{"gene":"MYO1C","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2002,"finding":"Myo1c is present in GLUT4-containing vesicles purified from adipocytes and functions in a PI(3)K-independent insulin signaling pathway to control movement of intracellular GLUT4-containing vesicles to the plasma membrane; dominant-negative Myo1c cargo domain inhibits insulin-stimulated GLUT4 translocation, and siRNA knockdown of Myo1c inhibits insulin-stimulated 2-deoxyglucose uptake.","method":"GLUT4 vesicle purification, co-localization microscopy, dominant-negative expression, siRNA knockdown, 2-deoxyglucose uptake assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (vesicle purification, dominant-negative, siRNA), replicated across subsequent studies","pmids":["12490950"],"is_preprint":false},{"year":2004,"finding":"Myo1c motor activity is required for membrane fusion of GLUT4-containing vesicles at the plasma membrane; enhanced Myo1c expression drives membrane ruffling and overrides the PI 3-kinase inhibitor block on membrane fusion, restoring GLUT4 display on the cell surface.","method":"PI 3-kinase inhibitor treatment (LY294002), Myo1c overexpression, ultrafast fluorescence microscopy of GLUT4-containing vesicle mobilization","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — overexpression rescue, inhibitor block, and live-cell imaging in single study with orthogonal approaches","pmids":["15169906"],"is_preprint":false},{"year":2007,"finding":"RalA interacts with Myo1c and functions as a cargo receptor for the Myo1c motor during insulin-stimulated GLUT4 trafficking; this interaction is modulated by calmodulin, which acts as the light chain for Myo1c. RalA also signals to the exocyst complex for GLUT4 targeting to the plasma membrane.","method":"Co-immunoprecipitation, dominant-negative mutants, siRNA knockdown, glucose transport assay","journal":"Developmental cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and functional rescue, single lab","pmids":["17765682"],"is_preprint":false},{"year":2007,"finding":"Calcium regulates calmodulin binding to Myo1c IQ motifs: calcium increases actin-activated ATPase activity but completely inhibits actin gliding; calmodulin bound to IQ1 (adjacent to motor domain) dissociates most rapidly in calcium (rate 60 s⁻¹), limited by a slow calcium-induced conformational change (3 s⁻¹), and is responsible for regulation of Myo1c ATPase and motile activity.","method":"Actin gliding assays, ATPase measurements, fluorescence spectroscopy, stopped-flow kinetics with fluorescently labeled calmodulin mutant","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution with multiple orthogonal methods (ATPase, stopped-flow, motility assay), single lab","pmids":["17910470"],"is_preprint":false},{"year":2007,"finding":"CaBP1 and CIB1 bind to the Myo1c regulatory domain IQ motifs and compete with calmodulin for binding; both proteins colocalize with endogenous Myo1c in cells and may specify subcellular localization of Myo1c.","method":"Pull-down experiments, fluorescence microscopy co-localization, in vitro binding competition assays","journal":"Journal of muscle research and cell motility","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pull-down plus colocalization, single lab, two orthogonal methods","pmids":["17994197"],"is_preprint":false},{"year":2008,"finding":"CaMKIIδ phosphorylates Myo1c at S701 in response to insulin, enhancing 14-3-3 binding and reducing calmodulin binding; CaMKII phosphorylation increases Myo1c ATPase activity in vitro; expression of S701A or ATPase-dead K111A Myo1c fails to rescue GLUT4 translocation after siRNA knockdown, demonstrating that insulin-regulated GLUT4 trafficking requires CaMKII-dependent phosphorylation and motor activity of Myo1c.","method":"In vitro kinase assay with recombinant CaMKII, siRNA knockdown of CaMKIIδ, site-directed mutagenesis (S701A, K111A), GLUT4 translocation assay, ATPase assay","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay plus mutagenesis plus cellular rescue, multiple orthogonal methods","pmids":["19046570"],"is_preprint":false},{"year":2008,"finding":"Rictor forms a biochemically distinct complex with Myo1c (separate from mTORC2) in adipocytes; both Rictor and Myo1c are required for paxillin Y118 phosphorylation and cortical actin remodeling (membrane ruffling), and Myo1c-induced membrane ruffling is compromised by Rictor knockdown.","method":"Co-immunoprecipitation, RNAi knockdown, paxillin phosphorylation assay, membrane ruffling imaging","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and functional knockdown phenotypes, single lab","pmids":["18426911"],"is_preprint":false},{"year":2010,"finding":"Myo1c motor activity is required for both contraction-stimulated and insulin-stimulated glucose uptake in mouse skeletal muscle in vivo; expression of ATPase-dead K111A-Myo1c decreases both stimulated glucose uptake, while wild-type Myo1c increases it, without altering GLUT4 expression or upstream signaling.","method":"In vivo electroporation of skeletal muscle, ATPase-dead mutant (K111A), in vivo glucose uptake assay, in situ contraction","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo loss/gain of function with ATPase-dead mutant and defined phenotypic readout","pmids":["21127070"],"is_preprint":false},{"year":2011,"finding":"Myo1c directly interacts with Neph1 and nephrin in an actin-dependent manner, and this interaction is required for targeting these slit diaphragm proteins to the podocyte cell membrane; dominant-negative Myo1c and Myo1c depletion reduce membrane localization of Neph1 and nephrin, and impair cell migration and tight junction formation.","method":"Co-immunoprecipitation, in vitro binding assay, dominant-negative expression, RNAi knockdown, transepithelial resistance assay, wound migration assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct binding assays plus dominant-negative plus RNAi with multiple phenotypic readouts","pmids":["21402783"],"is_preprint":false},{"year":2011,"finding":"A disease-associated Myo1c R156W mutation (associated with hearing loss) has a lower duty ratio than wild-type; it reduces ATPase activity >4-fold likely by decreasing phosphate release rate, and is less force-sensitive than wild-type in frictional loading assays, while actin gliding rate is unaffected at high myosin density but reduced at low surface densities.","method":"Recombinant protein expression, transient kinetic analyses, steady-state ATPase assay, in vitro motility assay, frictional loading assay","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution with multiple orthogonal assays in single study","pmids":["21265502"],"is_preprint":false},{"year":2012,"finding":"Myo1c binding to submembrane actin filaments is required for insulin-induced tethering of GLUT4 vesicles at the plasma membrane in muscle cells; actin-binding-deficient Myo1c mutant abolishes vesicle immobilization and increases vesicle velocity in the TIRF zone, while Myo1c overexpression promotes vesicle tethering and GLUT4 surface delivery.","method":"TIRF microscopy, GLUT4 vesicle tracking, actin-binding-deficient mutant expression, RNAi knockdown, GLUT4 externalization assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — live TIRF imaging plus gain/loss-of-function with actin-binding mutant, multiple orthogonal readouts","pmids":["22918957"],"is_preprint":false},{"year":2012,"finding":"Myo1c is the first motor protein identified to drive formation of recycling tubules from the perinuclear recycling compartment, specifically mediating recycling of lipid-raft-associated GPI-linked cargo proteins (but not transferrin receptor) to the cell surface; Myo1c depletion traps GPI-linked raft markers in the perinuclear compartment and impairs cell spreading, migration, and Salmonella invasion.","method":"RNAi knockdown, dominant-negative overexpression, fluorescence microscopy of recycling tubules and GPI-cargo trafficking, cell spreading and migration assays, Salmonella invasion assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNAi, dominant-negative, live imaging) with specific cargo selectivity demonstrated","pmids":["22328521"],"is_preprint":false},{"year":2012,"finding":"Myo1c tail domain interacts with G-actin (monomeric actin), and Myo1c motor domain activity is required for vectorial transport of G-actin to the leading edge of migrating endothelial cells; Myo1c knockdown reduces G-actin delivery to the leading edge and impairs cell motility.","method":"Mass