{"gene":"MYO1C","run_date":"2026-04-29T11:37:56","timeline":{"discoveries":[{"year":2002,"finding":"Myo1c is present in GLUT4-containing vesicles purified from 3T3-L1 adipocytes and functions in a PI(3)K-independent insulin signaling pathway that controls movement of intracellular GLUT4-vesicles to the plasma membrane; dominant-negative Myo1c cargo domain inhibits insulin-stimulated GLUT4 translocation, and siRNA-mediated knockdown of Myo1c inhibits insulin-stimulated 2-deoxyglucose uptake.","method":"Subcellular fractionation/vesicle purification, dominant-negative overexpression, siRNA knockdown, glucose uptake assay, colocalization imaging in adipocytes","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (purification, DN, siRNA, functional assay), foundational paper with 219 citations","pmids":["12490950"],"is_preprint":false},{"year":2004,"finding":"Myo1c promotes membrane fusion of GLUT4-containing vesicles with the plasma membrane in adipocytes; enhanced Myo1c expression overrides PI3K inhibitor-induced block of membrane fusion and causes membrane ruffling that mobilizes GLUT4 vesicles to the cell surface.","method":"Overexpression in 3T3-L1 adipocytes with PI3K inhibitor LY294002, ultrafast microscopy of GLUT4-GFP vesicle dynamics","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — live-cell imaging combined with pharmacological and genetic manipulation, replicated in same cellular system as PMID:12490950","pmids":["15169906"],"is_preprint":false},{"year":2007,"finding":"RalA interacts directly with Myo1c and functions as a cargo receptor for the Myo1c motor during insulin-stimulated GLUT4 trafficking; calmodulin, acting as Myo1c light chain, modulates the RalA–Myo1c interaction. RalA also links the exocyst complex to GLUT4 vesicle tethering at the plasma membrane.","method":"Co-immunoprecipitation, dominant-negative and siRNA knockdown of RalA, glucose transport assay in adipocytes","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus functional siRNA rescue, strong citation count (171)","pmids":["17765682"],"is_preprint":false},{"year":2006,"finding":"Myo1c interacts with NEMO/IKK-γ and is required for insulin-dependent trafficking of NEMO to membrane ruffles, where NEMO interacts with IRS-1; this Myo1c–NEMO axis is essential for TNF-α-induced serine-307 phosphorylation of IRS-1 and the resulting insulin resistance.","method":"Co-immunoprecipitation, dominant-negative Myo1c cargo domain overexpression, siRNA knockdown, immunofluorescence, phospho-IRS-1 immunoblotting","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods establishing pathway position and mechanism","pmids":["16754954"],"is_preprint":false},{"year":2008,"finding":"CaMKIIδ phosphorylates Myo1c at serine 701 in response to insulin, leading to enhanced 14-3-3 binding and reduced calmodulin binding; phosphorylation increases Myo1c ATPase activity in vitro, and the phosphorylation-mimetic but not S701A or ATPase-dead (K111A) Myo1c rescues GLUT4 translocation after siRNA knockdown of endogenous Myo1c.","method":"In vitro CaMKII phosphorylation assay, siRNA knockdown of CaMKIIδ, mutagenesis (S701A, K111A), ATPase activity assay, GLUT4 translocation assay","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1 — in vitro kinase assay + mutagenesis + in vivo rescue, multiple orthogonal methods","pmids":["19046570"],"is_preprint":false},{"year":2008,"finding":"Rictor forms a biochemically distinct complex with Myo1c in adipocytes (separate from mTORC2); this Rictor–Myo1c complex participates in cortical actin remodeling and paxillin tyrosine-118 phosphorylation, and Myo1c-induced membrane ruffling is compromised after Rictor knockdown.","method":"Co-immunoprecipitation distinct from mTOR complex, RNAi depletion of Rictor and Myo1c, paxillin phosphorylation immunoblotting, morphological analysis of membrane ruffles","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP distinguishing from known complex, functional RNAi phenotype with defined readout","pmids":["18426911"],"is_preprint":false},{"year":2007,"finding":"Calcium binding to regulatory-domain-associated calmodulin regulates myo1c motor activity: calcium moderately increases actin-activated ATPase but completely inhibits actin gliding; calmodulin dissociates most rapidly from IQ1 (adjacent to motor domain) in the presence of calcium (rate 60 s⁻¹), limited by a slow calcium-induced conformational change (3 s⁻¹), making IQ1-bound calmodulin the primary site of calcium regulation.","method":"Actin gliding assay, ATPase measurements, stopped-flow fluorescence kinetics, fluorescence anisotropy with labeled calmodulin mutant N111C, peptide binding assays","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro biochemical assays with multiple orthogonal kinetic methods","pmids":["17910470"],"is_preprint":false},{"year":2007,"finding":"CIB1 and CaBP1 bind to the myo1c IQ motifs in the regulatory domain, compete with calmodulin for binding (more effectively in the presence of calcium), and colocalize with endogenous myo1c in cells; these myristoylated calcium-binding proteins may specify myo1c subcellular targeting.","method":"Pull-down experiments, fluorescence microscopy colocalization, competitive binding assays with calmodulin","journal":"Journal of muscle research and cell motility","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, pull-down plus colocalization without full functional rescue","pmids":["17994197"],"is_preprint":false},{"year":2010,"finding":"Expression of wild-type Myo1c in mouse tibialis anterior muscle in vivo significantly increases both contraction-stimulated and insulin-stimulated glucose uptake, whereas expression of the ATPase-dead mutant K111A-Myo1c decreases both, demonstrating that Myo1c motor activity is required for glucose uptake in skeletal muscle.","method":"In vivo electroporation of wild-type and K111A mutant Myo1c into mouse tibialis anterior, in vivo glucose uptake assay after contraction and insulin injection","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — in vivo mutagenesis rescue experiment with quantitative functional readout","pmids":["21127070"],"is_preprint":false},{"year":2011,"finding":"Myo1c directly interacts with the podocyte slit diaphragm protein Neph1 in an actin-dependent manner and mediates Neph1 transport to the podocyte cell membrane; dominant-negative Myo1c or Myo1c depletion significantly reduces Neph1 membrane localization and impairs tight junction formation and cell migration.","method":"In vitro and in vivo co-immunoprecipitation, dominant-negative Myo1c overexpression, siRNA knockdown, transepithelial electric resistance, BSA permeability assay, wound migration assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, dominant-negative and KD with multiple defined functional readouts","pmids":["21402783"],"is_preprint":false},{"year":2011,"finding":"A hearing-loss-associated myo1c point mutation R156W (in switch 1 region) decreases the actin-activated ATPase rate >4-fold (likely by reducing phosphate release), reduces the duty ratio, and renders actin gliding less sensitive to resisting forces in a frictional loading assay, without affecting ATP binding or ADP release rates substantially.","method":"Transient kinetic ATPase analysis at 37°C, in vitro motility assay at multiple myosin densities, frictional loading assay using recombinant myo1c(3IQ) and R156W-myo1c(3IQ)","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — rigorous in vitro reconstitution and mutagenesis with multiple kinetic methods","pmids":["21265502"],"is_preprint":false},{"year":2012,"finding":"Myo1c is a lipid-raft-associated motor protein that drives formation of recycling tubules from the perinuclear recycling compartment, selectively promoting recycling of GPI-linked raft cargo (but not transferrin receptor) back to the cell surface via an Arf6-dependent pathway; loss of Myo1c traps GPI-linked proteins in the recycling compartment and impairs cell spreading, migration, and Salmonella invasion.","method":"RNAi knockdown, dominant-negative overexpression, live-cell imaging of recycling tubules, biochemical lipid raft fractionation, Salmonella invasion assay, wound healing/migration assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, selective cargo specificity demonstrated, functional consequences in multiple assays","pmids":["22328521"],"is_preprint":false},{"year":2012,"finding":"Myo1c associates with both mobile and tethered GLUT4 vesicles in the TIRF zone beneath the plasma membrane of muscle cells; Myo1c knockdown or overexpression of an actin-binding-deficient mutant abolishes insulin-induced vesicle immobilization and increases vesicle velocity, preventing GLUT4 externalization. Interaction of vesicular Myo1c with cortical actin filaments is required for insulin-mediated tethering of GLUT4 vesicles.","method":"TIRF microscopy of GLUT4-GFP vesicle dynamics, siRNA knockdown, actin-binding-deficient mutant overexpression, single-vesicle tracking, GLUT4 surface exposure assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — live TIRF imaging with quantitative vesicle tracking plus genetic manipulations","pmids":["22918957"],"is_preprint":false},{"year":2012,"finding":"Myo1c identifies G-actin as a cargo via its tail domain and transports G-actin (actin monomers) vectorially to the leading edge of migrating endothelial cells; the motor domain is required for transport. Local microinjection of Myo1c promotes G-actin accumulation and membrane ruffling, and Myo1c knockdown reduces G-actin delivery to the leading edge and impairs cell motility.","method":"Mass spectrometric identification of G-actin as Myo1c tail interactor, photoactivatable non-polymerizable actin tracking in live cells, Myo1c microinjection, siRNA knockdown with motility readout","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — MS identification of cargo + live-cell vectorial transport tracking + functional knockdown","pmids":["22778278"],"is_preprint":false},{"year":2012,"finding":"Myo1c is required for VEGFR2 delivery to the endothelial cell plasma membrane in response to VEGF; Myo1c depletion increases VEGFR2 lysosomal degradation, reduces VEGFR2 phosphorylation at Y1175, and attenuates ERK1/2 and c-Src activation, leading to reduced cell proliferation and migration. VEGFR2 colocalizes with Myo1c and caveolin-1 in response to VEGF.","method":"siRNA knockdown in primary human endothelial cells, surface VEGFR2 measurement, subcellular density-gradient fractionation, phospho-VEGFR2/ERK/Src immunoblotting, rescue with WT vs mutant Myo1c","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 2 — KD plus WT/mutant rescue, multiple downstream signaling readouts","pmids":["23262137"],"is_preprint":false},{"year":2013,"finding":"Myo1c is required for normal zebrafish glomerular development; morpholino knockdown of Myo1c in zebrafish causes pericardial edema, dilated renal tubules, abnormal podocyte morphology, and absence of the slit diaphragm, which is rescued by co-injection of mouse Myo1c mRNA.","method":"Antisense morpholino knockdown in zebrafish, immunofluorescence, in situ hybridization, electron microscopy, mRNA rescue experiment","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 — morpholino KD with morphological rescue by orthologous mRNA, ultrastructural analysis","pmids":["23715127"],"is_preprint":false},{"year":2014,"finding":"Loss of functional MYO1C disrupts autophagosome–lysosome fusion: MYO1C depletion causes accumulation of cholesterol-enriched membranes, increases total cellular cholesterol, and blocks autophagic cargo degradation without affecting endocytic cargo (EGFR) degradation or lysosomal pH/hydrolase activity, indicating that correct lipid (cholesterol) composition governed by MYO1C is required for autophagosome–lysosome fusion.","method":"siRNA and dominant-negative knockdown, transmission electron microscopy, immunofluorescence for LC3/LAMP1, EGFR degradation assay, lysosomal activity assay, cholesterol quantification","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal assays demonstrating selective pathway block with mechanistic specificity","pmids":["25551774"],"is_preprint":false},{"year":2010,"finding":"Three hearing-loss-associated missense mutations in the Myo1c motor domain (R156W, V252A, T380M) differentially affect nucleotide binding and actin interactions: R156W disrupts the nucleotide-binding pocket and calcium binding by disrupting switch 1; V252A reduces actin affinity by disrupting communication between actin- and nucleotide-binding sites; T380M causes aberrant kinetic changes and uncoupling of ATPase from motility.","method":"Transient kinetic analyses, steady-state ATPase assay, in vitro motility assay, homology modeling with truncated Myo1c(1IQ-SAH) construct","journal":"Cellular and molecular life sciences","confidence":"High","confidence_rationale":"Tier 1 — in vitro biochemical reconstitution with mutagenesis across multiple kinetic parameters","pmids":["20640478"],"is_preprint":false},{"year":2004,"finding":"Nuclear myosin I (NMI/Myo1c isoform with 16-aa N-terminal extension) is associated with rDNA and is required for RNA polymerase I transcription; antibody microinjection or siRNA depletion of NMI decreases Pol I transcription, overexpression augments pre-rRNA synthesis, and in vitro recombinant NMI activates Pol I transcription. NMI binds Pol I through the transcription initiation factor TIF-IA, requiring phosphorylation of TIF-IA at Ser649 by RSK kinase.","method":"Antibody microinjection, siRNA depletion, overexpression, in vitro Pol I transcription assay on naked DNA and chromatin, co-immunoprecipitation of NMI with TIF-IA/Pol I, kinase dependency assay","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution assay, antibody inhibition, siRNA, OE all converge; 327 citations","pmids":["15558034"],"is_preprint":false},{"year":2000,"finding":"A nuclear isoform of myosin I beta (Myo1c) containing a unique 16-amino acid N-terminal extension is identified; it colocalizes with RNA polymerase II in an alpha-amanitin- and actinomycin D-sensitive manner, co-immunoprecipitates RNA polymerase II, and antibody against the 16-aa extension blocks in vitro RNA synthesis.","method":"Affinity-purified antibody to 16-aa peptide, confocal and electron microscopy, co-immunoprecipitation, in vitro RNA synthesis inhibition assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — nuclear isoform identification with co-IP and functional in vitro inhibition, foundational paper (197 citations)","pmids":["11030652"],"is_preprint":false},{"year":2008,"finding":"Myosin I (myo1c) acts as a molecular force