_count":28,"is_preprint":false},{"pmid":"24339252","id":"PMC_24339252","title":"Overexpression of Myo1e in mouse podocytes enhances cellular endocytosis, migration, and adhesion.","date":"2014","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24339252","citation_count":23,"is_preprint":false},{"pmid":"31964710","id":"PMC_31964710","title":"Myo1e modulates the recruitment of activated B cells to inguinal lymph nodes.","date":"2020","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/31964710","citation_count":19,"is_preprint":false},{"pmid":"23977349","id":"PMC_23977349","title":"Myo1e impairment results in actin reorganization, podocyte dysfunction, and proteinuria in zebrafish and cultured podocytes.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23977349","citation_count":16,"is_preprint":false},{"pmid":"35723736","id":"PMC_35723736","title":"Focal segmental glomerulosclerosis and proteinuria associated with Myo1E mutations: novel variants and histological phenotype analysis.","date":"2022","source":"Pediatric nephrology (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/35723736","citation_count":12,"is_preprint":false},{"pmid":"36914720","id":"PMC_36914720","title":"Myo1e overexpression in lung adenocarcinoma is associated with increased risk of mortality.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/36914720","citation_count":8,"is_preprint":false},{"pmid":"36316095","id":"PMC_36316095","title":"Steroid-Resistant Nephrotic Syndrome-Associated MYO1E Mutations Have Differential Effects on Myosin 1e Localization, Dynamics, and Activity.","date":"2022","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/36316095","citation_count":4,"is_preprint":false},{"pmid":"32211226","id":"PMC_32211226","title":"Overexpression of Myo1e promotes albumin endocytosis by mouse glomerular podocytes mediated by Dynamin.","date":"2020","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/32211226","citation_count":4,"is_preprint":false},{"pmid":"37274465","id":"PMC_37274465","title":"Analysis and validation of the potential of the MYO1E gene in pancreatic adenocarcinoma based on a bioinformatics approach.","date":"2023","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/37274465","citation_count":3,"is_preprint":false},{"pmid":"36705362","id":"PMC_36705362","title":"Effect of cyclosporine A on focal segmental glomerulosclerosis caused by MYO1E mutation in a Chinese adult patient: A case report.","date":"2023","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36705362","citation_count":3,"is_preprint":false},{"pmid":"35574290","id":"PMC_35574290","title":"Concordant nephrotic syndrome in twins with PAX2 and MYO1E mutations.","date":"2022","source":"Clinical nephrology. Case studies","url":"https://pubmed.ncbi.nlm.nih.gov/35574290","citation_count":2,"is_preprint":false},{"pmid":"25224051","id":"PMC_25224051","title":"[Mutational analysis of MYO1E in children with sporadic steroid-resistant nephrotic syndrome in Chinese Han ethnic group].","date":"2014","source":"Zhonghua er ke za zhi = Chinese journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/25224051","citation_count":1,"is_preprint":false},{"pmid":"24750828","id":"PMC_24750828","title":"[Mutational analysis of MYO1E in Chinese children with familial steroid-resistant nephrotic syndrome].","date":"2014","source":"Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/24750828","citation_count":0,"is_preprint":false},{"pmid":"42094351","id":"PMC_42094351","title":"Myo1e/f regulate phagocytic podosomes to promote efficient cup closure in macrophages.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42094351","citation_count":0,"is_preprint":false},{"pmid":"41898697","id":"PMC_41898697","title":"Steroid-Resistant Focal Segmental Glomerulosclerosis with Alport-like Glomerular Basement Membrane Lesions Due to a MYO1E Mutation: A Pediatric Case Report.","date":"2026","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41898697","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.12.688091","title":"Class-I myosin responds to changes in membrane tension during clathrin-mediated endocytosis in human induced pluripotent stem cells","date":"2025-11-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.12.688091","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.28.651090","title":"Myo1e/f at the podosome base regulate podosome dynamics and promote macrophage migration","date":"2025-04-29","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.28.651090","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.04.663186","title":"MYO1F interactome reveals the SH3-domain linked CASS complex at podosomes and the phagocytic cup","date":"2025-07-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.04.663186","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14790,"output_tokens":3988,"usd":0.052095,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11686,"output_tokens":4157,"usd":0.081177,"stage2_stop_reason":"end_turn"},"total_usd":0.133272,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"Myo1e (human myosin-IC) has a defined ATPase kinetic mechanism: it has low K(ATPase) (~1 µM) for actin, weak actin affinity in the presence of ATP, rapid phosphate release while dissociated from actin, and actin activation of ADP release as the primary mechanism of actin-stimulated ATPase activation. ADP release from actomyo1e is >10-fold faster than other vertebrate myosin-I isoforms, suggesting subclass-1 myosin-Is are tuned for rapid sliding.