spectrometry identification, photoactivatable non-polymerizable actin tracking in live cells, Myo1c knockdown, microinjection of Myo1c","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — live-cell tracking of G-actin transport plus MS identification plus knockdown, multiple orthogonal methods","pmids":["22778278"],"is_preprint":false},{"year":2006,"finding":"Myo1c interacts with NEMO/IKK-γ and acts as a motor to traffic NEMO to membrane ruffles; enhanced Myo1c expression increases the NEMO-IRS-1 interaction required for TNF-α-induced Ser307 phosphorylation of IRS-1, while dominant-negative Myo1c cargo domain inhibits this interaction and blocks IRS-1 phosphorylation.","method":"Co-immunoprecipitation, dominant-negative and overexpression constructs, IRS-1 phosphorylation assay, glucose uptake assay","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus gain/loss-of-function with phosphorylation readout, single lab","pmids":["16754954"],"is_preprint":false},{"year":2010,"finding":"Myo1c mutations associated with hearing loss (R156W, V252A, T380M) cause defects in nucleotide and/or actin interactions: R156W disrupts switch 1 movement affecting nucleotide binding and calcium regulation; V252A reduces actin affinity; T380M uncouples ATPase from motility.","method":"Transient kinetic analyses, steady-state ATPase assay, in vitro motility assay, homology modeling with truncated Myo1c construct","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution with multiple assays characterizing each mutant","pmids":["20640478"],"is_preprint":false},{"year":2014,"finding":"Loss of functional MYO1C causes accumulation of autophagic structures due to a block in autophagosome-lysosome fusion, while endocytic EGFR degradation remains unaffected; this is attributable to abnormal cholesterol/lipid distribution in autophagosomes and lysosomes caused by MYO1C loss.","method":"RNAi knockdown, dominant-negative expression, transmission electron microscopy, fluorescence microscopy of autophagosome markers, EGFR degradation assay, cholesterol staining","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi plus dominant-negative with defined morphological and cargo-specific phenotypes, single lab","pmids":["25551774"],"is_preprint":false},{"year":2012,"finding":"Myo1c is required for VEGFR2 delivery to the cell surface in endothelial cells; VEGF stimulation recruits VEGFR2 to caveolin-1- and Myo1c-enriched membrane fractions, and Myo1c depletion reroutes VEGFR2 to lysosomes, reducing VEGFR2 phosphorylation (Y1175), ERK1/2 and c-Src activation, and cell proliferation/migration.","method":"siRNA knockdown, wild-type vs. mutant Myo1c rescue, subcellular density gradient fractionation, surface VEGFR2 measurement, VEGFR2 phosphorylation assay","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown plus rescue with wild-type vs mutant, fractionation showing compartment redistribution, single lab","pmids":["23262137"],"is_preprint":false},{"year":2013,"finding":"Myo1c interacts directly with nephrin and neph1 and is required for podocyte morphogenesis in zebrafish; morpholino knockdown of Myo1c causes loss of slit diaphragm and abnormal podocyte morphology, rescued by co-injection with mouse Myo1c mRNA.","method":"Antisense morpholino knockdown in zebrafish, mRNA rescue, immunofluorescence, in situ hybridization, transmission electron microscopy of glomerulus","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino knockdown with mRNA rescue and ultrastructural phenotype, single lab","pmids":["23715127"],"is_preprint":false},{"year":2016,"finding":"Myo1c is a structural component of a SHIP2-containing protein complex (with filamin A) at lamellipodia; Myo1c depletion impairs SHIP2 localization at lamellipodia and ruffles, reduces FAK Tyr397 phosphorylation, focal adhesion length, and PI(4,5)P2 levels, and strongly reduces cell migration.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence localization, FAK phosphorylation assay, cell migration assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus knockdown with multiple molecular readouts, single lab","pmids":["27246739"],"is_preprint":false},{"year":2016,"finding":"Structural analysis by small angle X-ray scattering of full-length Myo1c reveals an extended S-shaped conformation; Neph1 attaches to the C-terminal tail of Myo1c without inducing a significant conformational change; a critical point mutation in Neph1 abolishes the Myo1c interaction in vitro and in live cells; FRAP analysis confirmed Myo1c-dependent vesicular movement and turnover of Neph1 at the membrane.","method":"Small angle X-ray scattering (SAXS), site-directed mutagenesis, in vitro binding assay, live-cell imaging, FRAP","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — SAXS structural data plus mutagenesis plus live-cell FRAP, multiple orthogonal methods in single study","pmids":["27044863"],"is_preprint":false},{"year":2017,"finding":"The three alternatively spliced MYO1C isoforms (MYO1CC, MYO1C16, MYO1C35), differing only in N-terminal regions (NTRs), have distinct ATPase kinetics: MYO1CC favors the actomyosin closed state, MYO1C16 equally populates open and closed states, and MYO1C35 favors the open state; full-length constructs undergo an isomerization before ADP release not seen in truncated constructs; NTR35 residue Arg-21 interaction with post-relay helix Glu-469 affects power stroke mechanics.","method":"Recombinant protein purification from HEK cells, ATPase kinetic assays, global numerical simulation, homology modeling, NTR peptide addition experiments, R21G mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution with all three purified isoforms, mutagenesis, and global kinetic modeling in single study","pmids":["28893906"],"is_preprint":false},{"year":2019,"finding":"MYO1C stabilizes F-actin at Golgi-associated actin dots and is required for Golgi complex integrity; MYO1C depletion causes Golgi fragmentation and decompaction, loss of cellular F-actin, and delays arrival of incoming transport carriers from both anterograde and retrograde routes.","method":"siRNA depletion, fluorescence microscopy of Golgi morphology and actin structures, transport carrier arrival assay","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown with defined Golgi morphology and trafficking phenotypes, single lab","pmids":["30872458"],"is_preprint":false},{"year":2019,"finding":"Nuclear Myo1c (rather than cytoplasmic) controls TGF-β signaling in podocytes by directly binding to the GDF-15 promoter and regulating transcription of TGF-β-responsive genes; podocyte-specific Myo1c knockout mice are resistant to fibrotic injury and show blunted canonical and non-canonical TGF-β signaling.","method":"Podocyte-specific knockout mouse model, chromatin immunoprecipitation (ChIP) for GDF-15 promoter binding, differential gene expression analysis, fibrosis models (Adriamycin, nephrotoxic serum, UUO)","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout in vivo plus ChIP demonstrating direct promoter binding, multiple disease models tested","pmids":["31097328"],"is_preprint":false},{"year":2019,"finding":"MYO1C interacts with F-actin and associates with LC3 (autophagosome marker) and LAMP1 (lysosome marker); cepharanthine downregulates MYO1C, blocking MYO1C and F-actin colocalization with LC3/LAMP1 and preventing autophagosome-lysosome fusion; overexpression of MYO1C restores this colocalization.","method":"Co-immunoprecipitation, immunofluorescence colocalization, siRNA knockdown, MYO1C overexpression, Western blot for autophagy markers, transmission electron microscopy","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus gain/loss-of-function with fluorescence and EM readouts, single lab","pmids":["31699152"],"is_preprint":false},{"year":2021,"finding":"MYO1C localizes to photoreceptor inner and outer segments and directly interacts with rhodopsin; loss of MYO1C in knockout mice causes rhodopsin mislocalization to rod inner segments and cell bodies, progressive shortening of outer segments, and progressive loss of photoreceptor function.","method":"Myo1c knockout mice, electroretinogram, immunohistochemistry, direct binding assay (rhodopsin-MYO1C), histology and electron microscopy","journal":"Cells","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse model plus direct binding assay plus multiple phenotypic readouts (ERG, IHC, EM)","pmids":["34073294"],"is_preprint":false},{"year":2024,"finding":"RNF41 induces K27- and K63-linked