sensor: single-molecule optical trap measurements show that the rate of myo1c detachment from actin decreases >75-fold under tension of ≤2 pN, causing myo1c to transition from a low duty-ratio (<0.2) to a high duty-ratio (>0.9) motor, supporting its role in tension-sensitive membrane and cytoskeletal processes.","method":"Single-molecule optical trap assay measuring displacement and actin-attachment kinetics under varying loads","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — single-molecule biophysical reconstitution with quantitative force-kinetics measurement; 192 citations","pmids":["18599791"],"is_preprint":false},{"year":2016,"finding":"The structural solution conformation of full-length Myo1c bound to its cargo protein Neph1 was determined by small-angle X-ray scattering, revealing an extended S-shaped Myo1c with Neph1 attached to the C-terminal tail without inducing significant conformational change in Myo1c. A critical Neph1 residue at the interaction surface was identified; point mutation at this site abolished Myo1c–Neph1 interaction in vitro and in live cells, and FRAP confirmed Myo1c-dependent vesicular movement of Neph1.","method":"Small-angle X-ray scattering (SAXS) structural modeling, point mutagenesis, in vitro binding assay, live-cell FRAP imaging","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — SAXS structure plus mutagenesis validation plus live-cell functional imaging","pmids":["27044863"],"is_preprint":false},{"year":2017,"finding":"The MYO1C gene produces three alternatively spliced isoforms differing only in N-terminal regions (NTRs); full-length kinetic analysis shows MYO1Cc favors the actomyosin closed state (AMC), MYO1C16 populates AMC and AMO equally, and MYO1C35 favors the actomyosin open (AMO) state. The NTR35 residue Arg-21 engages Glu-469 in the post-relay helix, affecting power stroke mechanics; an R21G mutation abolishes MYO1C35-like kinetics, and adding NTR35 peptide to MYO1Cc transiently confers MYO1C35 behavior.","method":"Overexpression and purification of three full-length isoforms from HEK cells, transient kinetics, global numerical simulation, homology modeling, NTR peptide addition experiments, mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — purified full-length protein kinetics with mutagenesis and peptide competition, mechanistically rigorous","pmids":["28893906"],"is_preprint":false},{"year":2019,"finding":"MYO1C depletion causes Golgi complex fragmentation and decompaction and loss of cellular F-actin; MYO1C accumulates at dynamic Golgi-associated actin dots and stabilizes actin at the Golgi, facilitating the arrival of both anterograde and retrograde transport carriers. This function is phenotypically similar to loss of the Arp2/3 complex.","method":"siRNA depletion, live-cell imaging of Golgi-associated structures, F-actin quantification, transport carrier arrival assay (anterograde and retrograde routes)","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — KD with multiple functional readouts and pathway comparison to Arp2/3","pmids":["30872458"],"is_preprint":false},{"year":2019,"finding":"Podocyte-specific Myo1c knockout mice are resistant to fibrotic injury (Adriamycin, nephrotoxic serum, unilateral ureteral obstruction); loss of Myo1c blunts canonical and non-canonical TGF-β signaling. Nuclear Myo1c directly binds the GDF-15 promoter and transcriptionally regulates this TGF-β-responsive gene, and GDF15 is upregulated in FSGS patient glomeruli.","method":"Conditional (podocyte-specific) Myo1c knockout mouse models, multiple injury paradigms, ChIP for nuclear Myo1c at GDF-15 promoter, differential gene expression analysis of nuclear Myo1c-associated promoters, TGF-β pathway immunoblotting","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with multiple disease models, ChIP evidence for direct promoter binding","pmids":["31097328"],"is_preprint":false},{"year":2019,"finding":"Cepharanthine downregulates MYO1C, which in turn disrupts MYO1C/F-actin interaction with autophagic markers LC3 and LAMP1, blocking autophagosome–lysosome fusion; overexpression of MYO1C restores this colocalization. MYO1C promotes autophagosome–lysosome fusion through F-actin network remodeling.","method":"Co-immunoprecipitation of MYO1C with LC3/LAMP1, siRNA knockdown and overexpression, immunofluorescence colocalization, transmission electron microscopy","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, co-IP plus imaging, mechanistic follow-up of prior findings","pmids":["31699152"],"is_preprint":false},{"year":2021,"finding":"Systemic MYO1C knockout mice show progressive loss of photoreceptor function; MYO1C localizes to photoreceptor inner and outer segments and directly interacts with rhodopsin (binding assay); in Myo1c-KO retinas, rhodopsin mislocalizes to rod inner segments and cell bodies, demonstrating MYO1C is required for rhodopsin transport to the outer segment.","method":"Myo1c knockout mice, electroretinogram analysis, immunohistochemistry, direct rhodopsin–MYO1C binding assay, ultrastructural examination","journal":"Cells","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with direct binding assay and defined mislocalization phenotype","pmids":["34073294"],"is_preprint":false},{"year":2016,"finding":"Myo1c interacts with SHIP2 and filamin A in glioblastoma cells; Myo1c depletion impairs SHIP2 localization at lamellipodia, causes cells to cluster, reduces FAK Tyr397 phosphorylation, decreases focal adhesion length, and strongly reduces cell migration, demonstrating Myo1c is required for lamellipodia formation and a SHIP2-containing migration complex.","method":"Co-immunoprecipitation identifying Myo1c–SHIP2–filamin A complex, siRNA knockdown, immunofluorescence of lamellipodia, FAK phosphorylation immunoblotting, migration assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, co-IP plus functional KD with defined signaling readout","pmids":["27246739"],"is_preprint":false},{"year":2016,"finding":"Lowered MYO1C expression in endometrial carcinoma cells stimulates cell proliferation, suppresses cell adhesion, and accelerates AKT phosphorylation in response to serum; conversely, MYO1C overexpression reduces basal pAKT, suggesting MYO1C suppresses the PI3K/AKT pathway.","method":"siRNA knockdown and overexpression in endometrial carcinoma cell lines, proliferation assay, adhesion assay, pAKT immunoblotting after serum stimulation","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, functional KD/OE with defined signaling readout but limited mechanistic depth","pmids":["27716847"],"is_preprint":false},{"year":2005,"finding":"Myo1c expressed in M1 mouse collecting duct cells localizes to discrete plasma membrane domains; expression of full-length or truncated (dominant-negative, lacking ATPase/actin domains) Myo1c modulates antidiuretic hormone (ADH)-stimulated short-circuit current and reduces amiloride-sensitive Na+ channel activity; the IQ region is required for proper Myo1c targeting.","method":"Overexpression of WT and truncated Myo1c in M1 cells, electrophysiological short-circuit current measurements, EGFP-Myo1c targeting analysis","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2/3 — functional electrophysiology with defined IQ-region targeting requirement, single lab","pmids":["15716323"],"is_preprint":false},{"year":2024,"finding":"Liraglutide directly binds Myo1c at arginine 93, stabilizing Myo1c and enhancing the Myo1c/Dock5 interaction; this promotes Dock5-dependent keratinocyte proliferation, migration, and adhesion to accelerate diabetic wound healing. Keratinocyte-specific Dock5 knockout abrogates liraglutide's wound-healing effect.","method":"Molecular binding assay (liraglutide–Myo1c at R93), co-immunoprecipitation of Myo1c/Dock5, keratinocyte-specific Dock5 knockout mouse, wound closure assay in db/db and STZ diabetic mice","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — binding site identified, KO mouse with functional readout, single lab","pmids":["39159301"],"is_preprint":false},{"year":2024,"finding":"RNF41 E3 ubiquitin ligase induces non-canonical K27- and K63-linked polyubiquitination of MYO1C to enhance its stability (rather than degradation), promoting actin remodeling and prostate cancer bone metastasis; inhibition of RNF41 reduces MYO1C levels and suppresses PCa metastasis in an intraarterial bone-metastasis xenograft model.","method":"Co-immunoprecipitation, ubiquitination assay defining K27/K63 linkage, RNF41 siRNA knockdown, in vivo bone-metastasis xenograft model, MYO1C rescue","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — ubiquitin linkage biochemistry plus in vivo model, single lab","pmids":["39112516"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of actin-bound myo1c in the presence and absence of ADP reveal a unique actin interface that reorients the motor domain compared with myo1b/other myosins, skewing the lever arm swing and explaining why myo1c propels actin in leftward circles. The N-terminal extension plays a unique role in force sensing. The structures explain why force primarily regulates ATP binding (not ADP release) in myo1c, and enable modeling of full-length myo1c during force generation.","method":"Cryo-EM structure determination of actin-bound myo1c ± ADP, integration with crystallography structures for full-length modeling","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 1 — high-resolution cryo-EM with structural and mechanistic interpretation, preprint but mechanistically novel","pmids":["bio_10.1101_2025.01.10.632429"],"is_preprint":true},{"year":2025,"finding":"Nuclear Myo1c (NM1) positively regulates ERα clustering on enhancers and promotes condensate formation on chromatin genome-wide; NM1 depletion causes a genome-wide reduction in ERα occupancy and condensates, though estrogen-regulated gene expression remains largely robust, revealing a role for Myo1c in transcription factor clustering without strictly controlling transcriptional output.","method":"ChIP-seq for ERα occupancy, super-resolution/condensate imaging, NM1 depletion by siRNA, genome-wide analysis in estrogen-stimulated cells","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide ChIP-seq with functional depletion, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.01.29.635522"],"is_preprint":true},{"year":2025,"finding":"Chlamydia trachomatis recruits MYO1C to its intracellular inclusion throughout its lifecycle; loss or inhibition of MYO1C activity reduces Ct infection and progeny production. In vitro reconstitution showed that purified MYO1C alone is necessary and sufficient to build an actin cage around giant membranous vesicles, functioning as a dynamic tether that assembles the actin cage around the inclusion membrane.","method":"Immunofluorescence of Ct-infected cells, MYO1C inhibition (pentachloropseudilin), siRNA depletion, in vitro reconstitution assay with purified MYO1C and giant membranous vesicles","journal":"Microbiological research","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with purified protein demonstrating sufficiency, combined with cell-based loss-of-function","pmids":["41242206"],"is_preprint":false},{"year":2007,"finding":"Emerin directly binds nuclear myosin I (NMI/Myo1c) in vitro; bead-conjugated emerin affinity-purifies NMI from HeLa nuclear lysates, and this interaction is stable regardless of ATP (motor activity), placing NMI in a distinct emerin-containing complex at the nuclear envelope separate from gene-regulatory complexes.","method":"Recombinant bead affinity purification from HeLa nuclear lysates, in vitro direct binding assay, ATP-independence test, mass spectrometry identification","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct in vitro binding plus co-purification from cells, single lab","pmids":["17620012"],"is_preprint":false},{"year":2025,"finding":"MYO1C interacts with Jagged1 (Notch ligand) under static conditions in endothelial cells, as confirmed by coimmunoprecipitation; shear stress reduces this interaction. Myo1c knockout inhibits Jagged1 polarization downstream of shear and its nucleograde transport, while Myo1c knockdown reduces membrane levels of Jagged1 under static but not shear conditions, revealing a role for Myo1c in hemodynamic control of Jagged1 localization.","method":"Jagged1-APEX2 proximity labeling, co-immunoprecipitation, Myo1c knockout/knockdown, orbital shaker shear stress platform, confocal imaging of Jagged1 localization","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 — proximity labeling + co-IP + KO with defined trafficking phenotype, single lab","pmids":["41321631"],"is_preprint":false}],"current_model":"MYO1C is an actin-based unconventional class-I myosin motor that functions as a molecular force sensor (transitioning to high duty-ratio under ≥2 pN tension) and operates through three alternatively spliced isoforms with distinct kinetic properties determined by N-terminal extensions; in the cytoplasm it transports GLUT4-containing vesicles to the plasma membrane via a PI3K-independent, CaMKII-phosphorylation (S701)-regulated mechanism involving RalA as cargo receptor and calmodulin as light chain, tethers vesicles to cortical actin for fusion, recycles lipid-raft/GPI-linked cargo from the perinuclear compartment to the cell surface, mediates autophagosome–lysosome fusion through F-actin remodeling, transports slit-diaphragm proteins Neph1/nephrin and rhodopsin to their membrane destinations, and facilitates G-actin delivery to the leading edge; a nuclear isoform (NM1, bearing a 16-aa N-terminal extension) binds RNA Pol I via TIF-IA and RNA Pol II to activate transcription, stabilizes Golgi-associated actin, and regulates ERα enhancer clustering, while cryo-EM structures reveal a unique actin interface and skewed lever-arm trajectory that explain its leftward actin-gliding path and force sensing through ATP-binding rather than ADP-release."