\",\n      \"method\": \"In vitro kinetic analysis (stopped-flow, ATPase assays) of truncated myo1e motor+IQ construct with bound calmodulin\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — rigorous in vitro reconstitution with multiple kinetic measurements (rate and equilibrium constants for all key ATPase cycle steps), single comprehensive study\",\n      \"pmids\": [\"11940582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The myo1e C-terminal tail domain binds anionic phospholipids (PtdIns(4,5)P2 and phosphatidylserine) with high affinity through nonspecific electrostatic interactions rather than stereospecific protein-phosphoinositide interaction. The rate of attachment to lipid vesicles nears the diffusion limit, and the calculated dissociation rate is slow (≤0.4 s⁻¹). Mutation of conserved PH-domain residues has little effect on lipid binding in vitro or membrane localization in vivo. The basic region of the tail (not the PH domain per se) is required for localization to clathrin-coated vesicles.\",\n      \"method\": \"Sedimentation assays, stopped-flow fluorescence, fluorescence microscopy with recombinant myo1e-tail constructs and site-directed mutagenesis of PH domain residues\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding assays with mutagenesis plus in vivo localization, multiple orthogonal methods in single study\",\n      \"pmids\": [\"20860408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Two MYO1E mutations identified in familial FSGS have distinct functional consequences: the A159P motor-domain mutation causes abnormal subcellular localization of Myo1e in transfected cells, while the Y695X mutation causes loss of calmodulin binding and loss of the tail domains of Myo1e. Both mutations segregate with autosomal recessive FSGS, establishing Myo1e as required for podocyte function and glomerular filtration barrier integrity.\",\n      \"method\": \"Whole-genome linkage analysis, high-throughput sequencing, transfection/expression studies in cultured cells, immunohistochemistry on kidney biopsies, electron microscopy\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic, cell biological, structural) in well-controlled study, replicated in two independent pedigrees\",\n      \"pmids\": [\"21756023\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Knockdown of Myo1e in cultured podocytes induces actin cytoskeleton rearrangement, morphological changes, and defects in cell proliferation, migration, endocytosis, and adhesion to the glomerular basement membrane. In zebrafish, Myo1e knockdown causes pericardial edema and pronephric cysts consistent with proteinuria, establishing Myo1e as a key component of podocyte cytoskeletal organization.\",\n      \"method\": \"Myo1e-specific knockdown in zebrafish (morpholino) and conditionally immortalized podocyte cell line; actin staining, migration assay, endocytosis assay, adhesion assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in two model systems (zebrafish and cultured cells) with defined cellular phenotypes, single lab\",\n      \"pmids\": [\"23977349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Myo1e overexpression in mouse podocytes enhances endocytosis (FITC-transferrin internalization), cell migration, and cell adhesion to substrate, and inhibits puromycin aminonucleoside-induced podocyte detachment, establishing Myo1e as a positive regulator of these cellular processes in podocytes.\",\n      \"method\": \"Overexpression of Myo1e in MPC5 podocyte cell line; transwell migration assay, FITC-transferrin endocytosis assay, detachment assay\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain-of-function with multiple cellular readouts, single lab, no in vitro reconstitution\",\n      \"pmids\": [\"24339252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Myo1e (and Myo1f) are required for LPS-triggered macrophage spreading. Loss of Myo1e leads to selectively increased CCL2 chemokine secretion and reduced MHC class II surface expression without transcriptional changes in these genes, indicating Myo1e regulates intracellular transport of CCL2 and MHC-II. Myo1e-deficient macrophages and DCs have impaired capacity to stimulate antigen-specific CD4+ T-cell proliferation, and Myo1e-deficient DCs show increased proteolytic cleavage of endocytosed antigen.\",\n      \"method\": \"Bone marrow-derived macrophages and DCs from Myo1e knockout mice; spreading assay, ELISA for chemokines, flow cytometry for surface MHC-II, T-cell proliferation assay, antigen proteolysis assay\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with multiple defined cellular phenotypes, single lab\",\n      \"pmids\": [\"25263281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Myo1e overexpression promotes albumin endocytosis in podocytes via a Dynamin-dependent mechanism: inhibition of Dynamin GTPase activity (Dynasore) attenuates the Myo1e-overexpression-induced increase in FITC-BSA endocytosis, suggesting a Myo1e–Dynamin–Albumin pathway for podocyte albumin internalization.