noncanonical polyubiquitination of MYO1C to enhance its stability, promoting actin remodeling and prostate cancer bone metastasis; RNF41 silencing or targeting MYO1C stability suppresses bone metastasis in xenograft models.","method":"Co-immunoprecipitation, ubiquitination assays (K27/K63-linkage), RNF41 silencing, MYO1C stability assay, in vitro and in vivo metastasis models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and ubiquitination assay plus in vivo xenograft, single lab","pmids":["39112516"],"is_preprint":false},{"year":2024,"finding":"Liraglutide directly binds to Myo1c at arginine 93, stabilizing Myo1c and enhancing its interaction with Dock5 (dedicator of cytokinesis 5) by targeting the Dock5 promoter, thereby promoting keratinocyte proliferation, migration, and adhesion to accelerate diabetic wound healing; these effects are abrogated in keratinocyte-specific Dock5 knockout mice.","method":"Direct binding assay (liraglutide-Myo1c), site identification (R93), Dock5 keratinocyte-specific knockout mice, diabetic mouse wound models, cell proliferation/migration/adhesion assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding with site identification plus in vivo KO rescue, single lab","pmids":["39159301"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of actin-bound myo1c with and without ADP reveal a unique actin interface that reorients the motor domain relative to other myosins, a skewed lever arm swing trajectory (explaining leftward circular actin gliding), and unique nucleotide-dependent behavior of the N-terminal extension that underlies force-sensing via ATP binding isomerization rather than ADP release.","method":"Cryo-EM structure determination of actin-myo1c complexes (±ADP), integration with crystallographic data, full-length atomic modeling","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structures with functional validation integrated into mechanistic model, preprint but rigorous structural study","pmids":["bio_10.1101_2025.01.10.632429"],"is_preprint":true},{"year":2025,"finding":"Nuclear myosin 1 (NM1/Myo1c) acts as a positive regulator of ERα clustering on enhancers and promotes condensate formation on chromatin; NM1 depletion leads to genome-wide reduction in ERα occupancy and condensates, though transcriptional output remains largely unaffected despite disrupted clustering.","method":"ChIP-seq, ERα occupancy mapping, NM1 depletion, condensate imaging, estrogen-regulated gene expression analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus depletion with genome-wide readout, preprint, single lab","pmids":["bio_10.1101_2025.01.29.635522"],"is_preprint":true},{"year":2025,"finding":"Myo1c (Drosophila ortholog) directs counterclockwise circumferential F-actin flows in macrophages and dictates sinistral cell chirality; in a modified in vitro motility assay, Myo1c induces random (non-chiral) F-actin flow, contrasting with Myo1D which induces clockwise chiral F-actin rings.","method":"Drosophila genetics, live-cell F-actin flow imaging in macrophages, modified in vitro motility assay with near-physiological actin concentrations","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic manipulation plus in vitro motility assay, preprint, Drosophila ortholog","pmids":["bio_10.1101_2025.05.06.648335"],"is_preprint":true},{"year":2025,"finding":"Myo1c interacts with the Notch ligand Jagged1 under static conditions (confirmed by co-immunoprecipitation), and this interaction is reduced by shear stress; Myo1c knockout inhibits Jagged1 polarization downstream of shear and Myo1c knockdown reduces membrane levels of Jagged1 under static conditions.","method":"Proximity labeling (APEX2) followed by proteomics, co-immunoprecipitation, Myo1c knockout and knockdown, Jagged1 localization assay under shear stress","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling confirmed by co-IP plus KO/KD with defined localization phenotypes, single lab","pmids":["41321631"],"is_preprint":false}],"current_model":"MYO1C is an unconventional class I myosin motor whose ATP hydrolysis-driven movement along actin filaments mediates membrane and vesicle trafficking in multiple cell types: it tethers and delivers GLUT4 vesicles to the plasma membrane in response to insulin (via a PI3K-independent, CaMKII phosphorylation-dependent mechanism at S701), drives recycling of lipid-raft-enriched membranes from the perinuclear compartment to the cell surface, transports cargo proteins (Neph1, nephrin, VEGFR2, rhodopsin) to specific membrane domains, facilitates autophagosome-lysosome fusion via F-actin remodeling, stabilizes actin at the Golgi to support incoming vesicle traffic, and—as nuclear myosin 1—directly binds gene promoters (e.g., GDF-15) to regulate transcription; its mechanochemical properties are tuned by calmodulin binding to IQ motifs, alternative N-terminal splicing, and RNF41-mediated non-canonical polyubiquitination, while cryo-EM structures reveal a unique actin-binding orientation and skewed lever arm trajectory that explains its leftward actin gliding and primary force sensing through ATP-binding isomerization rather than ADP release."},"narrative":{"mechanistic_narrative":"MYO1C is an unconventional class I myosin motor that couples ATP hydrolysis and actin binding to the targeted delivery, tethering, and surface display of membrane cargo across diverse cell types [PMID:12490950, PMID:22918957]. Its best-characterized role is in insulin-stimulated GLUT4 trafficking, where it operates in a PI3K-independent branch: motor activity is required for GLUT4 vesicle movement, plasma-membrane tethering on submembrane actin, and fusion-dependent surface display [PMID:12490950, PMID:15169906, PMID:22918957], and is licensed by CaMKIIδ phosphorylation at S701, which enhances 14-3-3 binding, reduces calmodulin binding, and elevates ATPase activity [PMID:19046570]. RalA serves as a cargo receptor linking the motor to the exocyst, while calmodulin acts as its regulatory light chain [PMID:17765682]. Both motor activity (abolished by the ATPase-dead K111A mutant) and actin binding are essential for stimulated glucose uptake in skeletal muscle in vivo [PMID:21127070, PMID:22918957]. Beyond GLUT4, MYO1C drives recycling of lipid-raft/GPI-anchored cargo from the perinuclear recycling compartment to the surface [PMID:22328521], delivers slit-diaphragm proteins Neph1 and nephrin in podocytes [PMID:21402783, PMID:23715127, PMID:27044863], targets VEGFR2 to the endothelial surface [PMID:23262137], traffics rhodopsin in photoreceptors [PMID:34073294], stabilizes F-actin at the Golgi to sustain transport-carrier arrival [PMID:30872458], and facilitates autophagosome-lysosome fusion through F-actin remodeling and lipid distribution [PMID:25551774, PMID:31699152]. As nuclear myosin 1, MYO1C directly binds the GDF-15 promoter to control TGF-β-responsive transcription in podocytes [PMID:31097328]. Its mechanochemistry is tuned by calcium-dependent calmodulin binding to IQ motifs [PMID:17910470], alternative N-terminal splicing that sets actomyosin state occupancy [PMID:28893906], and cryo-EM-resolved features including a unique actin interface, skewed lever-arm trajectory, and force sensing through ATP-binding isomerization rather than ADP release [PMID:bio_10.1101_2025.01.10.632429]. Disease-associated mutations (R156W, V252A, T380M) that disrupt nucleotide handling, actin affinity, or ATPase-motility coupling are linked to hearing loss [PMID:21265502, PMID:20640478].","teleology":[{"year":2002,"claim":"Established that an unconventional myosin operates in the insulin-to-glucose axis, identifying MYO1C as a motor controlling GLUT4 vesicle movement to the plasma membrane independently of PI3K.","evidence":"GLUT4 vesicle purification, dominant-negative cargo domain, siRNA, and 2-deoxyglucose uptake in adipocytes","pmids":["12490950"],"confidence":"High","gaps":["Did not define the molecular step (transport vs tethering vs fusion) the motor acts on","Cargo receptor linking motor to GLUT4 vesicle unknown"]},{"year":2006,"claim":"Showed MYO1C also functions as a cargo motor in inflammatory signaling, trafficking NEMO to membrane ruffles to promote TNF-α-induced IRS-1 Ser307 phosphorylation.","evidence":"Co-IP, dominant-negative/overexpression constructs, IRS-1 phosphorylation and glucose uptake assays","pmids":["16754954"],"confidence":"Medium","gaps":["Single lab, no reciprocal structural validation of NEMO binding interface","Physiological significance