},"narrative":{"teleology":[{"year":2000,"claim":"The discovery of a nuclear Myo1c isoform (NM1) bearing a unique 16-amino-acid N-terminal extension, co-immunoprecipitating RNA polymerase II and blocking in vitro RNA synthesis, established for the first time that an unconventional myosin operates in the nucleus during transcription.","evidence":"Isoform-specific antibody, confocal/EM colocalization, co-IP of Pol II, in vitro transcription inhibition in mammalian cells","pmids":["11030652"],"confidence":"High","gaps":["No direct evidence for NM1-specific gene targets at this stage","Mechanism linking motor activity to transcription unknown"]},{"year":2002,"claim":"Identification of MYO1C on purified GLUT4 vesicles and demonstration that dominant-negative cargo domain and siRNA knockdown block insulin-stimulated GLUT4 translocation and glucose uptake answered how insulin mobilizes GLUT4 independently of PI3K, establishing MYO1C as the motor for this trafficking step.","evidence":"Vesicle purification, dominant-negative overexpression, siRNA knockdown, glucose uptake assay in 3T3-L1 adipocytes","pmids":["12490950"],"confidence":"High","gaps":["Cargo receptor linking MYO1C to GLUT4 vesicle unknown","Upstream signaling events activating MYO1C unresolved"]},{"year":2004,"claim":"NM1 was shown to be essential for RNA polymerase I transcription at rDNA via direct binding to TIF-IA (requiring RSK-mediated S649 phosphorylation), extending the nuclear role of MYO1C from Pol II association to a defined mechanism in ribosomal RNA synthesis.","evidence":"Antibody microinjection, siRNA, overexpression, in vitro Pol I transcription on chromatin templates, co-IP of NMI–TIF-IA–Pol I","pmids":["15558034"],"confidence":"High","gaps":["Whether NM1 plays a catalytic versus structural role in Pol I complex assembly unknown","No genome-wide assessment of NM1-dependent loci"]},{"year":2007,"claim":"Discovery that RalA acts as the cargo receptor linking MYO1C to GLUT4 vesicles—modulated by calmodulin—and simultaneously connects the exocyst for vesicle tethering resolved the missing cargo-recognition step in insulin-stimulated GLUT4 trafficking.","evidence":"Reciprocal co-IP, siRNA and dominant-negative RalA, glucose transport assay in adipocytes","pmids":["17765682"],"confidence":"High","gaps":["Structural basis of RalA–MYO1C interaction unresolved","Whether calmodulin dissociation is the switch for RalA engagement unclear"]},{"year":2007,"claim":"Reconstituted kinetic studies showed that calcium binding to IQ1-associated calmodulin regulates MYO1C motor activity—moderately stimulating ATPase but completely inhibiting actin gliding—establishing the primary regulatory site and mechanism for calcium-dependent control of the motor.","evidence":"In vitro ATPase, actin gliding, stopped-flow fluorescence with labeled calmodulin, peptide binding assays","pmids":["17910470"],"confidence":"High","gaps":["In vivo relevance of calcium-induced calmodulin dissociation from IQ1 not directly tested","Role of alternative light chains (CIB1, CaBP1) in modulating this regulation unclear"]},{"year":2008,"claim":"Single-molecule optical trapping revealed that MYO1C undergoes a dramatic load-dependent transition from low (<0.2) to high (>0.9) duty ratio at ≥2 pN tension, establishing it as a bona fide molecular force sensor—a property that explains its roles in membrane tethering and tension-dependent processes.","evidence":"Single-molecule optical trap measuring displacement and detachment kinetics under controlled loads","pmids":["18599791"],"confidence":"High","gaps":["Structural basis for force-dependent detachment slowing unknown at this time","How force sensing integrates with cargo-specific functions in cells not addressed"]},{"year":2008,"claim":"Identification of CaMKIIδ-mediated phosphorylation of MYO1C at S701 as the insulin-responsive switch—enhancing ATPase activity, promoting 14-3-3 binding, reducing calmodulin binding, and being required for GLUT4 translocation—connected upstream insulin signaling to motor activation.","evidence":"In vitro kinase assay, S701A/K111A mutagenesis, siRNA rescue, GLUT4 translocation assay in adipocytes","pmids":["19046570"],"confidence":"High","gaps":["How 14-3-3 binding alters MYO1C localization or interaction with RalA not defined","Whether S701 phosphorylation regulates non-GLUT4 cargoes unknown"]},{"year":2010,"claim":"Hearing-loss-associated motor-domain mutations (R156W, V252A, T380M) were shown to differentially impair ATPase kinetics, actin affinity, and motility, linking specific mechanochemical defects to human disease and validating the kinetic cycle as a drug/mutation target.","evidence":"Transient kinetic analyses, steady-state ATPase, in vitro motility with purified mutant proteins","pmids":["20640478","21265502"],"confidence":"High","gaps":["No in vivo confirmation that these mutations cause hearing loss via MYO1C loss-of-function","Structural explanation for switch-1 disruption by R156W not yet available"]},{"year":2012,"claim":"A series of studies expanded MYO1C's cargo repertoire beyond GLUT4: it was shown to tether GLUT4 vesicles to cortical actin via TIRF imaging, selectively recycle GPI-anchored/lipid-raft cargo from the perinuclear compartment, transport Neph1 to the podocyte membrane, deliver G-actin monomers to the leading edge, and traffic VEGFR2 to the endothelial surface—establishing MYO1C as a general membrane-cargo transporter with selectivity for specific membrane domains.","evidence":"TIRF single-vesicle tracking, siRNA and dominant-negative studies, raft fractionation, mass spectrometry cargo identification, photoactivatable actin tracking, VEGFR2 surface assays in multiple cell types","pmids":["22918957","22328521","21402783","22778278","23262137"],"confidence":"High","gaps":["Whether all cargoes use the same tail-domain binding surface unclear","Mechanisms selecting which cargo is loaded at a given time unknown"]},{"year":2013,"claim":"Zebrafish morpholino knockdown of Myo1c causing pericardial edema, dilated tubules, and absent slit diaphragm—rescued by mouse Myo1c mRNA—demonstrated an essential in vivo requirement for MYO1C in glomerular development and podocyte integrity.","evidence":"Morpholino knockdown in zebrafish, electron microscopy, mRNA rescue","pmids":["23715127"],"confidence":"High","gaps":["Whether MYO1C loss causes kidney disease in mammals not yet shown at this point","Cargo(s) responsible for slit-diaphragm defect not identified in this model"]},{"year":2014,"claim":"MYO1C depletion was shown to block autophagosome–lysosome fusion selectively (without affecting endocytic degradation or lysosomal activity) by causing cholesterol-enriched membrane accumulation, revealing a lipid-homeostasis-dependent mechanism by which MYO1C supports autophagy.","evidence":"siRNA/dominant-negative knockdown, TEM, LC3/LAMP1 colocalization, EGFR degradation control, cholesterol quantification","pmids":["25551774"],"confidence":"High","gaps":["Whether MYO1C directly transports cholesterol or indirectly regulates its distribution unclear","Actin remodeling contribution versus lipid redistribution not fully dissected"]},{"year":2017,"claim":"Full-length kinetic characterization of the three MYO1C splice isoforms revealed that N-terminal extensions allosterically shift the actomyosin equilibrium between open and closed states—mediated by a specific Arg-21/Glu-469 salt bridge in the NTR35 isoform—explaining how a single gene produces motors with distinct force-generating properties.","evidence":"Purified full-length isoform kinetics from HEK cells, global numerical simulation, R21G mutagenesis, NTR peptide addition","pmids":["28893906"],"confidence":"High","gaps":["Isoform-specific cargo assignments not established","Tissue-specific expression ratios of isoforms not systematically mapped"]},{"year":2019,"claim":"Two studies revealed MYO1C's roles beyond vesicle transport: it stabilizes Golgi-associated actin required for both anterograde and retrograde carrier arrival (phenocopying Arp2/3 loss), and podocyte-specific knockout in mice conferred resistance to fibrotic kidney injury by blunting TGF-β signaling, with nuclear MYO1C directly binding the GDF-15 promoter.","evidence":"siRNA with Golgi transport assays and F-actin quantification; conditional KO mice with multiple injury models, ChIP at GDF-15 promoter","pmids":["30872458","31097328"],"confidence":"High","gaps":["Whether Golgi actin stabilization requires MYO1C motor activity or passive tethering not tested","Genome-wide map of nuclear MYO1C promoter occupancy incomplete"]},{"year":2021,"claim":"Systemic Myo1c knockout mice exhibited progressive photoreceptor degeneration with rhodopsin mislocalization to inner segments, and direct MYO1C–rhodopsin binding was demonstrated, extending MYO1C's cargo transport function to sensory neurons.","evidence":"Myo1c KO mice, electroretinography, immunohistochemistry, direct binding assay","pmids":["34073294"],"confidence":"High","gaps":["Whether MYO1C transports rhodopsin via the connecting cilium or an alternative route unknown","Other visual-cycle cargoes of MYO1C not explored"]},{"year":2024,"claim":"Non-canonical K27/K63-linked polyubiquitination of MYO1C by RNF41 was found to stabilize (rather than degrade) MYO1C, promoting actin remodeling and prostate cancer bone metastasis, identifying a post-translational mechanism controlling MYO1C protein levels.","evidence":"Ubiquitination assay defining linkage type, RNF41 knockdown, in vivo bone-metastasis xenograft, MYO1C rescue","pmids":["39112516"],"confidence":"Medium","gaps":["Deubiquitinase counteracting RNF41 not identified","Whether K27/K63-Ub stabilization operates in non-cancer contexts unknown"]},{"year":2025,"claim":"Cryo-EM structures of actin-bound MYO1C ± ADP revealed a unique actin interface that reorients the motor domain relative to other myosin-I family members, skewing the lever-arm swing to explain leftward actin gliding; the N-terminal extension was shown to participate in force sensing through regulation of ATP binding rather than ADP release.","evidence":"Cryo-EM structure determination of actomyosin-MYO1C ± ADP, integration with crystallography for full-length modeling (preprint)","pmids":["bio_10.1101_2025.01.10.632429"],"confidence":"High","gaps":["Structures not yet peer-reviewed","No structure with cargo bound to the tail domain","How NTR isoform differences alter the actin interface is not resolved structurally"]},{"year":2025,"claim":"MYO1C was shown to interact with the Notch ligand Jagged1 and to be required for its polarized trafficking under static conditions, with shear stress reducing the MYO1C–Jagged1 interaction, and separately, purified MYO1C was demonstrated sufficient to assemble an actin cage around giant membranes in vitro, explaining how Chlamydia exploits MYO1C for inclusion integrity.","evidence":"Proximity labeling + co-IP + KO with shear-stress platform for Jagged1; in vitro reconstitution of actin cage assembly with purified MYO1C for Chlamydia inclusion","pmids":["41321631","41242206"],"confidence":"High","gaps":["Whether Jagged1 transport uses the same tail-domain surface as Neph1/rhodopsin not tested","In vitro actin cage assembly conditions may not recapitulate physiological membrane composition"]},{"year":null,"claim":"Key unresolved questions include: how isoform-specific cargoes are assigned in vivo; the full structural basis of tail-domain cargo recognition; whether nuclear MYO1C transcriptional functions require motor activity or tension; and how force sensing integrates with specific trafficking decisions at the single-molecule level inside cells.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No atomic-resolution structure of MYO1C tail bound to any cargo","Isoform-specific knockout models not yet reported","Single-molecule force measurements inside living cells not achieved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[0,1,8,10,12,20,22,32]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[4,10,20,22]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[12,13,23,34]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[11,16]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[18,19,24]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,9,11,12,14,29]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,1,2,12]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[18,19,24,33,35]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[5,13,23,34]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[13,27]}],"pathway":[{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,1,2,4,8,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,14,28]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[18,19,24]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[16,25]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[8,29]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[9,11,14,26]}],"complexes":[],"partners":["RALA","CALM1","IKBKG","RPTOR","KIRREL1","RHO","FLNA","EMD"],"other_free_text":[]},"mechanistic_narrative":"MYO1C is an actin-based unconventional class-I myosin motor that functions as a force-sensitive molecular tether and cargo transporter across diverse membrane trafficking, transcriptional, and cytoskeletal processes. In the cytoplasm, MYO1C drives insulin-stimulated GLUT4 vesicle translocation and tethering to cortical actin at the plasma membrane through a PI3K-independent pathway regulated by CaMKIIδ phosphorylation at S701, with RalA serving as the vesicular cargo receptor and calmodulin as the regulatory light chain [PMID:12490950, PMID:19046570, PMID:17765682, PMID:22918957]; it additionally transports specific membrane cargoes—including Neph1, nephrin, rhodopsin, VEGFR2, Jagged1, and GPI-anchored proteins—to their surface destinations, stabilizes Golgi-associated actin for vesicle carrier arrival, delivers G-actin monomers to the leading edge of migrating cells, and promotes autophagosome–lysosome fusion through F-actin remodeling [PMID:21402783, PMID:34073294, PMID:23262137, PMID:22328521, PMID:22778278, PMID:30872458, PMID:25551774]. A nuclear isoform (NM1, bearing a 16-amino-acid N-terminal extension) associates with RNA polymerases I and II, activates rDNA transcription via TIF-IA, binds gene promoters such as GDF-15, and regulates ERα enhancer clustering, while single-molecule biophysics reveals that tension of ≥2 pN converts MYO1C from a low- to a high-duty-ratio motor by slowing actin detachment, and cryo-EM structures show a unique actin interface and skewed lever-arm trajectory that explain its leftward gliding path and force-sensing through ATP binding rather than ADP release [PMID:15558034, PMID:11030652, PMID:31097328, PMID:18599791, PMID:28893906]."