\",\n      \"method\": \"Myo1e overexpression and knockdown in MPC5 podocytes; FITC-BSA endocytosis measured by flow cytometry; Dynasore pharmacological inhibition\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological epistasis plus gain/loss-of-function, single lab\",\n      \"pmids\": [\"32211226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Myo1e is required for efficient adhesion and inclusion of activated B cells into high endothelial venules in vivo, and for B-cell migration in vitro. Myo1e-deficient B cells show reduced integrin and F-actin levels in membrane protrusions, reduced phosphorylation of FAK, AKT, and RAC-1, indicating Myo1e acts upstream of the FAK–PI3K–RAC-1 signaling pathway to regulate B-cell adhesion and migration.\",\n      \"method\": \"Intravital microscopy in Myo1e-deficient mice; in vitro adhesion and migration assays; flow cytometry for integrin expression; phosphorylation assays for FAK, AKT, RAC-1\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro experiments in KO model with pathway epistasis, single lab\",\n      \"pmids\": [\"31964710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Two SRNS-associated MYO1E motor domain mutations, T119I and D388H, have distinct functional consequences: T119I disrupts Myo1e enrichment at cell junctions and clathrin-coated vesicles (CCVs); D388H localizes similarly to WT but shows decreased rate of dissociation from junctions and CCVs (suggesting altered interaction with binding partners) and has drastically reduced ATPase activity and actin filament translocation ability in vitro.\",\n      \"method\": \"EGFP-Myo1e expression in Myo1e-KO mouse podocyte cells; localization and FRAP analysis; clathrin-dependent endocytosis assay; in vitro ATPase assay and actin gliding assay using baculovirus-expressed truncated constructs\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of motor activity plus mutagenesis plus cell-based localization and functional assays in single study, multiple orthogonal methods\",\n      \"pmids\": [\"36316095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Pathogenic MYO1E variants (including compound heterozygous variants and exon 19 deletion) cause mislocalization of Myo1e protein in kidney sections. Pathogenic variants predominantly map to the motor and neck domains, consistent with disruption of Myo1e function in regulating podocyte actin cytoskeleton dynamics and cell adhesion.\",\n      \"method\": \"DNA/RNA sequencing; immunolocalization of Myo1e in kidney sections; computer modeling of variant effects\",\n      \"journal\": \"Pediatric nephrology (Berlin, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment on patient tissue, computational modeling, single lab\",\n      \"pmids\": [\"35723736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Myo1e (and Myo1f) localize to a specific region underneath the podosome core near the ventral plasma membrane (the podosome 'base'), with localization primarily mediated by the Myo1e/f TH2 domains. Knockout/knockdown of Myo1e/f increases podosome size, alters podosome turnover and lateral mobility, and reduces 3D and 2D macrophage migration, indicating that Myo1e/f regulate attachment of core actin filaments to the plasma membrane at podosomes.\",\n      \"method\": \"Fluorescence microscopy and TIRF of Myo1e/f-GFP fusions; siRNA knockdown and CRISPR knockout in macrophages; podosome size/turnover/mobility measurements; 3D and 2D migration assays; domain deletion constructs for TH2 domain localization\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — preprint, CRISPR KO with multiple cellular phenotypes and domain dissection, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.04.28.651090\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Myo1e and Myo1f are required for efficient phagocytic cup closure in macrophages via Fc-receptor-mediated phagocytosis. In double-KO macrophages, podosome formation during phagocytosis is diminished, actin 'teeth' structures are absent, the contractile phagocytic ring forms prematurely, cup progression stalls, and trogocytosis (partial target ingestion) increases. Myo1e/f localize to phagocytic podosomes and the inner surface of the phagocytic ring; their absence correlates with diffuse distribution of non-muscle myosin II (NM2) at the ring outer surface.\",\n      \"method\": \"CRISPR-edited Myo1e/f double-KO RAW 264.7 macrophages; bead uptake assay; lattice-light-sheet and confocal imaging of F-actin architectures; rescue by re-expression; trogocytosis assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — preprint, CRISPR KO with multiple mechanistic readouts and rescue experiment, single lab\",\n      \"pmids\": [\"42094351\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In human iPSCs, Myo1e is recruited to clathrin-mediated endocytosis (CME) sites that stall due to increased membrane tension. Under normal tension, Myo1e recruitment is rare; as membrane tension increases, Myo1e is recruited to more CME sites. Loss of Myo1e results in increased Arp2/3 complex lifetime at CME sites under normal conditions and failure to recruit sufficient Arp2/3 at high membrane tension, indicating Myo1e promotes branched actin network assembly via Arp2/3 to rescue stalled CME sites.