relative to GLUT4 role unclear"]},{"year":2008,"claim":"Defined the regulatory switch for the GLUT4 function, showing CaMKIIδ phosphorylation at S701 (not just calmodulin) gates motor activity and is required for insulin-stimulated translocation.","evidence":"In vitro kinase assay, S701A and K111A mutants, CaMKIIδ knockdown, GLUT4 translocation and ATPase assays","pmids":["19046570","17765682","18426911"],"confidence":"High","gaps":["How 14-3-3 binding mechanistically alters cargo transport not resolved","Distinct Rictor-MYO1C complex function separate from mTORC2 incompletely defined"]},{"year":2007,"claim":"Resolved how calcium tunes the motor, showing calmodulin dissociation from IQ1 inhibits actin gliding while raising ATPase, and that CaBP1/CIB1 can compete for the IQ motifs.","evidence":"ATPase, stopped-flow kinetics, actin gliding assays, pull-downs and colocalization","pmids":["17910470","17994197"],"confidence":"High","gaps":["In vivo relevance of CaBP1/CIB1 substitution for calmodulin not established","Link between calcium regulation and specific trafficking events unclear"]},{"year":2010,"claim":"Demonstrated physiological requirement in vivo, showing motor activity (ATPase-dead K111A) is needed for both contraction- and insulin-stimulated glucose uptake in skeletal muscle.","evidence":"In vivo electroporation of K111A and WT MYO1C, in vivo glucose uptake, in situ contraction; plus hearing-loss mutant biochemistry","pmids":["21127070","20640478"],"confidence":"High","gaps":["Whether muscle and adipocyte mechanisms are identical not shown","Disease mutations characterized biochemically but not in an in vivo hearing model here"]},{"year":2012,"claim":"Broadened MYO1C function beyond GLUT4, establishing it as a motor for perinuclear recycling of raft/GPI cargo, submembrane actin-dependent vesicle tethering, and vectorial G-actin transport to the leading edge.","evidence":"TIRF vesicle tracking, actin-binding-deficient mutant, RNAi, live-cell GPI-cargo and photoactivatable G-actin imaging, VEGFR2 fractionation","pmids":["22918957","22328521","22778278","23262137"],"confidence":"High","gaps":["Cargo-selectivity determinants (raft vs non-raft) not defined","Whether G-actin transport and vesicle tethering use the same molecular mode unclear"]},{"year":2013,"claim":"Identified MYO1C as the motor delivering slit-diaphragm proteins, directly binding Neph1 and nephrin to drive their membrane targeting and podocyte morphogenesis.","evidence":"Co-IP and direct binding, dominant-negative, RNAi, zebrafish morpholino with mRNA rescue, ultrastructure","pmids":["21402783","23715127"],"confidence":"High","gaps":["Cargo handoff mechanism at the membrane not defined","Structural basis of Neph1/nephrin binding to tail not yet resolved here"]},{"year":2016,"claim":"Refined the cargo-binding architecture and motile-component roles, showing an extended S-shaped conformation with Neph1 docking on the C-terminal tail, and structural participation in a SHIP2/filamin A lamellipodial complex governing migration.","evidence":"SAXS, mutagenesis, FRAP, live-cell imaging; co-IP and FAK phosphorylation/migration assays","pmids":["27044863","27246739"],"confidence":"High","gaps":["Atomic-resolution tail-cargo interface absent","Whether SHIP2-complex role is motor-dependent or scaffolding unclear"]},{"year":2017,"claim":"Explained isoform diversity by showing the three N-terminally spliced variants set distinct actomyosin state occupancy and that full-length motors undergo a pre-ADP-release isomerization absent in truncated constructs.","evidence":"Recombinant purification of all three isoforms, ATPase kinetics, global modeling, NTR peptide and R21G mutagenesis","pmids":["28893906"],"confidence":"High","gaps":["Cell-type-specific functional consequences of each isoform not mapped","Link between NTR-set kinetics and specific cargo trafficking unresolved"]},{"year":2019,"claim":"Expanded MYO1C into Golgi integrity, autophagy, and a distinct nuclear transcriptional role, including direct GDF-15 promoter binding controlling TGF-β signaling and fibrosis resistance.","evidence":"siRNA Golgi/transport assays; LC3/LAMP1 colocalization and EM; podocyte-specific knockout mouse and ChIP for GDF-15 promoter","pmids":["30872458","31699152","31097328"],"confidence":"High","gaps":["How a single motor partitions between cytoplasmic trafficking and nuclear chromatin roles unclear","Mechanism of promoter recognition by a myosin not defined"]},{"year":2021,"claim":"Demonstrated tissue-level cargo specificity in vision, showing MYO1C directly binds rhodopsin and is required for its localization and photoreceptor outer-segment maintenance.","evidence":"Myo1c knockout mice, ERG, IHC, EM, direct rhodopsin binding assay","pmids":["34073294"],"confidence":"High","gaps":["Trafficking route of rhodopsin via MYO1C not mapped","Relationship to ciliary/connecting cilium transport unaddressed"]},{"year":2024,"claim":"Revealed regulation of MYO1C stability and small-molecule targeting, showing RNF41-mediated noncanonical K27/K63 ubiquitination stabilizes MYO1C to drive metastasis, and liraglutide binds R93 to stabilize MYO1C and promote wound healing.","evidence":"Co-IP, K27/K63 ubiquitination assays, RNF41 silencing, xenograft metastasis; direct liraglutide binding (R93), Dock5 keratinocyte KO mice","pmids":["39112516","39159301"],"confidence":"Medium","gaps":["Single-lab findings, mechanism linking stabilization to actin remodeling indirect","How ubiquitin linkage type alters motor function unresolved"]},{"year":2025,"claim":"Provided the structural basis of MYO1C's distinctive mechanics and extended its roles, with cryo-EM defining a unique actin interface, skewed lever arm and ATP-binding force-sensing, plus chiral F-actin flow, ERα chromatin clustering, and shear-regulated Jagged1 trafficking.","evidence":"Cryo-EM of actin-MYO1C ±ADP (preprint); Drosophila genetics and in vitro motility (preprint); ChIP-seq/condensate imaging (preprint); APEX2 proteomics and co-IP with KO/KD","pmids":["bio_10.1101_2025.01.10.632429","bio_10.1101_2025.05.06.648335","bio_10.1101_2025.01.29.635522","41321631"],"confidence":"High","gaps":["Several findings are preprints awaiting peer review","Whether nuclear ERα clustering role has transcriptional consequence is unresolved given unchanged output"]},{"year":null,"claim":"How a single motor is partitioned and regulated to select among its many cargoes (GLUT4, raft cargo, slit-diaphragm proteins, VEGFR2, rhodopsin, Jagged1) and between cytoplasmic trafficking and nuclear chromatin functions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model of cargo-selection determinants","Mechanism of nuclear targeting and promoter recognition undefined","Isoform-to-function mapping incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3,5,7,9,20]},{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[0,1,10,27]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[10,12,21,23,27]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[22,28]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[22]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,8,10,16,24]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[21]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[15,23]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[22,28]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[12,18,21,23]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,10,11,16,24]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[15,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,16,22,30]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[22,28]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[8,17,24]}],"complexes":["SHIP2-filamin A lamellipodial complex"],"partners":["RALA","NEPH1","NEPHRIN","RICTOR","NEMO","RHODOPSIN","RNF41","JAGGED1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00159","full_name":"Unconventional myosin-Ic","aliases":["Myosin I beta","MMI-beta","MMIb"],"length_aa":1063,"mass_kda":121.7,"function":"Myosins are actin-based motor molecules with ATPase activity. 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Myo1c inhibits insulin-stimulated 2-deoxyglucose uptake.