},"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. Unconventional myosins serve in intracellular movements. Their highly divergent tails are presumed to bind to membranous compartments, which would be moved relative to actin filaments. Involved in glucose transporter recycling in response to insulin by regulating movement of intracellular GLUT4-containing vesicles to the plasma membrane. Component of the hair cell's (the sensory cells of the inner ear) adaptation-motor complex. Acts as a mediator of adaptation of mechanoelectrical transduction in stereocilia of vestibular hair cells. Binds phosphoinositides and links the actin cytoskeleton to cellular membranes Involved in regulation of transcription. Associated with transcriptional active ribosomal genes. Appears to cooperate with the WICH chromatin-remodeling complex to facilitate transcription. Necessary for the formation of the first phosphodiester bond during transcription initiation","subcellular_location":"Nucleus, nucleoplasm; Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/O00159/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYO1C","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000197879","cell_line_id":"CID001441","localizations":[{"compartment":"membrane","grade":3},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"CALD1","stoichiometry":0.2},{"gene":"CALM1","stoichiometry":0.2},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"COMMD2","stoichiometry":0.2},{"gene":"CTTN","stoichiometry":0.2},{"gene":"FXR1","stoichiometry":0.2},{"gene":"MYO1B","stoichiometry":0.2},{"gene":"CALM2;CALM3;CALM1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001441","total_profiled":1310},"omim":[{"mim_id":"618303","title":"CAVEOLAE-ASSOCIATED PROTEIN 3; CAVIN3","url":"https://www.omim.org/entry/618303"},{"mim_id":"616998","title":"LLP HOMOLOG, LONG-TERM SYNAPTIC FACILITATION FACTOR; LLPH","url":"https://www.omim.org/entry/616998"},{"mim_id":"613215","title":"CHROMOSOME 17p13.3, CENTROMERIC, DUPLICATION SYNDROME","url":"https://www.omim.org/entry/613215"},{"mim_id":"611622","title":"IQ MOTIF-CONTAINING PROTEIN J; IQCJ","url":"https://www.omim.org/entry/611622"},{"mim_id":"607432","title":"LISSENCEPHALY 1; LIS1","url":"https://www.omim.org/entry/607432"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nuclear bodies","reliability":"Enhanced"},{"location":"Plasma membrane","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MYO1C"},"hgnc":{"alias_symbol":["myr2","NMI","MyoIC"],"prev_symbol":[]},"alphafold":{"accession":"O00159","domains":[{"cath_id":"1.20.58.530","chopping":"455-593","consensus_level":"high","plddt":83.7147,"start":455,"end":593},{"cath_id":"3.30.70.1590","chopping":"670-765","consensus_level":"high","plddt":89.9842,"start":670,"end":765},{"cath_id":"-","chopping":"813-863","consensus_level":"high","plddt":81.0808,"start":813,"end":863},{"cath_id":"2.30.29.30","chopping":"867-899_909-1058","consensus_level":"high","plddt":83.2842,"start":867,"end":1058}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00159","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00159-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00159-F1-predicted_aligned_error_v6.png","plddt_mean":84.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYO1C","jax_strain_url":"https://www.jax.org/strain/search?query=MYO1C"},"sequence":{"accession":"O00159","fasta_url":"https://rest.uniprot.org/uniprotkb/O00159.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00159/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00159"}},"corpus_meta":[{"pmid":"9989503","id":"PMC_9989503","title":"Functional association of Nmi with Stat5 and Stat1 in IL-2- and IFNgamma-mediated signaling.","date":"1999","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9989503","citation_count":251,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12490950","id":"PMC_12490950","title":"Glucose transporter recycling in response to insulin is facilitated by myosin Myo1c.","date":"2002","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12490950","citation_count":219,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17765682","id":"PMC_17765682","title":"Activation of RalA is required for insulin-stimulated Glut4 trafficking to the plasma membrane via the exocyst and the motor protein Myo1c.","date":"2007","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/17765682","citation_count":171,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15169906","id":"PMC_15169906","title":"Unconventional myosin Myo1c promotes membrane fusion in a regulated exocytic 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novel partner of Myc proteins.","date":"1996","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/8668343","citation_count":93,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22328521","id":"PMC_22328521","title":"Myo1c regulates lipid raft recycling to control cell spreading, migration and Salmonella invasion.","date":"2012","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/22328521","citation_count":77,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29038465","id":"PMC_29038465","title":"NMI and IFP35 serve as proinflammatory DAMPs during cellular infection and injury.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/29038465","citation_count":76,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21402783","id":"PMC_21402783","title":"Motor protein Myo1c is a podocyte protein that facilitates the transport of slit diaphragm protein Neph1 to the podocyte membrane.","date":"2011","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21402783","citation_count":76,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25551774","id":"PMC_25551774","title":"Loss of functional MYO1C/myosin 1c, a motor protein involved in lipid raft trafficking, disrupts autophagosome-lysosome fusion.","date":"2014","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/25551774","citation_count":65,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"19358268","id":"PMC_19358268","title":"Nmi (N-Myc interactor) inhibits Wnt/beta-catenin signaling and retards tumor growth.","date":"2009","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19358268","citation_count":64,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22918957","id":"PMC_22918957","title":"Myo1c binding to submembrane actin mediates insulin-induced tethering of GLUT4 vesicles.","date":"2012","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/22918957","citation_count":63,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16754954","id":"PMC_16754954","title":"Myosin motor Myo1c and its receptor NEMO/IKK-gamma promote TNF-alpha-induced serine307 phosphorylation of IRS-1.","date":"2006","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16754954","citation_count":57,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18426911","id":"PMC_18426911","title":"A Rictor-Myo1c complex participates in dynamic cortical actin events in 3T3-L1 adipocytes.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18426911","citation_count":55,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23956435","id":"PMC_23956435","title":"Negative regulation of Nmi on virus-triggered type I IFN production by targeting 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myo1c mutation (R156W) decreases the myosin duty ratio and force sensitivity.","date":"2011","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21265502","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9781816","id":"PMC_9781816","title":"Interferon-induced upregulation and cytoplasmic localization of Myc-interacting protein Nmi.","date":"1998","source":"Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/9781816","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36513634","id":"PMC_36513634","title":"SMOC2 promotes aggressive behavior of fibroblast-like synoviocytes in rheumatoid arthritis through transcriptional and post-transcriptional regulating MYO1C.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36513634","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21255164","id":"PMC_21255164","title":"The Arabidopsis Myb genes MYR1 and MYR2 are redundant negative regulators of flowering time under decreased light intensity.","date":"2011","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/21255164","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22974759","id":"PMC_22974759","title":"A critical role of N-myc and STAT interactor (Nmi) in foot-and-mouth disease virus (FMDV) 2C-induced apoptosis.","date":"2012","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/22974759","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10597290","id":"PMC_10597290","title":"Nmi protein interacts with regions that differ between MycN and Myc and is localized in the cytoplasm of neuroblastoma cells in 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multiple orthogonal methods (vesicle purification, dominant-negative, siRNA) in a foundational paper, widely replicated\",\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 with the plasma membrane; enhanced Myo1c expression overrides PI3K inhibitor-induced block in membrane fusion, restoring GLUT4 surface display; Myo1c accumulates at regions of membrane ruffling where GLUT4 vesicles fuse.\",\n      \"method\": \"PI3K inhibitor treatment, Myo1c overexpression, ultrafast microscopy of GLUT4 vesicle dynamics in 3T3-L1 adipocytes\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods including live imaging and functional rescue, consistent with foundational work\",\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 serves as the light chain for Myo1c; RalA also signals through the exocyst to target GLUT4 vesicles to the plasma membrane.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative mutants, siRNA knockdown, glucose transport assay in adipocytes\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, dominant-negative, siRNA with functional readout; replicated across multiple experiments\",\n      \"pmids\": [\"17765682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Myo1c undergoes insulin-dependent phosphorylation at S701 by CaMKIIdelta; phosphorylation enhances 14-3-3 binding and reduces calmodulin binding; CaMKII phosphorylation increases Myo1c ATPase activity in vitro; the S701A phospho-dead mutant and ATPase-dead K111A mutant fail to rescue GLUT4 translocation after Myo1c knockdown.\",\n      \"method\": \"In vitro kinase assay, siRNA knockdown of CaMKIIdelta, CaMKII inhibitors, Co-IP for 14-3-3 and calmodulin, ATPase assay, GLUT4 translocation rescue\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay plus mutagenesis plus multiple cellular readouts\",\n      \"pmids\": [\"19046570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Myo1c forms a complex with Rictor that is biochemically distinct from mTORC2; this Rictor-Myo1c complex regulates cortical actin remodeling and paxillin phosphorylation at Y118; Rictor knockdown impairs Myo1c-induced membrane ruffling.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, paxillin Y118 phosphorylation assay, membrane ruffling assay in 3T3-L1 adipocytes\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, multiple siRNA knockdowns with defined phenotypic readouts\",\n      \"pmids\": [\"18426911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Myo1c interacts with NEMO/IKK-gamma; Myo1c motor activity is required for NEMO trafficking to membrane ruffles and for subsequent NEMO-IRS-1 interaction; increased Myo1c expression enhances TNF-alpha-induced IRS-1 Ser307 phosphorylation, while dominant-negative Myo1c cargo domain inhibits this phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative overexpression, siRNA knockdown, phosphorylation assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, dominant-negative and siRNA with specific phosphorylation readout\",\n      \"pmids\": [\"16754954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Myo1c promotes both insulin-stimulated and contraction-stimulated glucose uptake in skeletal muscle in vivo; expression of ATPase-dead K111A-Myo1c decreases both, indicating that Myo1c motor activity is required.\",\n      \"method\": \"In vivo electroporation of wild-type and K111A mutant Myo1c into mouse tibialis anterior, in vivo glucose uptake assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mutagenesis with functional ATPase-dead construct and defined glucose uptake readout\",\n      \"pmids\": [\"21127070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Myo1c directly interacts with the slit diaphragm protein Neph1 in an actin-dependent manner; dominant-negative Myo1c and Myo1c depletion reduce Neph1 localization at the podocyte cell membrane and cell junctions; Myo1c also binds nephrin and reduces its membrane localization; Myo1c knockdown impairs cell migration and tight junction formation.\",\n      \"method\": \"Co-IP, pulldown, dominant-negative overexpression, siRNA knockdown, live-cell imaging, wound assay, TER and BSA permeability assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including Co-IP, dominant-negative, siRNA with defined cellular phenotypes\",\n      \"pmids\": [\"21402783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Myo1c is a lipid-raft-associated motor protein that drives formation of recycling tubules from the perinuclear recycling compartment; it specifically promotes recycling of GPI-linked lipid-raft cargo to the cell surface via an Arf6-dependent pathway, but is not required for transferrin receptor recycling; Myo1c loss impairs cell spreading, migration, and cholesterol-dependent Salmonella invasion.\",\n      \"method\": \"RNAi knockdown, dominant-negative overexpression, live-cell imaging, cholesterol/GPI-cargo trafficking assays, Salmonella invasion assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods with pathway specificity demonstrated by selective cargo effects\",\n      \"pmids\": [\"22328521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Myo1c interaction with submembrane actin filaments is required for insulin-induced tethering of GLUT4 vesicles beneath the plasma membrane in muscle cells; an actin-binding-deficient Myo1c mutant abolishes vesicle immobilization and prevents GLUT4 externalization; Myo1c overexpression immobilizes GLUT4 vesicles in the TIRF zone and promotes GLUT4 surface delivery.\",\n      \"method\": \"TIRF microscopy, siRNA knockdown, actin-binding mutant overexpression, GLUT4 surface exposure assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — live TIRF imaging with mutagenesis and siRNA, multiple orthogonal readouts\",\n      \"pmids\": [\"22918957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Myo1c facilitates vectorial transport of G-actin (monomeric actin) to the leading edge of migrating endothelial cells; the cargo-binding tail domain of Myo1c interacts with G-actin and the motor domain is required for transport; Myo1c knockdown reduces G-actin delivery and cell motility.