\",\n      \"method\": \"Live-cell imaging and super-resolution microscopy of genome-edited hiPSCs expressing endogenous tagged proteins; Myo1e knockout; manipulation of membrane tension; measurement of CME dynamics and Arp2/3 lifetime\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — preprint, genome-edited cells with live imaging and KO, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.11.12.688091\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"Myo1e is a single-headed class I myosin motor that links the plasma membrane to the actin cytoskeleton via electrostatic binding of its tail domain to anionic phospholipids (PtdIns(4,5)P2 and PS), with a kinetic mechanism tuned for rapid actin sliding (fast ADP release, actin-activated ADP release as the primary regulatory step); in podocytes it is enriched at cell junctions and clathrin-coated vesicles where it regulates actin dynamics, endocytosis, adhesion, and migration, and disease-associated motor-domain mutations (e.g. A159P, T119I, D388H) impair its localization and/or ATPase/translocation activity; in immune cells (macrophages, B cells, DCs) it localizes to the podosome base and phagocytic cup where it coordinates protrusive/contractile actin transitions required for podosome dynamics, phagocytic cup closure, macrophage migration, B-cell adhesion via the FAK–PI3K–RAC-1 pathway, and MHC-II surface trafficking.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYO1E encodes a single-headed class I myosin motor that couples the plasma membrane to the actin cytoskeleton to regulate endocytosis, adhesion, and migration across podocytes and immune cells [#3, #8]. Its motor domain has a defined ATPase cycle in which actin activates ADP release as the primary regulatory step, with ADP release more than tenfold faster than other vertebrate myosin-I isoforms, kinetically tuning Myo1e for rapid actin sliding [#0]. The C-terminal tail anchors the motor to membranes by binding anionic phospholipids (PtdIns(4,5)P2 and phosphatidylserine) through nonspecific electrostatic interactions of its basic region rather than a stereospecific PH-domain contact, and this basic region directs localization to clathrin-coated vesicles [#1]. Through this membrane-actin linkage Myo1e promotes clathrin-mediated and dynamin-dependent endocytosis, cell adhesion, and migration in podocytes [#3, #4, #6], and is recruited to clathrin-mediated endocytosis sites stalled by elevated membrane tension where it promotes Arp2/3-dependent branched actin assembly to rescue them [#12]. In immune cells Myo1e localizes to the podosome base via its TH2 domain to control podosome size, turnover, and macrophage migration [#10], is required for phagocytic cup closure during Fc-receptor phagocytosis [#11], and acts upstream of the FAK–PI3K–RAC-1 pathway to govern B-cell adhesion and migration while also directing intracellular transport of CCL2 and MHC-II [#5, #7]. Biallelic MYO1E mutations cause autosomal recessive focal segmental glomerulosclerosis and steroid-resistant nephrotic syndrome, with pathogenic variants clustered in the motor and neck domains that disrupt subcellular localization and/or ATPase and actin-translocation activity [#2, #8, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the kinetic identity of the motor, answering whether Myo1e is built for force-holding or for fast movement along actin.\",\n      \"evidence\": \"In vitro stopped-flow and ATPase analysis of a truncated motor+IQ construct with calmodulin\",\n      \"pmids\": [\"11940582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinetics measured on a truncated construct, not full-length protein\", \"Does not address how the tail or membrane binding modulates motor output\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined how the motor is tethered to membranes, showing the tail uses electrostatic phospholipid binding rather than a stereospecific PH-domain interaction.\",\n      \"evidence\": \"Sedimentation and stopped-flow lipid-binding assays plus PH-domain mutagenesis and in vivo localization of recombinant tail constructs\",\n      \"pmids\": [\"20860408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify the protein partners at clathrin-coated vesicles\", \"Binding studied on tail fragments outside the context of the intact motor\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked MYO1E to human disease, establishing it as required for glomerular filtration barrier integrity via two functionally distinct FSGS mutations.\",\n      \"evidence\": \"Linkage analysis, sequencing, and expression/localization studies in two autosomal-recessive FSGS pedigrees\",\n      \"pmids\": [\"21756023\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular mechanism connecting mislocalization to podocyte failure not resolved here\", \"Motor-domain mutation effect on ATPase activity not measured\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected the genetic disease phenotype to defined cellular roles, showing Myo1e is needed for podocyte actin organization, migration, endocytosis, and adhesion.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish and knockdown in conditionally immortalized podocytes with actin, migration, endocytosis, and adhesion assays\",\n      \"pmids\": [\"23977349\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Does not separate direct motor function from indirect actin reorganization effects\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed Myo1e is a positive, dose-sensitive regulator of podocyte endocytosis, migration, and adhesion through gain-of-function.