\",\n      \"method\": \"GLUT4 vesicle purification, co-localization microscopy, dominant-negative expression, siRNA knockdown, 2-deoxyglucose uptake assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (vesicle purification, dominant-negative, siRNA), replicated across subsequent studies\",\n      \"pmids\": [\"12490950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Myo1c motor activity is required for membrane fusion of GLUT4-containing vesicles at the plasma membrane; enhanced Myo1c expression drives membrane ruffling and overrides the PI 3-kinase inhibitor block on membrane fusion, restoring GLUT4 display on the cell surface.\",\n      \"method\": \"PI 3-kinase inhibitor treatment (LY294002), Myo1c overexpression, ultrafast fluorescence microscopy of GLUT4-containing vesicle mobilization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression rescue, inhibitor block, and live-cell imaging in single study with orthogonal approaches\",\n      \"pmids\": [\"15169906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RalA interacts with Myo1c and functions as a cargo receptor for the Myo1c motor during insulin-stimulated GLUT4 trafficking; this interaction is modulated by calmodulin, which acts as the light chain for Myo1c. RalA also signals to the exocyst complex for GLUT4 targeting to the plasma membrane.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative mutants, siRNA knockdown, glucose transport assay\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and functional rescue, single lab\",\n      \"pmids\": [\"17765682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Calcium regulates calmodulin binding to Myo1c IQ motifs: calcium increases actin-activated ATPase activity but completely inhibits actin gliding; calmodulin bound to IQ1 (adjacent to motor domain) dissociates most rapidly in calcium (rate 60 s⁻¹), limited by a slow calcium-induced conformational change (3 s⁻¹), and is responsible for regulation of Myo1c ATPase and motile activity.\",\n      \"method\": \"Actin gliding assays, ATPase measurements, fluorescence spectroscopy, stopped-flow kinetics with fluorescently labeled calmodulin mutant\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution with multiple orthogonal methods (ATPase, stopped-flow, motility assay), single lab\",\n      \"pmids\": [\"17910470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CaBP1 and CIB1 bind to the Myo1c regulatory domain IQ motifs and compete with calmodulin for binding; both proteins colocalize with endogenous Myo1c in cells and may specify subcellular localization of Myo1c.\",\n      \"method\": \"Pull-down experiments, fluorescence microscopy co-localization, in vitro binding competition assays\",\n      \"journal\": \"Journal of muscle research and cell motility\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pull-down plus colocalization, single lab, two orthogonal methods\",\n      \"pmids\": [\"17994197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CaMKIIδ phosphorylates Myo1c at S701 in response to insulin, enhancing 14-3-3 binding and reducing calmodulin binding; CaMKII phosphorylation increases Myo1c ATPase activity in vitro; expression of S701A or ATPase-dead K111A Myo1c fails to rescue GLUT4 translocation after siRNA knockdown, demonstrating that insulin-regulated GLUT4 trafficking requires CaMKII-dependent phosphorylation and motor activity of Myo1c.\",\n      \"method\": \"In vitro kinase assay with recombinant CaMKII, siRNA knockdown of CaMKIIδ, site-directed mutagenesis (S701A, K111A), GLUT4 translocation assay, ATPase assay\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay plus mutagenesis plus cellular rescue, multiple orthogonal methods\",\n      \"pmids\": [\"19046570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Rictor forms a biochemically distinct complex with Myo1c (separate from mTORC2) in adipocytes; both Rictor and Myo1c are required for paxillin Y118 phosphorylation and cortical actin remodeling (membrane ruffling), and Myo1c-induced membrane ruffling is compromised by Rictor knockdown.\",\n      \"method\": \"Co-immunoprecipitation, RNAi knockdown, paxillin phosphorylation assay, membrane ruffling imaging\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and functional knockdown phenotypes, single lab\",\n      \"pmids\": [\"18426911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Myo1c motor activity is required for both contraction-stimulated and insulin-stimulated glucose uptake in mouse skeletal muscle in vivo; expression of ATPase-dead K111A-Myo1c decreases both stimulated glucose uptake, while wild-type Myo1c increases it, without altering GLUT4 expression or upstream signaling.\",\n      \"method\": \"In vivo electroporation of skeletal muscle, ATPase-dead mutant (K111A), in vivo glucose uptake assay, in situ contraction\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss/gain of function with ATPase-dead mutant and defined phenotypic readout\",\n      \"pmids\": [\"21127070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Myo1c directly interacts with Neph1 and nephrin in an actin-dependent manner, and this interaction is required for targeting these slit diaphragm proteins to the podocyte cell membrane; dominant-negative Myo1c and Myo1c depletion reduce membrane localization of Neph1 and nephrin, and impair cell migration and tight junction formation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay, dominant-negative expression, RNAi knockdown, transepithelial resistance assay, wound migration assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct binding assays plus dominant-negative plus RNAi with multiple phenotypic readouts\",\n      \"pmids\": [\"21402783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A disease-associated Myo1c R156W mutation (associated with hearing loss) has a lower duty ratio than wild-type; it reduces ATPase activity >4-fold likely by decreasing phosphate release rate, and is less force-sensitive than wild-type in frictional loading assays, while actin gliding rate is unaffected at high myosin density but reduced at low surface densities.\",\n      \"method\": \"Recombinant protein expression, transient kinetic analyses, steady-state ATPase assay, in vitro motility assay, frictional loading assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution with multiple orthogonal assays in single study\",\n      \"pmids\": [\"21265502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Myo1c binding to submembrane actin filaments is required for insulin-induced tethering of GLUT4 vesicles at the plasma membrane in muscle cells; actin-binding-deficient Myo1c mutant abolishes vesicle immobilization and increases vesicle velocity in the TIRF zone, while Myo1c overexpression promotes vesicle tethering and GLUT4 surface delivery.\",\n      \"method\": \"TIRF microscopy, GLUT4 vesicle tracking, actin-binding-deficient mutant expression, RNAi knockdown, GLUT4 externalization assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live TIRF imaging plus gain/loss-of-function with actin-binding mutant, multiple orthogonal readouts\",\n      \"pmids\": [\"22918957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Myo1c is the first motor protein identified to drive formation of recycling tubules from the perinuclear recycling compartment, specifically mediating recycling of lipid-raft-associated GPI-linked cargo proteins (but not transferrin receptor) to the cell surface; Myo1c depletion traps GPI-linked raft markers in the perinuclear compartment and impairs cell spreading, migration, and Salmonella invasion.\",\n      \"method\": \"RNAi knockdown, dominant-negative overexpression, fluorescence microscopy of recycling tubules and GPI-cargo trafficking, cell spreading and migration assays, Salmonella invasion assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNAi, dominant-negative, live imaging) with specific cargo selectivity demonstrated\",\n      \"pmids\": [\"22328521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Myo1c tail domain interacts with G-actin (monomeric actin), and Myo1c motor domain activity is required for vectorial transport of G-actin to the leading edge of migrating endothelial cells; Myo1c knockdown reduces G-actin delivery to the leading edge and impairs cell motility.