\",\n      \"method\": \"Photoactivatable actin tracking, mass spectrometry identification, Co-IP/pulldown, microinjection, siRNA knockdown, motility assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — live-cell actin tracking with mass spectrometry and functional knockdown, multiple orthogonal methods\",\n      \"pmids\": [\"22778278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Myo1c interacts with VEGFR2 and caveolin-1 in response to VEGF stimulation; Myo1c is required for delivery of VEGFR2 to the plasma membrane; Myo1c depletion increases VEGFR2 lysosomal degradation and reduces VEGF-induced VEGFR2 phosphorylation at Y1175 and downstream ERK1/2 and c-Src activation, leading to reduced cell proliferation and migration.\",\n      \"method\": \"Subcellular density gradient fractionation, Co-IP, siRNA knockdown, surface receptor assay, phosphorylation assay, cell proliferation and migration assays\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods linking Myo1c to receptor trafficking and downstream signaling\",\n      \"pmids\": [\"23262137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of functional MYO1C disrupts autophagosome-lysosome fusion, causing accumulation of autophagic structures and defects in autophagic cargo degradation; MYO1C loss increases total cellular cholesterol and redistributes cholesterol-enriched membranes; endocytic EGFR degradation is unaffected, indicating pathway selectivity.\",\n      \"method\": \"RNAi knockdown, dominant-negative overexpression, electron microscopy, autophagy flux assays, cholesterol staining\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAi and dominant-negative with ultrastructural analysis and selective pathway controls\",\n      \"pmids\": [\"25551774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Calcium regulates calmodulin binding to myo1c IQ motifs; in the absence of calcium, calmodulin binds most tightly to IQ1 (adjacent to motor domain, dissociation rate 0.0007 s-1) and most loosely to IQ3 (0.5 s-1); calcium causes rapid calmodulin dissociation from IQ1 (60 s-1) limited by a slow conformational change (3 s-1); calcium moderately increases actin-activated ATPase but completely inhibits actin gliding, which is restored by exogenous calmodulin.\",\n      \"method\": \"Stopped-flow fluorescence kinetics, ATPase assay, actin gliding assay, fluorescence anisotropy\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with multiple quantitative biochemical assays\",\n      \"pmids\": [\"17910470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CIB1 and CaBP1 are myristoylated proteins that bind to the myo1c IQ motifs in the regulatory domain, competing with calmodulin; CaBP1 has higher affinity than CIB1; both preferentially displace calmodulin in the presence of calcium; both proteins colocalize with myo1c in cells.\",\n      \"method\": \"Pulldown, co-immunoprecipitation, fluorescence colocalization, calmodulin competition assay\",\n      \"journal\": \"Journal of muscle research and cell motility\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pulldown and co-IP with colocalization, single lab\",\n      \"pmids\": [\"17994197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The myo1c R156W hearing-loss mutation (near switch 1) decreases the duty ratio more than 4-fold by reducing phosphate release rate; mutant myo1c has reduced force sensitivity in a frictional loading assay; actin gliding rate is unaffected at high motor densities but substantially reduced at low surface densities.\",\n      \"method\": \"Recombinant protein expression, ATPase assay, in vitro motility assay, frictional loading assay, stopped-flow kinetics\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with site-specific mutant, multiple kinetic and motility measurements\",\n      \"pmids\": [\"21265502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Myo1c hearing-loss mutations R156W, V252A, and T380M in the motor domain affect distinct aspects of the ATPase cycle: R156W disrupts nucleotide binding and calcium-induced switch 1 movement; V252A reduces actin affinity and disrupts actin-nucleotide site communication; T380M shows uncoupling of ATPase from motility.\",\n      \"method\": \"Transient kinetic analyses, steady-state ATPase assay, in vitro motility assay, homology modeling\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with multiple mutants and kinetic characterization\",\n      \"pmids\": [\"20640478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Myo1c is concentrated at or near the plasma membrane in collecting duct cells; expression of full-length Myo1c or a truncated dominant-negative form modulates ADH-stimulated short-circuit current and amiloride-sensitive sodium transport; the IQ region of Myo1c is important for its correct subcellular targeting.\",\n      \"method\": \"Electrophysiology (short-circuit current), overexpression of wild-type and truncated Myo1c, EGFP-Myo1c localization imaging\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — electrophysiology with defined mutant constructs, single lab with moderate mechanistic detail\",\n      \"pmids\": [\"15716323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Myo1c directly interacts with Neph1 through the C-terminal tail; SAXS structural modeling reveals full-length Myo1c adopts an extended S-shaped conformation with Neph1 attached to its C-terminal tail without inducing a significant shape change; a point mutation in the Neph1 interaction surface abolishes binding in vitro and in live cells; FRAP demonstrates Myo1c-dependent intracellular vesicular movement and membrane turnover of Neph1.\",\n      \"method\": \"Small angle X-ray scattering (SAXS), site-directed mutagenesis, in vitro binding assay, live-cell Co-IP, FRAP\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural determination by SAXS combined with mutagenesis and live-cell imaging validation\",\n      \"pmids\": [\"27044863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The three alternatively spliced MYO1C isoforms (MYO1CC, MYO1C16, MYO1C35) differ in kinetic properties: MYO1CC favors the actomyosin closed state, MYO1C35 favors the open state, and MYO1C16 populates both equally; MYO1C35 residue Arg-21 in the N-terminal extension engages with post-relay helix residue Glu-469 to affect the power stroke mechanics; adding NTR35 peptide to MYO1CC transiently confers MYO1C35-like kinetics.\",\n      \"method\": \"Purified recombinant full-length isoforms from HEK cells, ATPase assays, stopped-flow kinetics, global numerical simulation, homology modeling, peptide addition experiment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with purified full-length isoforms, mutagenesis, and global kinetic simulation\",\n      \"pmids\": [\"28893906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MYO1C depletion induces Golgi complex fragmentation and decompaction; MYO1C accumulates at dynamic Golgi-associated actin dots and stabilizes actin at the Golgi; loss of MYO1C delays arrival of incoming transport carriers from both anterograde and retrograde routes at the Golgi.\",\n      \"method\": \"siRNA knockdown, live-cell imaging, Golgi morphology assays, transport carrier arrival assay in human cell lines\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — siRNA with live imaging, multiple transport routes tested, mechanistic link to actin stabilization\",\n      \"pmids\": [\"30872458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nuclear Myo1c (rather than cytoplasmic Myo1c) directly binds the GDF-15 gene promoter and regulates TGF-β-responsive gene expression; podocyte-specific Myo1c knockout mice are resistant to fibrotic injury (Adriamycin, nephrotoxic serum, UUO models); loss of Myo1c downregulates canonical and non-canonical TGF-β signaling pathways.\",\n      \"method\": \"Podocyte-specific KO mice, ChIP (Myo1c binding to GDF-15 promoter), multiple fibrosis models, transcriptional analysis\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with ChIP and multiple in vivo models\",\n      \"pmids\": [\"31097328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MYO1C interacts with F-actin and colocalizes with LC3 and LAMP1; cepharanthine-induced MYO1C downregulation blocks autophagosome-lysosome fusion by disrupting the F-actin network; MYO1C knockdown decreases MYO1C/F-actin colocalization with LC3 and LAMP1, while MYO1C overexpression restores these interactions and autophagosome-lysosome fusion.\",\n      \"method\": \"Co-IP, immunofluorescence colocalization, siRNA knockdown, MYO1C overexpression, autophagy flux assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and functional rescue in cancer cells, single lab\",\n      \"pmids\": [\"31699152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Myo1c interacts with SHIP2 and filamin A at lamellipodia; Myo1c depletion impairs SHIP2 localization to lamellipodia and ruffles, reduces FAK Y397 phosphorylation, decreases PI(4,5)P2 immunostaining, and markedly reduces cell migration in glioblastoma cells.\",\n      \"method\": \"Co-IP (identifying SHIP2/Myo1c/filamin A complex), siRNA knockdown, FAK phosphorylation assay, PI(4,5)P2 staining, migration assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and siRNA with functional readouts, single lab\",\n      \"pmids\": [\"27246739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss of MYO1C in mice causes progressive mislocalization of rhodopsin to photoreceptor inner segments and cell bodies instead of the outer segment; binding assays demonstrate a direct interaction between rhodopsin and MYO1C; MYO1C localizes to photoreceptor inner and outer segments; Myo1c-KO mice show progressive loss of photoreceptor function by electroretinogram.\",\n      \"method\": \"Myo1c knockout mice, electroretinography, immunohistochemistry, direct binding assay, ultrastructural examination\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with direct binding assay and functional (ERG) readout\",\n      \"pmids\": [\"34073294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Myo1c is required for zebrafish glomerular development; morpholino knockdown causes pericardial edema, dilated renal tubules, abnormal podocyte morphology, and absence of the slit diaphragm; rescue with mouse Myo1c mRNA restores normal morphology, confirming specificity.\",\n      \"method\": \"Morpholino knockdown in zebrafish, ultrastructural analysis, RNA rescue experiment\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — morpholino KD with mRNA rescue and ultrastructural phenotype in vertebrate model\",\n      \"pmids\": [\"23715127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Liraglutide directly binds to Myo1c at arginine 93, stabilizing Myo1c protein; stabilized Myo1c enhances its interaction with Dock5 by targeting the Dock5 promoter; the Myo1c/Dock5 axis promotes proliferation, migration, and adhesion of keratinocytes; keratinocyte-specific Dock5 knockout abolishes liraglutide-induced wound healing improvement.\",\n      \"method\": \"Binding assay (identifying liraglutide-Myo1c interaction at R93), Co-IP (Myo1c/Dock5), keratinocyte-specific KO mice, diabetic wound healing model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding assay plus conditional KO, but single lab and novel claim\",\n      \"pmids\": [\"39159301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RNF41 induces K27- and K63-linked non-canonical polyubiquitination of MYO1C to enhance its stability; stabilized MYO1C promotes actin remodeling and prostate cancer bone metastasis; RNF41 inhibition reduces MYO1C stability and suppresses metastasis in an intraarterial bone metastasis xenograft model.\",\n      \"method\": \"Ubiquitination assay (K27/K63 linkage typing), Co-IP, siRNA knockdown, overexpression, in vivo xenograft bone metastasis model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination assay with linkage specificity plus in vivo model, single lab\",\n      \"pmids\": [\"39112516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of actin-bound myo1c in the presence and absence of ADP reveal a unique actin interface that reorients the motor domain and produces a skewed lever arm swing; the N-terminal extension plays a unique role in force sensing by regulating ATP binding rather than ADP release; full-length atomic model of myo1c power stroke was constructed.\",\n      \"method\": \"Cryo-EM structure determination, comparison with crystallography structures, full-length modeling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM structures with mechanistic interpretation, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.01.10.632429\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nuclear Myo1c (NM1/Myo1c) promotes estrogen receptor-alpha (ERα) clustering on enhancers and condensate formation on chromatin; NM1 depletion leads to genome-wide reduction in ERα occupancy and condensates, though estrogen-regulated gene expression remains largely robust.\",\n      \"method\": \"ChIP-seq, NM1 depletion, ERα occupancy genome-wide analysis, condensate imaging\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq with functional depletion, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.01.29.635522\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Myo1c is recruited by Chlamydia trachomatis to the bacterial inclusion throughout its life cycle; MYO1C functions as a dynamic tether that assembles an actin cage around the inclusion membrane; in vitro reconstitution with purified MYO1C was necessary and sufficient to build an actin cage around giant membranous vesicles; loss of MYO1C reduces Ct infection and progeny production.\",\n      \"method\": \"Immunofluorescence, siRNA/inhibitor (pentachloropseudilin) knockdown, in vitro reconstitution with purified MYO1C and giant vesicles\",\n      \"journal\": \"Microbiological research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with purified protein plus cellular knockdown with functional readout\",\n      \"pmids\": [\"41242206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Myo1c interacts with the Notch ligand Jagged1 under static conditions (confirmed by Co-IP with Jagged1-APEX2 proximity labeling and co-immunoprecipitation); this interaction is reduced after shear stress exposure; Myo1c knockout inhibits Jagged1 polarization downstream of shear and nuclear transport; Myo1c knockdown reduces membrane levels of Jagged1 under static but not shear conditions.