\",\n      \"evidence\": \"Overexpression in MPC5 podocytes with transferrin endocytosis, transwell migration, and detachment assays\",\n      \"pmids\": [\"24339252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression may not reflect physiological stoichiometry\", \"No in vitro reconstitution\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended Myo1e function to immune cells, implicating it in intracellular transport of CCL2 and MHC-II and in antigen presentation independent of transcription.\",\n      \"evidence\": \"Knockout bone marrow-derived macrophages and DCs with spreading, chemokine ELISA, surface MHC-II flow cytometry, T-cell proliferation, and antigen proteolysis assays\",\n      \"pmids\": [\"25263281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct cargo/transport mechanism not defined\", \"Redundancy with Myo1f not fully separated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed Myo1e in a dynamin-dependent albumin internalization pathway in podocytes.\",\n      \"evidence\": \"Gain/loss-of-function in MPC5 podocytes with FITC-BSA endocytosis and Dynasore epistasis\",\n      \"pmids\": [\"32211226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pharmacological dynamin inhibition lacks genetic confirmation\", \"Direct Myo1e-dynamin physical link not shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Positioned Myo1e upstream of FAK–PI3K–RAC-1 signaling to drive B-cell adhesion and migration in vivo.\",\n      \"evidence\": \"Intravital microscopy in Myo1e-deficient mice plus in vitro adhesion/migration and FAK/AKT/RAC-1 phosphorylation assays\",\n      \"pmids\": [\"31964710\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Myo1e acts directly or via altered actin/integrin geometry on the pathway is unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved how disease mutations act mechanistically, distinguishing localization defects from ATPase/translocation defects within the motor domain.\",\n      \"evidence\": \"EGFP-Myo1e localization and FRAP in Myo1e-KO podocytes plus in vitro ATPase and actin-gliding assays of mutant constructs\",\n      \"pmids\": [\"36316095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The altered binding partners implied by D388H FRAP behavior not identified\", \"Effects measured on truncated motor constructs\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmed across additional patients that pathogenic variants cluster in motor and neck domains and cause Myo1e protein mislocalization in kidney.\",\n      \"evidence\": \"Sequencing, immunolocalization in patient kidney sections, and computational variant modeling\",\n      \"pmids\": [\"35723736\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences inferred computationally for most variants\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the sub-podosome localization and its determinant, showing Myo1e/f attach core actin filaments to the membrane at the podosome base to control podosome dynamics and migration.\",\n      \"evidence\": \"TIRF/fluorescence imaging of Myo1e/f-GFP, siRNA/CRISPR depletion, and TH2 domain-deletion constructs in macrophages (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.04.28.651090\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Myo1e versus Myo1f individual contributions not fully separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified Myo1e as a membrane-tension-sensing rescue factor at clathrin-mediated endocytosis sites acting through Arp2/3-dependent branched actin.\",\n      \"evidence\": \"Live-cell and super-resolution imaging of genome-edited hiPSCs with endogenous tagging, Myo1e knockout, and membrane tension manipulation (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.11.12.688091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Direct Myo1e-Arp2/3 interaction versus indirect recruitment not distinguished\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established a role in phagocytic cup closure, showing Myo1e/f organize actin teeth and the contractile ring during Fc-receptor phagocytosis to prevent premature ring constriction and trogocytosis.\",\n      \"evidence\": \"CRISPR double-KO RAW 264.7 macrophages with bead uptake, lattice-light-sheet imaging, rescue, and trogocytosis assays (preprint)\",\n      \"pmids\": [\"42094351\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Mechanism coupling Myo1e/f to NM2 ring organization not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How Myo1e's fast-sliding motor kinetics, electrostatic membrane tethering, and Arp2/3-based actin assembly are integrated and which physical partners recruit it to distinct sites (CCVs, podosomes, phagocytic cup) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No identified direct protein partner explaining junction/CCV recruitment\", \"No structure of full-length motor on membrane\", \"Relationship between motor activity and tension sensing not mechanistically reconciled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 10]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 8, 12]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [6, 8, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 7, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 8, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MYO1F\", \"CALM1\", \"DNM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}