\",\n      \"method\": \"Mass spectrometry identification, photoactivatable non-polymerizable actin tracking in live cells, Myo1c knockdown, microinjection of Myo1c\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell tracking of G-actin transport plus MS identification plus knockdown, multiple orthogonal methods\",\n      \"pmids\": [\"22778278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Myo1c interacts with NEMO/IKK-γ and acts as a motor to traffic NEMO to membrane ruffles; enhanced Myo1c expression increases the NEMO-IRS-1 interaction required for TNF-α-induced Ser307 phosphorylation of IRS-1, while dominant-negative Myo1c cargo domain inhibits this interaction and blocks IRS-1 phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative and overexpression constructs, IRS-1 phosphorylation assay, glucose uptake assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus gain/loss-of-function with phosphorylation readout, single lab\",\n      \"pmids\": [\"16754954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Myo1c mutations associated with hearing loss (R156W, V252A, T380M) cause defects in nucleotide and/or actin interactions: R156W disrupts switch 1 movement affecting nucleotide binding and calcium regulation; V252A reduces actin affinity; T380M uncouples ATPase from motility.\",\n      \"method\": \"Transient kinetic analyses, steady-state ATPase assay, in vitro motility assay, homology modeling with truncated Myo1c construct\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution with multiple assays characterizing each mutant\",\n      \"pmids\": [\"20640478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of functional MYO1C causes accumulation of autophagic structures due to a block in autophagosome-lysosome fusion, while endocytic EGFR degradation remains unaffected; this is attributable to abnormal cholesterol/lipid distribution in autophagosomes and lysosomes caused by MYO1C loss.\",\n      \"method\": \"RNAi knockdown, dominant-negative expression, transmission electron microscopy, fluorescence microscopy of autophagosome markers, EGFR degradation assay, cholesterol staining\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi plus dominant-negative with defined morphological and cargo-specific phenotypes, single lab\",\n      \"pmids\": [\"25551774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Myo1c is required for VEGFR2 delivery to the cell surface in endothelial cells; VEGF stimulation recruits VEGFR2 to caveolin-1- and Myo1c-enriched membrane fractions, and Myo1c depletion reroutes VEGFR2 to lysosomes, reducing VEGFR2 phosphorylation (Y1175), ERK1/2 and c-Src activation, and cell proliferation/migration.\",\n      \"method\": \"siRNA knockdown, wild-type vs. mutant Myo1c rescue, subcellular density gradient fractionation, surface VEGFR2 measurement, VEGFR2 phosphorylation assay\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown plus rescue with wild-type vs mutant, fractionation showing compartment redistribution, single lab\",\n      \"pmids\": [\"23262137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Myo1c interacts directly with nephrin and neph1 and is required for podocyte morphogenesis in zebrafish; morpholino knockdown of Myo1c causes loss of slit diaphragm and abnormal podocyte morphology, rescued by co-injection with mouse Myo1c mRNA.\",\n      \"method\": \"Antisense morpholino knockdown in zebrafish, mRNA rescue, immunofluorescence, in situ hybridization, transmission electron microscopy of glomerulus\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino knockdown with mRNA rescue and ultrastructural phenotype, single lab\",\n      \"pmids\": [\"23715127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Myo1c is a structural component of a SHIP2-containing protein complex (with filamin A) at lamellipodia; Myo1c depletion impairs SHIP2 localization at lamellipodia and ruffles, reduces FAK Tyr397 phosphorylation, focal adhesion length, and PI(4,5)P2 levels, and strongly reduces cell migration.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence localization, FAK phosphorylation assay, cell migration assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus knockdown with multiple molecular readouts, single lab\",\n      \"pmids\": [\"27246739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Structural analysis by small angle X-ray scattering of full-length Myo1c reveals an extended S-shaped conformation; Neph1 attaches to the C-terminal tail of Myo1c without inducing a significant conformational change; a critical point mutation in Neph1 abolishes the Myo1c interaction in vitro and in live cells; FRAP analysis confirmed Myo1c-dependent vesicular movement and turnover of Neph1 at the membrane.\",\n      \"method\": \"Small angle X-ray scattering (SAXS), site-directed mutagenesis, in vitro binding assay, live-cell imaging, FRAP\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — SAXS structural data plus mutagenesis plus live-cell FRAP, multiple orthogonal methods in single study\",\n      \"pmids\": [\"27044863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The three alternatively spliced MYO1C isoforms (MYO1CC, MYO1C16, MYO1C35), differing only in N-terminal regions (NTRs), have distinct ATPase kinetics: MYO1CC favors the actomyosin closed state, MYO1C16 equally populates open and closed states, and MYO1C35 favors the open state; full-length constructs undergo an isomerization before ADP release not seen in truncated constructs; NTR35 residue Arg-21 interaction with post-relay helix Glu-469 affects power stroke mechanics.\",\n      \"method\": \"Recombinant protein purification from HEK cells, ATPase kinetic assays, global numerical simulation, homology modeling, NTR peptide addition experiments, R21G mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution with all three purified isoforms, mutagenesis, and global kinetic modeling in single study\",\n      \"pmids\": [\"28893906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MYO1C stabilizes F-actin at Golgi-associated actin dots and is required for Golgi complex integrity; MYO1C depletion causes Golgi fragmentation and decompaction, loss of cellular F-actin, and delays arrival of incoming transport carriers from both anterograde and retrograde routes.\",\n      \"method\": \"siRNA depletion, fluorescence microscopy of Golgi morphology and actin structures, transport carrier arrival assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown with defined Golgi morphology and trafficking phenotypes, single lab\",\n      \"pmids\": [\"30872458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nuclear Myo1c (rather than cytoplasmic) controls TGF-β signaling in podocytes by directly binding to the GDF-15 promoter and regulating transcription of TGF-β-responsive genes; podocyte-specific Myo1c knockout mice are resistant to fibrotic injury and show blunted canonical and non-canonical TGF-β signaling.\",\n      \"method\": \"Podocyte-specific knockout mouse model, chromatin immunoprecipitation (ChIP) for GDF-15 promoter binding, differential gene expression analysis, fibrosis models (Adriamycin, nephrotoxic serum, UUO)\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout in vivo plus ChIP demonstrating direct promoter binding, multiple disease models tested\",\n      \"pmids\": [\"31097328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MYO1C interacts with F-actin and associates with LC3 (autophagosome marker) and LAMP1 (lysosome marker); cepharanthine downregulates MYO1C, blocking MYO1C and F-actin colocalization with LC3/LAMP1 and preventing autophagosome-lysosome fusion; overexpression of MYO1C restores this colocalization.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, siRNA knockdown, MYO1C overexpression, Western blot for autophagy markers, transmission electron microscopy\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus gain/loss-of-function with fluorescence and EM readouts, single lab\",\n      \"pmids\": [\"31699152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYO1C localizes to photoreceptor inner and outer segments and directly interacts with rhodopsin; loss of MYO1C in knockout mice causes rhodopsin mislocalization to rod inner segments and cell bodies, progressive shortening of outer segments, and progressive loss of photoreceptor function.\",\n      \"method\": \"Myo1c knockout mice, electroretinogram, immunohistochemistry, direct binding assay (rhodopsin-MYO1C), histology and electron microscopy\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse model plus direct binding assay plus multiple phenotypic readouts (ERG, IHC, EM)\",\n      \"pmids\": [\"34073294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RNF41 induces K27- and K63-linked noncanonical polyubiquitination of MYO1C to enhance its stability, promoting actin remodeling and prostate cancer bone metastasis; RNF41 silencing or targeting MYO1C stability suppresses bone metastasis in xenograft models.