\",\n      \"method\": \"Proximity labeling (APEX2), co-immunoprecipitation, Myo1c knockout, Jagged1 localization imaging under shear stress\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proximity labeling confirmed by Co-IP, KO with defined localization phenotype, single lab\",\n      \"pmids\": [\"41321631\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYO1C is an actin-based unconventional class I myosin motor that tethers intracellular vesicles (including GLUT4, Neph1, VEGFR2, and rhodopsin) to cortical actin filaments and drives their delivery to the plasma membrane; its ATPase motor activity is regulated by calmodulin binding to IQ motifs (calcium-dependent) and by CaMKII-mediated phosphorylation at S701 (enhancing 14-3-3 binding and motor activity); it facilitates lipid raft recycling, Golgi-associated actin stabilization, autophagosome-lysosome fusion, and G-actin transport to the leading edge; a nuclear isoform directly binds gene promoters (e.g., GDF-15) to regulate transcription; cryo-EM structures reveal a unique actin interface and skewed lever arm swing that explains its leftward actin-gliding path and force sensing primarily through ATP binding isomerization rather than ADP release.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nPapers about NMI/N-Myc interactor (a different gene, not MYO1C): Papers [1],[5],[7],[9],[12],[16],[17],[19],[25],[28],[29],[30],[32],[35],[38],[39],[40],[42],[43],[44],[48],[49],[63],[64],[65],[66],[69],[70],[72],[74],[75],[76],[78],[81],[82],[87],[88],[89],[94],[95],[96],[97],[98],[99],[100] — EXCLUDE (alias collision: \"NMI\" = N-Myc Interactor, not MYO1C)\n\nPaper [23] — circMYO1C (circRNA from MYO1C locus) — EXCLUDE (alt-locus product, case B)\n\nPapers [27],[59],[68] — Arabidopsis MYR1/MYR2 — EXCLUDE (plant symbol collision)\n\nPapers [2],[3],[4],[6],[8],[10],[11],[13],[14],[15],[18],[20],[21],[24],[31],[33],[34],[36],[37],[45],[46],[47],[50],[51],[52],[53],[54],[55],[56],[57 - fish Nmi, not MYO1C],[60],[61],[62],[71],[77],[79],[80],[83],[84],[85],[86],[90],[91],[92],[93] — evaluate for MYO1C KEEP/EXCLUDE\n\nLarge-scale proteomics/interactome papers (gene2pubmed additional): [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[19],[20],[21],[22],[23],[24],[25],[26],[29],[30] from additional list — mostly large-scale datasets; [18],[27],[28] contain MYO1C-relevant mechanistic content — KEEP where mechanistic.\n\nLet me now identify KEEP papers about canonical MYO1C protein:\n\n**KEEP:** [2],[3],[4],[6],[8],[10],[11],[13],[14],[15],[18],[20],[21],[24],[31],[33],[34],[36],[37],[45],[46],[47],[50],[51],[52],[53],[54],[55],[56],[60],[61],[62],[71],[77],[79],[80],[83],[84],[85],[86],[90],[91],[92],[93] from main corpus; Additional [18],[27],[28] from gene2pubmed.\n\nPaper [57] is about fish Nmi protein (N-myc interactor in fish), not MYO1C — EXCLUDE.\nPaper [22] miR-137 targeting MYO1C — mentioned but no mechanistic detail about MYO1C function itself — EXCLUDE (expression correlation).\nPaper [26] SMOC2/MYO1C in RA — mentions MYO1C regulation but primarily about SMOC2 — borderline; includes MYO1C-dependent migration mechanism — KEEP.\nPaper [41] tumor suppressor candidate — expression analysis — EXCLUDE.\nPaper [46] masseter muscle expression — correlation study — EXCLUDE.\nPaper [52] AKT/PI3K — has functional KD data — KEEP.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"Myo1c is present in GLUT4-containing vesicles purified from 3T3-L1 adipocytes and functions in a PI(3)K-independent insulin signaling pathway that controls movement of intracellular GLUT4-vesicles to the plasma membrane; dominant-negative Myo1c cargo domain inhibits insulin-stimulated GLUT4 translocation, and siRNA-mediated knockdown of Myo1c inhibits insulin-stimulated 2-deoxyglucose uptake.\",\n      \"method\": \"Subcellular fractionation/vesicle purification, dominant-negative overexpression, siRNA knockdown, glucose uptake assay, colocalization imaging in adipocytes\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (purification, DN, siRNA, functional assay), foundational paper with 219 citations\",\n      \"pmids\": [\"12490950\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Myo1c promotes membrane fusion of GLUT4-containing vesicles with the plasma membrane in adipocytes; enhanced Myo1c expression overrides PI3K inhibitor-induced block of membrane fusion and causes membrane ruffling that mobilizes GLUT4 vesicles to the cell surface.\",\n      \"method\": \"Overexpression in 3T3-L1 adipocytes with PI3K inhibitor LY294002, ultrafast microscopy of GLUT4-GFP vesicle dynamics\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — live-cell imaging combined with pharmacological and genetic manipulation, replicated in same cellular system as PMID:12490950\",\n      \"pmids\": [\"15169906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RalA interacts directly with Myo1c and functions as a cargo receptor for the Myo1c motor during insulin-stimulated GLUT4 trafficking; calmodulin, acting as Myo1c light chain, modulates the RalA–Myo1c interaction. RalA also links the exocyst complex to GLUT4 vesicle tethering at the plasma membrane.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative and siRNA knockdown of RalA, glucose transport assay in adipocytes\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus functional siRNA rescue, strong citation count (171)\",\n      \"pmids\": [\"17765682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Myo1c interacts with NEMO/IKK-γ and is required for insulin-dependent trafficking of NEMO to membrane ruffles, where NEMO interacts with IRS-1; this Myo1c–NEMO axis is essential for TNF-α-induced serine-307 phosphorylation of IRS-1 and the resulting insulin resistance.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative Myo1c cargo domain overexpression, siRNA knockdown, immunofluorescence, phospho-IRS-1 immunoblotting\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods establishing pathway position and mechanism\",\n      \"pmids\": [\"16754954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"CaMKIIδ phosphorylates Myo1c at serine 701 in response to insulin, leading to enhanced 14-3-3 binding and reduced calmodulin binding; phosphorylation increases Myo1c ATPase activity in vitro, and the phosphorylation-mimetic but not S701A or ATPase-dead (K111A) Myo1c rescues GLUT4 translocation after siRNA knockdown of endogenous Myo1c.\",\n      \"method\": \"In vitro CaMKII phosphorylation assay, siRNA knockdown of CaMKIIδ, mutagenesis (S701A, K111A), ATPase activity assay, GLUT4 translocation assay\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay + mutagenesis + in vivo 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 in adipocytes (separate from mTORC2); this Rictor–Myo1c complex participates in cortical actin remodeling and paxillin tyrosine-118 phosphorylation, and Myo1c-induced membrane ruffling is compromised after Rictor knockdown.\",\n      \"method\": \"Co-immunoprecipitation distinct from mTOR complex, RNAi depletion of Rictor and Myo1c, paxillin phosphorylation immunoblotting, morphological analysis of membrane ruffles\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP distinguishing from known complex, functional RNAi phenotype with defined readout\",\n      \"pmids\": [\"18426911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Calcium binding to regulatory-domain-associated calmodulin regulates myo1c motor activity: calcium moderately increases actin-activated ATPase but completely inhibits actin gliding; calmodulin dissociates most rapidly from IQ1 (adjacent to motor domain) in the presence of calcium (rate 60 s⁻¹), limited by a slow calcium-induced conformational change (3 s⁻¹), making IQ1-bound calmodulin the primary site of calcium regulation.\",\n      \"method\": \"Actin gliding assay, ATPase measurements, stopped-flow fluorescence kinetics, fluorescence anisotropy with labeled calmodulin mutant N111C, peptide binding assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro biochemical assays with multiple orthogonal kinetic methods\",\n      \"pmids\": [\"17910470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CIB1 and CaBP1 bind to the myo1c IQ motifs in the regulatory domain, compete with calmodulin for binding (more effectively in the presence of calcium), and colocalize with endogenous myo1c in cells; these myristoylated calcium-binding proteins may specify myo1c subcellular targeting.\",\n      \"method\": \"Pull-down experiments, fluorescence microscopy colocalization, competitive binding assays with calmodulin\",\n      \"journal\": \"Journal of muscle research and cell motility\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, pull-down plus colocalization without full functional rescue\",\n      \"pmids\": [\"17994197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Expression of wild-type Myo1c in mouse tibialis anterior muscle in vivo significantly increases both contraction-stimulated and insulin-stimulated glucose uptake, whereas expression of the ATPase-dead mutant K111A-Myo1c decreases both, demonstrating that Myo1c motor activity is required for glucose uptake in skeletal muscle.\",\n      \"method\": \"In vivo electroporation of wild-type and K111A mutant Myo1c into mouse tibialis anterior, in vivo glucose uptake assay after contraction and insulin injection\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mutagenesis rescue experiment with quantitative functional readout\",\n      \"pmids\": [\"21127070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Myo1c directly interacts with the podocyte slit diaphragm protein Neph1 in an actin-dependent manner and mediates Neph1 transport to the podocyte cell membrane; dominant-negative Myo1c or Myo1c depletion significantly reduces Neph1 membrane localization and impairs tight junction formation and cell migration.\",\n      \"method\": \"In vitro and in vivo co-immunoprecipitation, dominant-negative Myo1c overexpression, siRNA knockdown, transepithelial electric resistance, BSA permeability assay, wound migration assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, dominant-negative and KD with multiple defined functional readouts\",\n      \"pmids\": [\"21402783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A hearing-loss-associated myo1c point mutation R156W (in switch 1 region) decreases the actin-activated ATPase rate >4-fold (likely by reducing phosphate release), reduces the duty ratio, and renders actin gliding less sensitive to resisting forces in a frictional loading assay, without affecting ATP binding or ADP release rates substantially.\",\n      \"method\": \"Transient kinetic ATPase analysis at 37°C, in vitro motility assay at multiple myosin densities, frictional loading assay using recombinant myo1c(3IQ) and R156W-myo1c(3IQ)\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — rigorous in vitro reconstitution and mutagenesis with multiple kinetic methods\",\n      \"pmids\": [\"21265502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Myo1c is a lipid-raft-associated motor protein that drives formation of recycling tubules from the perinuclear recycling compartment, selectively promoting recycling of GPI-linked raft cargo (but not transferrin receptor) back to the cell surface via an Arf6-dependent pathway; loss of Myo1c traps GPI-linked proteins in the recycling compartment and impairs cell spreading, migration, and Salmonella invasion.\",\n      \"method\": \"RNAi knockdown, dominant-negative overexpression, live-cell imaging of recycling tubules, biochemical lipid raft fractionation, Salmonella invasion assay, wound healing/migration assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, selective cargo specificity demonstrated, functional consequences in multiple assays\",\n      \"pmids\": [\"22328521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Myo1c associates with both mobile and tethered GLUT4 vesicles in the TIRF zone beneath the plasma membrane of muscle cells; Myo1c knockdown or overexpression of an actin-binding-deficient mutant abolishes insulin-induced vesicle immobilization and increases vesicle velocity, preventing GLUT4 externalization. Interaction of vesicular Myo1c with cortical actin filaments is required for insulin-mediated tethering of GLUT4 vesicles.\",\n      \"method\": \"TIRF microscopy of GLUT4-GFP vesicle dynamics, siRNA knockdown, actin-binding-deficient mutant overexpression, single-vesicle tracking, GLUT4 surface exposure assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — live TIRF imaging with quantitative vesicle tracking plus genetic manipulations\",\n      \"pmids\": [\"22918957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Myo1c identifies G-actin as a cargo via its tail domain and transports G-actin (actin monomers) vectorially to the leading edge of migrating endothelial cells; the motor domain is required for transport. Local microinjection of Myo1c promotes G-actin accumulation and membrane ruffling, and Myo1c knockdown reduces G-actin delivery to the leading edge and impairs cell motility.\",\n      \"method\": \"Mass spectrometric identification of G-actin as Myo1c tail interactor, photoactivatable non-polymerizable actin tracking in live cells, Myo1c microinjection, siRNA knockdown with motility readout\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS identification of cargo + live-cell vectorial transport tracking + functional knockdown\",\n      \"pmids\": [\"22778278\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Myo1c is required for VEGFR2 delivery to the endothelial cell plasma membrane in response to VEGF; Myo1c depletion increases VEGFR2 lysosomal degradation, reduces VEGFR2 phosphorylation at Y1175, and attenuates ERK1/2 and c-Src activation, leading to reduced cell proliferation and migration. VEGFR2 colocalizes with Myo1c and caveolin-1 in response to VEGF.\",\n      \"method\": \"siRNA knockdown in primary human endothelial cells, surface VEGFR2 measurement, subcellular density-gradient fractionation, phospho-VEGFR2/ERK/Src immunoblotting, rescue with WT vs mutant Myo1c\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KD plus WT/mutant rescue, multiple downstream signaling readouts\",\n      \"pmids\": [\"23262137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Myo1c is required for normal zebrafish glomerular development; morpholino knockdown of Myo1c in zebrafish causes pericardial edema, dilated renal tubules, abnormal podocyte morphology, and absence of the slit diaphragm, which is rescued by co-injection of mouse Myo1c mRNA.\",\n      \"method\": \"Antisense morpholino knockdown in zebrafish, immunofluorescence, in situ hybridization, electron microscopy, mRNA rescue experiment\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — morpholino KD with morphological rescue by orthologous mRNA, ultrastructural analysis\",\n      \"pmids\": [\"23715127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of functional MYO1C disrupts autophagosome–lysosome fusion: MYO1C depletion causes accumulation of cholesterol-enriched membranes, increases total cellular cholesterol, and blocks autophagic cargo degradation without affecting endocytic cargo (EGFR) degradation or lysosomal pH/hydrolase activity, indicating that correct lipid (cholesterol) composition governed by MYO1C is required for autophagosome–lysosome fusion.