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays (K27/K63-linkage), RNF41 silencing, MYO1C stability assay, in vitro and in vivo metastasis models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and ubiquitination assay plus in vivo xenograft, single lab\",\n      \"pmids\": [\"39112516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Liraglutide directly binds to Myo1c at arginine 93, stabilizing Myo1c and enhancing its interaction with Dock5 (dedicator of cytokinesis 5) by targeting the Dock5 promoter, thereby promoting keratinocyte proliferation, migration, and adhesion to accelerate diabetic wound healing; these effects are abrogated in keratinocyte-specific Dock5 knockout mice.\",\n      \"method\": \"Direct binding assay (liraglutide-Myo1c), site identification (R93), Dock5 keratinocyte-specific knockout mice, diabetic mouse wound models, cell proliferation/migration/adhesion assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding with site identification plus in vivo KO rescue, single lab\",\n      \"pmids\": [\"39159301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of actin-bound myo1c with and without ADP reveal a unique actin interface that reorients the motor domain relative to other myosins, a skewed lever arm swing trajectory (explaining leftward circular actin gliding), and unique nucleotide-dependent behavior of the N-terminal extension that underlies force-sensing via ATP binding isomerization rather than ADP release.\",\n      \"method\": \"Cryo-EM structure determination of actin-myo1c complexes (±ADP), integration with crystallographic data, full-length atomic modeling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structures with functional validation integrated into mechanistic model, preprint but rigorous structural study\",\n      \"pmids\": [\"bio_10.1101_2025.01.10.632429\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nuclear myosin 1 (NM1/Myo1c) acts as a positive regulator of ERα clustering on enhancers and promotes condensate formation on chromatin; NM1 depletion leads to genome-wide reduction in ERα occupancy and condensates, though transcriptional output remains largely unaffected despite disrupted clustering.\",\n      \"method\": \"ChIP-seq, ERα occupancy mapping, NM1 depletion, condensate imaging, estrogen-regulated gene expression analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus depletion with genome-wide readout, preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.01.29.635522\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Myo1c (Drosophila ortholog) directs counterclockwise circumferential F-actin flows in macrophages and dictates sinistral cell chirality; in a modified in vitro motility assay, Myo1c induces random (non-chiral) F-actin flow, contrasting with Myo1D which induces clockwise chiral F-actin rings.\",\n      \"method\": \"Drosophila genetics, live-cell F-actin flow imaging in macrophages, modified in vitro motility assay with near-physiological actin concentrations\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic manipulation plus in vitro motility assay, preprint, Drosophila ortholog\",\n      \"pmids\": [\"bio_10.1101_2025.05.06.648335\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Myo1c interacts with the Notch ligand Jagged1 under static conditions (confirmed by co-immunoprecipitation), and this interaction is reduced by shear stress; Myo1c knockout inhibits Jagged1 polarization downstream of shear and Myo1c knockdown reduces membrane levels of Jagged1 under static conditions.\",\n      \"method\": \"Proximity labeling (APEX2) followed by proteomics, co-immunoprecipitation, Myo1c knockout and knockdown, Jagged1 localization assay under shear stress\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling confirmed by co-IP plus KO/KD with defined localization phenotypes, single lab\",\n      \"pmids\": [\"41321631\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYO1C is an unconventional class I myosin motor whose ATP hydrolysis-driven movement along actin filaments mediates membrane and vesicle trafficking in multiple cell types: it tethers and delivers GLUT4 vesicles to the plasma membrane in response to insulin (via a PI3K-independent, CaMKII phosphorylation-dependent mechanism at S701), drives recycling of lipid-raft-enriched membranes from the perinuclear compartment to the cell surface, transports cargo proteins (Neph1, nephrin, VEGFR2, rhodopsin) to specific membrane domains, facilitates autophagosome-lysosome fusion via F-actin remodeling, stabilizes actin at the Golgi to support incoming vesicle traffic, and—as nuclear myosin 1—directly binds gene promoters (e.g., GDF-15) to regulate transcription; its mechanochemical properties are tuned by calmodulin binding to IQ motifs, alternative N-terminal splicing, and RNF41-mediated non-canonical polyubiquitination, while cryo-EM structures reveal a unique actin-binding orientation and skewed lever arm trajectory that explains its leftward actin gliding and primary force sensing through ATP-binding isomerization rather than ADP release.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYO1C is an unconventional class I myosin motor that couples ATP hydrolysis and actin binding to the targeted delivery, tethering, and surface display of membrane cargo across diverse cell types [#0, #10]. Its best-characterized role is in insulin-stimulated GLUT4 trafficking, where it operates in a PI3K-independent branch: motor activity is required for GLUT4 vesicle movement, plasma-membrane tethering on submembrane actin, and fusion-dependent surface display [#0, #1, #10], and is licensed by CaMKII\\u03b4 phosphorylation at S701, which enhances 14-3-3 binding, reduces calmodulin binding, and elevates ATPase activity [#5]. RalA serves as a cargo receptor linking the motor to the exocyst, while calmodulin acts as its regulatory light chain [#2]. Both motor activity (abolished by the ATPase-dead K111A mutant) and actin binding are essential for stimulated glucose uptake in skeletal muscle in vivo [#7, #10]. Beyond GLUT4, MYO1C drives recycling of lipid-raft/GPI-anchored cargo from the perinuclear recycling compartment to the surface [#11], delivers slit-diaphragm proteins Neph1 and nephrin in podocytes [#8, #17, #19], targets VEGFR2 to the endothelial surface [#16], traffics rhodopsin in photoreceptors [#24], stabilizes F-actin at the Golgi to sustain transport-carrier arrival [#21], and facilitates autophagosome-lysosome fusion through F-actin remodeling and lipid distribution [#15, #23]. As nuclear myosin 1, MYO1C directly binds the GDF-15 promoter to control TGF-\\u03b2-responsive transcription in podocytes [#22]. Its mechanochemistry is tuned by calcium-dependent calmodulin binding to IQ motifs [#3], alternative N-terminal splicing that sets actomyosin state occupancy [#20], and cryo-EM-resolved features including a unique actin interface, skewed lever-arm trajectory, and force sensing through ATP-binding isomerization rather than ADP release [#27]. Disease-associated mutations (R156W, V252A, T380M) that disrupt nucleotide handling, actin affinity, or ATPase-motility coupling are linked to hearing loss [#9, #14].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that an unconventional myosin operates in the insulin-to-glucose axis, identifying MYO1C as a motor controlling GLUT4 vesicle movement to the plasma membrane independently of PI3K.\",\n      \"evidence\": \"GLUT4 vesicle purification, dominant-negative cargo domain, siRNA, and 2-deoxyglucose uptake in adipocytes\",\n      \"pmids\": [\"12490950\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular step (transport vs tethering vs fusion) the motor acts on\", \"Cargo receptor linking motor to GLUT4 vesicle unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Showed MYO1C also functions as a cargo motor in inflammatory signaling, trafficking NEMO to membrane ruffles to promote TNF-\\u03b1-induced IRS-1 Ser307 phosphorylation.\",\n      \"evidence\": \"Co-IP, dominant-negative/overexpression constructs, IRS-1 phosphorylation and glucose uptake assays\",\n      \"pmids\": [\"16754954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, no reciprocal structural validation of NEMO binding interface\", \"Physiological significance relative to GLUT4 role unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the regulatory switch for the GLUT4 function, showing CaMKII\\u03b4 phosphorylation at S701 (not just calmodulin) gates motor activity and is required for insulin-stimulated translocation.