\",\n      \"method\": \"siRNA and dominant-negative knockdown, transmission electron microscopy, immunofluorescence for LC3/LAMP1, EGFR degradation assay, lysosomal activity assay, cholesterol quantification\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal assays demonstrating selective pathway block with mechanistic specificity\",\n      \"pmids\": [\"25551774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Three hearing-loss-associated missense mutations in the Myo1c motor domain (R156W, V252A, T380M) differentially affect nucleotide binding and actin interactions: R156W disrupts the nucleotide-binding pocket and calcium binding by disrupting switch 1; V252A reduces actin affinity by disrupting communication between actin- and nucleotide-binding sites; T380M causes aberrant kinetic changes and uncoupling of ATPase from motility.\",\n      \"method\": \"Transient kinetic analyses, steady-state ATPase assay, in vitro motility assay, homology modeling with truncated Myo1c(1IQ-SAH) construct\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemical reconstitution with mutagenesis across multiple kinetic parameters\",\n      \"pmids\": [\"20640478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Nuclear myosin I (NMI/Myo1c isoform with 16-aa N-terminal extension) is associated with rDNA and is required for RNA polymerase I transcription; antibody microinjection or siRNA depletion of NMI decreases Pol I transcription, overexpression augments pre-rRNA synthesis, and in vitro recombinant NMI activates Pol I transcription. NMI binds Pol I through the transcription initiation factor TIF-IA, requiring phosphorylation of TIF-IA at Ser649 by RSK kinase.\",\n      \"method\": \"Antibody microinjection, siRNA depletion, overexpression, in vitro Pol I transcription assay on naked DNA and chromatin, co-immunoprecipitation of NMI with TIF-IA/Pol I, kinase dependency assay\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution assay, antibody inhibition, siRNA, OE all converge; 327 citations\",\n      \"pmids\": [\"15558034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"A nuclear isoform of myosin I beta (Myo1c) containing a unique 16-amino acid N-terminal extension is identified; it colocalizes with RNA polymerase II in an alpha-amanitin- and actinomycin D-sensitive manner, co-immunoprecipitates RNA polymerase II, and antibody against the 16-aa extension blocks in vitro RNA synthesis.\",\n      \"method\": \"Affinity-purified antibody to 16-aa peptide, confocal and electron microscopy, co-immunoprecipitation, in vitro RNA synthesis inhibition assay\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — nuclear isoform identification with co-IP and functional in vitro inhibition, foundational paper (197 citations)\",\n      \"pmids\": [\"11030652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Myosin I (myo1c) acts as a molecular force sensor: single-molecule optical trap measurements show that the rate of myo1c detachment from actin decreases >75-fold under tension of ≤2 pN, causing myo1c to transition from a low duty-ratio (<0.2) to a high duty-ratio (>0.9) motor, supporting its role in tension-sensitive membrane and cytoskeletal processes.\",\n      \"method\": \"Single-molecule optical trap assay measuring displacement and actin-attachment kinetics under varying loads\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — single-molecule biophysical reconstitution with quantitative force-kinetics measurement; 192 citations\",\n      \"pmids\": [\"18599791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The structural solution conformation of full-length Myo1c bound to its cargo protein Neph1 was determined by small-angle X-ray scattering, revealing an extended S-shaped Myo1c with Neph1 attached to the C-terminal tail without inducing significant conformational change in Myo1c. A critical Neph1 residue at the interaction surface was identified; point mutation at this site abolished Myo1c–Neph1 interaction in vitro and in live cells, and FRAP confirmed Myo1c-dependent vesicular movement of Neph1.\",\n      \"method\": \"Small-angle X-ray scattering (SAXS) structural modeling, point mutagenesis, in vitro binding assay, live-cell FRAP imaging\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — SAXS structure plus mutagenesis validation plus live-cell functional imaging\",\n      \"pmids\": [\"27044863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The MYO1C gene produces three alternatively spliced isoforms differing only in N-terminal regions (NTRs); full-length kinetic analysis shows MYO1Cc favors the actomyosin closed state (AMC), MYO1C16 populates AMC and AMO equally, and MYO1C35 favors the actomyosin open (AMO) state. The NTR35 residue Arg-21 engages Glu-469 in the post-relay helix, affecting power stroke mechanics; an R21G mutation abolishes MYO1C35-like kinetics, and adding NTR35 peptide to MYO1Cc transiently confers MYO1C35 behavior.\",\n      \"method\": \"Overexpression and purification of three full-length isoforms from HEK cells, transient kinetics, global numerical simulation, homology modeling, NTR peptide addition experiments, mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — purified full-length protein kinetics with mutagenesis and peptide competition, mechanistically rigorous\",\n      \"pmids\": [\"28893906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MYO1C depletion causes Golgi complex fragmentation and decompaction and loss of cellular F-actin; MYO1C accumulates at dynamic Golgi-associated actin dots and stabilizes actin at the Golgi, facilitating the arrival of both anterograde and retrograde transport carriers. This function is phenotypically similar to loss of the Arp2/3 complex.\",\n      \"method\": \"siRNA depletion, live-cell imaging of Golgi-associated structures, F-actin quantification, transport carrier arrival assay (anterograde and retrograde routes)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KD with multiple functional readouts and pathway comparison to Arp2/3\",\n      \"pmids\": [\"30872458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Podocyte-specific Myo1c knockout mice are resistant to fibrotic injury (Adriamycin, nephrotoxic serum, unilateral ureteral obstruction); loss of Myo1c blunts canonical and non-canonical TGF-β signaling. Nuclear Myo1c directly binds the GDF-15 promoter and transcriptionally regulates this TGF-β-responsive gene, and GDF15 is upregulated in FSGS patient glomeruli.\",\n      \"method\": \"Conditional (podocyte-specific) Myo1c knockout mouse models, multiple injury paradigms, ChIP for nuclear Myo1c at GDF-15 promoter, differential gene expression analysis of nuclear Myo1c-associated promoters, TGF-β pathway immunoblotting\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with multiple disease models, ChIP evidence for direct promoter binding\",\n      \"pmids\": [\"31097328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cepharanthine downregulates MYO1C, which in turn disrupts MYO1C/F-actin interaction with autophagic markers LC3 and LAMP1, blocking autophagosome–lysosome fusion; overexpression of MYO1C restores this colocalization. MYO1C promotes autophagosome–lysosome fusion through F-actin network remodeling.\",\n      \"method\": \"Co-immunoprecipitation of MYO1C with LC3/LAMP1, siRNA knockdown and overexpression, immunofluorescence colocalization, transmission electron microscopy\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, co-IP plus imaging, mechanistic follow-up of prior findings\",\n      \"pmids\": [\"31699152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Systemic MYO1C knockout mice show progressive loss of photoreceptor function; MYO1C localizes to photoreceptor inner and outer segments and directly interacts with rhodopsin (binding assay); in Myo1c-KO retinas, rhodopsin mislocalizes to rod inner segments and cell bodies, demonstrating MYO1C is required for rhodopsin transport to the outer segment.\",\n      \"method\": \"Myo1c knockout mice, electroretinogram analysis, immunohistochemistry, direct rhodopsin–MYO1C binding assay, ultrastructural examination\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with direct binding assay and defined mislocalization phenotype\",\n      \"pmids\": [\"34073294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Myo1c interacts with SHIP2 and filamin A in glioblastoma cells; Myo1c depletion impairs SHIP2 localization at lamellipodia, causes cells to cluster, reduces FAK Tyr397 phosphorylation, decreases focal adhesion length, and strongly reduces cell migration, demonstrating Myo1c is required for lamellipodia formation and a SHIP2-containing migration complex.\",\n      \"method\": \"Co-immunoprecipitation identifying Myo1c–SHIP2–filamin A complex, siRNA knockdown, immunofluorescence of lamellipodia, FAK phosphorylation immunoblotting, migration assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, co-IP plus functional KD with defined signaling readout\",\n      \"pmids\": [\"27246739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Lowered MYO1C expression in endometrial carcinoma cells stimulates cell proliferation, suppresses cell adhesion, and accelerates AKT phosphorylation in response to serum; conversely, MYO1C overexpression reduces basal pAKT, suggesting MYO1C suppresses the PI3K/AKT pathway.\",\n      \"method\": \"siRNA knockdown and overexpression in endometrial carcinoma cell lines, proliferation assay, adhesion assay, pAKT immunoblotting after serum stimulation\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, functional KD/OE with defined signaling readout but limited mechanistic depth\",\n      \"pmids\": [\"27716847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Myo1c expressed in M1 mouse collecting duct cells localizes to discrete plasma membrane domains; expression of full-length or truncated (dominant-negative, lacking ATPase/actin domains) Myo1c modulates antidiuretic hormone (ADH)-stimulated short-circuit current and reduces amiloride-sensitive Na+ channel activity; the IQ region is required for proper Myo1c targeting.\",\n      \"method\": \"Overexpression of WT and truncated Myo1c in M1 cells, electrophysiological short-circuit current measurements, EGFP-Myo1c targeting analysis\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — functional electrophysiology with defined IQ-region targeting requirement, single lab\",\n      \"pmids\": [\"15716323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Liraglutide directly binds Myo1c at arginine 93, stabilizing Myo1c and enhancing the Myo1c/Dock5 interaction; this promotes Dock5-dependent keratinocyte proliferation, migration, and adhesion to accelerate diabetic wound healing. Keratinocyte-specific Dock5 knockout abrogates liraglutide's wound-healing effect.\",\n      \"method\": \"Molecular binding assay (liraglutide–Myo1c at R93), co-immunoprecipitation of Myo1c/Dock5, keratinocyte-specific Dock5 knockout mouse, wound closure assay in db/db and STZ diabetic mice\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — binding site identified, KO mouse with functional readout, single lab\",\n      \"pmids\": [\"39159301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RNF41 E3 ubiquitin ligase induces non-canonical K27- and K63-linked polyubiquitination of MYO1C to enhance its stability (rather than degradation), promoting actin remodeling and prostate cancer bone metastasis; inhibition of RNF41 reduces MYO1C levels and suppresses PCa metastasis in an intraarterial bone-metastasis xenograft model.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay defining K27/K63 linkage, RNF41 siRNA knockdown, in vivo bone-metastasis xenograft model, MYO1C rescue\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitin linkage biochemistry plus in vivo model, single lab\",\n      \"pmids\": [\"39112516\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of actin-bound myo1c in the presence and absence of ADP reveal a unique actin interface that reorients the motor domain compared with myo1b/other myosins, skewing the lever arm swing and explaining why myo1c propels actin in leftward circles. The N-terminal extension plays a unique role in force sensing. The structures explain why force primarily regulates ATP binding (not ADP release) in myo1c, and enable modeling of full-length myo1c during force generation.\",\n      \"method\": \"Cryo-EM structure determination of actin-bound myo1c ± ADP, integration with crystallography structures for full-length modeling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM with structural and mechanistic interpretation, preprint but mechanistically novel\",\n      \"pmids\": [\"bio_10.1101_2025.01.10.632429\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nuclear Myo1c (NM1) positively regulates ERα clustering on enhancers and promotes condensate formation on chromatin genome-wide; NM1 depletion causes a genome-wide reduction in ERα occupancy and condensates, though estrogen-regulated gene expression remains largely robust, revealing a role for Myo1c in transcription factor clustering without strictly controlling transcriptional output.\",\n      \"method\": \"ChIP-seq for ERα occupancy, super-resolution/condensate imaging, NM1 depletion by siRNA, genome-wide analysis in estrogen-stimulated cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq with functional depletion, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.01.29.635522\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Chlamydia trachomatis recruits MYO1C to its intracellular inclusion throughout its lifecycle; loss or inhibition of MYO1C activity reduces Ct infection and progeny production. In vitro reconstitution showed that purified MYO1C alone is necessary and sufficient to build an actin cage around giant membranous vesicles, functioning as a dynamic tether that assembles the actin cage around the inclusion membrane.\",\n      \"method\": \"Immunofluorescence of Ct-infected cells, MYO1C inhibition (pentachloropseudilin), siRNA depletion, in vitro reconstitution assay with purified MYO1C and giant membranous vesicles\",\n      \"journal\": \"Microbiological research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with purified protein demonstrating sufficiency, combined with cell-based loss-of-function\",\n      \"pmids\": [\"41242206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Emerin directly binds nuclear myosin I (NMI/Myo1c) in vitro; bead-conjugated emerin affinity-purifies NMI from HeLa nuclear lysates, and this interaction is stable regardless of ATP (motor activity), placing NMI in a distinct emerin-containing complex at the nuclear envelope separate from gene-regulatory complexes.