\",\n      \"evidence\": \"In vitro kinase assay, S701A and K111A mutants, CaMKII\\u03b4 knockdown, GLUT4 translocation and ATPase assays\",\n      \"pmids\": [\"19046570\", \"17765682\", \"18426911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How 14-3-3 binding mechanistically alters cargo transport not resolved\", \"Distinct Rictor-MYO1C complex function separate from mTORC2 incompletely defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Resolved how calcium tunes the motor, showing calmodulin dissociation from IQ1 inhibits actin gliding while raising ATPase, and that CaBP1/CIB1 can compete for the IQ motifs.\",\n      \"evidence\": \"ATPase, stopped-flow kinetics, actin gliding assays, pull-downs and colocalization\",\n      \"pmids\": [\"17910470\", \"17994197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of CaBP1/CIB1 substitution for calmodulin not established\", \"Link between calcium regulation and specific trafficking events unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated physiological requirement in vivo, showing motor activity (ATPase-dead K111A) is needed for both contraction- and insulin-stimulated glucose uptake in skeletal muscle.\",\n      \"evidence\": \"In vivo electroporation of K111A and WT MYO1C, in vivo glucose uptake, in situ contraction; plus hearing-loss mutant biochemistry\",\n      \"pmids\": [\"21127070\", \"20640478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether muscle and adipocyte mechanisms are identical not shown\", \"Disease mutations characterized biochemically but not in an in vivo hearing model here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Broadened MYO1C function beyond GLUT4, establishing it as a motor for perinuclear recycling of raft/GPI cargo, submembrane actin-dependent vesicle tethering, and vectorial G-actin transport to the leading edge.\",\n      \"evidence\": \"TIRF vesicle tracking, actin-binding-deficient mutant, RNAi, live-cell GPI-cargo and photoactivatable G-actin imaging, VEGFR2 fractionation\",\n      \"pmids\": [\"22918957\", \"22328521\", \"22778278\", \"23262137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo-selectivity determinants (raft vs non-raft) not defined\", \"Whether G-actin transport and vesicle tethering use the same molecular mode unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified MYO1C as the motor delivering slit-diaphragm proteins, directly binding Neph1 and nephrin to drive their membrane targeting and podocyte morphogenesis.\",\n      \"evidence\": \"Co-IP and direct binding, dominant-negative, RNAi, zebrafish morpholino with mRNA rescue, ultrastructure\",\n      \"pmids\": [\"21402783\", \"23715127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo handoff mechanism at the membrane not defined\", \"Structural basis of Neph1/nephrin binding to tail not yet resolved here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Refined the cargo-binding architecture and motile-component roles, showing an extended S-shaped conformation with Neph1 docking on the C-terminal tail, and structural participation in a SHIP2/filamin A lamellipodial complex governing migration.\",\n      \"evidence\": \"SAXS, mutagenesis, FRAP, live-cell imaging; co-IP and FAK phosphorylation/migration assays\",\n      \"pmids\": [\"27044863\", \"27246739\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution tail-cargo interface absent\", \"Whether SHIP2-complex role is motor-dependent or scaffolding unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Explained isoform diversity by showing the three N-terminally spliced variants set distinct actomyosin state occupancy and that full-length motors undergo a pre-ADP-release isomerization absent in truncated constructs.\",\n      \"evidence\": \"Recombinant purification of all three isoforms, ATPase kinetics, global modeling, NTR peptide and R21G mutagenesis\",\n      \"pmids\": [\"28893906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific functional consequences of each isoform not mapped\", \"Link between NTR-set kinetics and specific cargo trafficking unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Expanded MYO1C into Golgi integrity, autophagy, and a distinct nuclear transcriptional role, including direct GDF-15 promoter binding controlling TGF-\\u03b2 signaling and fibrosis resistance.\",\n      \"evidence\": \"siRNA Golgi/transport assays; LC3/LAMP1 colocalization and EM; podocyte-specific knockout mouse and ChIP for GDF-15 promoter\",\n      \"pmids\": [\"30872458\", \"31699152\", \"31097328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single motor partitions between cytoplasmic trafficking and nuclear chromatin roles unclear\", \"Mechanism of promoter recognition by a myosin not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated tissue-level cargo specificity in vision, showing MYO1C directly binds rhodopsin and is required for its localization and photoreceptor outer-segment maintenance.\",\n      \"evidence\": \"Myo1c knockout mice, ERG, IHC, EM, direct rhodopsin binding assay\",\n      \"pmids\": [\"34073294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Trafficking route of rhodopsin via MYO1C not mapped\", \"Relationship to ciliary/connecting cilium transport unaddressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Revealed regulation of MYO1C stability and small-molecule targeting, showing RNF41-mediated noncanonical K27/K63 ubiquitination stabilizes MYO1C to drive metastasis, and liraglutide binds R93 to stabilize MYO1C and promote wound healing.\",\n      \"evidence\": \"Co-IP, K27/K63 ubiquitination assays, RNF41 silencing, xenograft metastasis; direct liraglutide binding (R93), Dock5 keratinocyte KO mice\",\n      \"pmids\": [\"39112516\", \"39159301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings, mechanism linking stabilization to actin remodeling indirect\", \"How ubiquitin linkage type alters motor function unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided the structural basis of MYO1C's distinctive mechanics and extended its roles, with cryo-EM defining a unique actin interface, skewed lever arm and ATP-binding force-sensing, plus chiral F-actin flow, ER\\u03b1 chromatin clustering, and shear-regulated Jagged1 trafficking.\",\n      \"evidence\": \"Cryo-EM of actin-MYO1C \\u00b1ADP (preprint); Drosophila genetics and in vitro motility (preprint); ChIP-seq/condensate imaging (preprint); APEX2 proteomics and co-IP with KO/KD\",\n      \"pmids\": [\"bio_10.1101_2025.01.10.632429\", \"bio_10.1101_2025.05.06.648335\", \"bio_10.1101_2025.01.29.635522\", \"41321631\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Several findings are preprints awaiting peer review\", \"Whether nuclear ER\\u03b1 clustering role has transcriptional consequence is unresolved given unchanged output\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single motor is partitioned and regulated to select among its many cargoes (GLUT4, raft cargo, slit-diaphragm proteins, VEGFR2, rhodopsin, Jagged1) and between cytoplasmic trafficking and nuclear chromatin functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model of cargo-selection determinants\", \"Mechanism of nuclear targeting and promoter recognition undefined\", \"Isoform-to-function mapping incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3, 5, 7, 9, 20]},\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0, 1, 10, 27]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [10, 12, 21, 23, 27]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [22, 28]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [22]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 8, 10, 16, 24]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [15, 23]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [22, 28]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [12, 18, 21, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 10, 11, 16, 24]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [15, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 16, 22, 30]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [22, 28]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [8, 17, 24]}\n    ],\n    \"complexes\": [\"SHIP2-filamin A lamellipodial complex\"],\n    \"partners\": [\"RalA\", \"Neph1\", \"Nephrin\", \"Rictor\", \"NEMO\", \"Rhodopsin\", \"RNF41\", \"Jagged1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}