\",\n      \"method\": \"Recombinant bead affinity purification from HeLa nuclear lysates, in vitro direct binding assay, ATP-independence test, mass spectrometry identification\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct in vitro binding plus co-purification from cells, single lab\",\n      \"pmids\": [\"17620012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MYO1C interacts with Jagged1 (Notch ligand) under static conditions in endothelial cells, as confirmed by coimmunoprecipitation; shear stress reduces this interaction. Myo1c knockout inhibits Jagged1 polarization downstream of shear and its nucleograde transport, while Myo1c knockdown reduces membrane levels of Jagged1 under static but not shear conditions, revealing a role for Myo1c in hemodynamic control of Jagged1 localization.\",\n      \"method\": \"Jagged1-APEX2 proximity labeling, co-immunoprecipitation, Myo1c knockout/knockdown, orbital shaker shear stress platform, confocal imaging of Jagged1 localization\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proximity labeling + co-IP + KO with defined trafficking phenotype, single lab\",\n      \"pmids\": [\"41321631\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYO1C is an actin-based unconventional class-I myosin motor that functions as a molecular force sensor (transitioning to high duty-ratio under ≥2 pN tension) and operates through three alternatively spliced isoforms with distinct kinetic properties determined by N-terminal extensions; in the cytoplasm it transports GLUT4-containing vesicles to the plasma membrane via a PI3K-independent, CaMKII-phosphorylation (S701)-regulated mechanism involving RalA as cargo receptor and calmodulin as light chain, tethers vesicles to cortical actin for fusion, recycles lipid-raft/GPI-linked cargo from the perinuclear compartment to the cell surface, mediates autophagosome–lysosome fusion through F-actin remodeling, transports slit-diaphragm proteins Neph1/nephrin and rhodopsin to their membrane destinations, and facilitates G-actin delivery to the leading edge; a nuclear isoform (NM1, bearing a 16-aa N-terminal extension) binds RNA Pol I via TIF-IA and RNA Pol II to activate transcription, stabilizes Golgi-associated actin, and regulates ERα enhancer clustering, while cryo-EM structures reveal a unique actin interface and skewed lever-arm trajectory that explain its leftward actin-gliding path and force sensing through ATP-binding rather than ADP-release.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MYO1C is an unconventional class I myosin motor that uses ATP-dependent actin-based motility to tether and deliver intracellular vesicles—including GLUT4, Neph1, VEGFR2, rhodopsin, and lipid-raft cargo—to the plasma membrane, thereby coupling vesicle trafficking to cortical actin dynamics [PMID:12490950, PMID:22918957, PMID:23262137, PMID:34073294, PMID:22328521]. Its motor activity is regulated by CaMKIIδ-mediated phosphorylation at S701, which enhances ATPase activity and 14-3-3 binding while reducing calmodulin association, and by calcium-dependent calmodulin occupancy of its IQ motifs that controls lever arm function [PMID:19046570, PMID:17910470]. Beyond cytoplasmic cargo transport, MYO1C stabilizes Golgi-associated actin to maintain Golgi integrity, promotes autophagosome–lysosome fusion through F-actin network organization, and transports G-actin monomers to the leading edge during cell migration [PMID:30872458, PMID:25551774, PMID:22778278]. A nuclear isoform directly binds gene promoters such as GDF-15 to regulate TGF-β-responsive transcription and promotes estrogen receptor-α clustering on enhancers, establishing MYO1C as both a cytoplasmic motor and a nuclear transcriptional regulator [PMID:31097328].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"The first demonstration that MYO1C participates in insulin-stimulated GLUT4 vesicle trafficking established it as a cargo motor linking vesicle transport to glucose uptake.\",\n      \"evidence\": \"Vesicle purification, dominant-negative cargo domain, siRNA knockdown, and glucose uptake assay in 3T3-L1 adipocytes\",\n      \"pmids\": [\"12490950\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of vesicle–membrane fusion step not resolved\", \"Whether MYO1C motor activity per se or scaffolding function was required remained unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showing that MYO1C motor activity drives the final membrane fusion step of GLUT4 vesicles—and can bypass PI3K inhibition—separated its role from upstream signaling.\",\n      \"evidence\": \"MYO1C overexpression rescuing PI3K-inhibitor block, ultrafast microscopy of vesicle fusion in adipocytes\",\n      \"pmids\": [\"15169906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical evidence for MYO1C at the fusion pore not provided\", \"Identity of adaptor linking MYO1C to GLUT4 vesicles not yet known\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identification of RalA as the cargo receptor connecting MYO1C to GLUT4 vesicles, with calmodulin modulating this interaction, defined the motor–cargo linkage mechanism.\",\n      \"evidence\": \"Reciprocal Co-IP, dominant-negative mutants, siRNA knockdown with glucose transport readout in adipocytes\",\n      \"pmids\": [\"17765682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the RalA–MYO1C interface unknown\", \"Whether RalA GTPase cycling regulates cargo release not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Quantitative biochemical characterization of calmodulin binding to IQ motifs revealed how calcium acts as a molecular switch controlling MYO1C motility—calcium dissociates calmodulin from IQ1, inhibiting gliding.\",\n      \"evidence\": \"Stopped-flow kinetics, ATPase and actin gliding assays with purified myo1c\",\n      \"pmids\": [\"17910470\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How calcium regulation integrates with CaMKII phosphorylation in cells not addressed\", \"CIB1 and CaBP1 competition with calmodulin characterized only in vitro\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovery that CaMKIIδ phosphorylates MYO1C at S701—enhancing ATPase activity and 14-3-3 binding—provided the first post-translational regulatory mechanism directly controlling motor output during insulin signaling.\",\n      \"evidence\": \"In vitro kinase assay, mutagenesis (S701A and K111A), Co-IP for 14-3-3 and calmodulin, GLUT4 translocation rescue\",\n      \"pmids\": [\"19046570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other kinases also phosphorylate MYO1C not explored\", \"Structural consequence of S701 phosphorylation on lever arm not determined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of a Rictor–MYO1C complex distinct from mTORC2 linked MYO1C to cortical actin remodeling and integrin signaling via paxillin Y118 phosphorylation.\",\n      \"evidence\": \"Reciprocal Co-IP, siRNA knockdown, paxillin phosphorylation and membrane ruffling assays\",\n      \"pmids\": [\"18426911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Rictor modulates MYO1C motor activity biochemically unknown\", \"Whether this complex operates outside adipocytes not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"In vivo electroporation of ATPase-dead MYO1C into mouse skeletal muscle demonstrated that motor activity is required for both insulin- and contraction-stimulated glucose uptake, extending the adipocyte findings to intact muscle.\",\n      \"evidence\": \"In vivo electroporation of WT and K111A MYO1C into mouse tibialis anterior with glucose uptake assay\",\n      \"pmids\": [\"21127070\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Muscle-specific adaptor proteins for GLUT4–MYO1C coupling not identified\", \"Relative contribution vs. other myosins in muscle not quantified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Kinetic analysis of the hearing-loss mutation R156W revealed that MYO1C functions as a force sensor whose duty ratio and phosphate release are critical for mechanotransduction, linking biochemical parameters to auditory function.\",\n      \"evidence\": \"Purified recombinant R156W mutant, ATPase assay, in vitro motility, frictional loading, stopped-flow kinetics\",\n      \"pmids\": [\"21265502\", \"20640478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether these mutations cause human deafness or only model mouse hearing loss remains ambiguous\", \"Structural basis of switch-1 disruption not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that MYO1C transports the slit diaphragm protein Neph1 to podocyte junctions established its role in kidney filtration barrier assembly, later confirmed by zebrafish knockdown showing slit diaphragm absence.\",\n      \"evidence\": \"Co-IP, pulldown, dominant-negative and siRNA in podocytes; morpholino knockdown with mRNA rescue in zebrafish\",\n      \"pmids\": [\"21402783\", \"23715127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MYO1C mutations cause human glomerular disease not established\", \"How MYO1C distinguishes Neph1 from nephrin as cargo not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Multiple 2012 studies collectively expanded MYO1C's cargo repertoire beyond GLUT4: it selectively recycles lipid-raft GPI-cargo via Arf6, delivers VEGFR2 to the endothelial cell surface controlling VEGF signaling, transports G-actin monomers to the leading edge, and tethers GLUT4 vesicles to submembrane actin via direct actin binding.\",\n      \"evidence\": \"RNAi, dominant-negative, live-cell TIRF imaging, photoactivatable actin tracking, fractionation, Co-IP across adipocytes, endothelial cells, and epithelial cells\",\n      \"pmids\": [\"22328521\", \"23262137\", \"22778278\", \"22918957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether lipid-raft recycling and GLUT4 transport are mechanistically coupled or independent unclear\", \"Structural basis for cargo selectivity (GPI-cargo vs. transferrin receptor) not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstration that MYO1C loss blocks autophagosome–lysosome fusion without affecting EGFR endocytic degradation revealed a selective role in autophagy linked to cholesterol membrane distribution.\",\n      \"evidence\": \"RNAi, dominant-negative, electron microscopy, autophagy flux assays, cholesterol staining\",\n      \"pmids\": [\"25551774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MYO1C directly tethers autophagosomes to lysosomes or acts indirectly via actin not distinguished\", \"Identity of autophagosomal MYO1C-binding partner unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Characterization of three MYO1C splice isoforms showed they differ in ATPase kinetics and power-stroke mechanics via N-terminal extension interactions, explaining how alternative splicing tunes motor output for distinct cellular contexts.\",\n      \"evidence\": \"Purified full-length isoforms from HEK cells, stopped-flow kinetics, global kinetic simulation, peptide addition experiments\",\n      \"pmids\": [\"28893906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isoform-specific cellular functions not systematically mapped\", \"Whether isoforms are differentially regulated post-translationally not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Podocyte-specific knockout and ChIP established that a nuclear MYO1C isoform directly binds gene promoters (GDF-15) and regulates TGF-β-responsive transcription, with KO mice resistant to renal fibrosis—revealing a transcriptional function distinct from cytoplasmic motor activity.\",\n      \"evidence\": \"Podocyte-specific KO mice, ChIP at GDF-15 promoter, multiple fibrosis models (Adriamycin, NTS, UUO)\",\n      \"pmids\": [\"31097328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide binding targets of nuclear MYO1C not comprehensively mapped\", \"Mechanism by which MYO1C activates transcription (chromatin remodeling vs. polymerase recruitment) not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"MYO1C depletion causing Golgi fragmentation and delayed carrier arrival showed its role in maintaining Golgi structural integrity through stabilization of Golgi-associated actin.\",\n      \"evidence\": \"siRNA, live-cell imaging, Golgi morphology and transport carrier arrival assays\",\n      \"pmids\": [\"30872458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MYO1C acts as a tether or generates force at the Golgi not distinguished\", \"Golgi-specific MYO1C recruitment factor not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"MYO1C knockout in mice caused progressive rhodopsin mislocalization from photoreceptor outer segments and loss of photoreceptor function, establishing MYO1C as essential for polarized protein delivery in sensory neurons.\",\n      \"evidence\": \"Myo1c KO mice, electroretinography, direct rhodopsin–MYO1C binding assay, immunohistochemistry\",\n      \"pmids\": [\"34073294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MYO1C transports rhodopsin-laden vesicles through the connecting cilium or acts at a different step not resolved\", \"Redundancy with other myosins in photoreceptors not assessed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cryo-EM structures of actin-bound MYO1C revealed a unique actin interface producing a skewed lever arm swing, and showed the N-terminal extension controls force sensing through ATP binding isomerization rather than ADP release—providing the first atomic-level explanation of MYO1C's distinctive motility.\",\n      \"evidence\": \"Cryo-EM structures with and without ADP, full-length atomic modeling (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.01.10.632429\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"How the unique actin interface relates to cargo-specific functions not addressed\", \"Force-sensing model not yet validated by single-molecule experiments with full-length protein\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"In vitro reconstitution demonstrated MYO1C is necessary and sufficient to build an actin cage around membranes, explaining how Chlamydia trachomatis co-opts this motor to stabilize its intracellular inclusion.\",\n      \"evidence\": \"Purified MYO1C reconstitution on giant vesicles, siRNA and inhibitor knockdown, infection assays\",\n      \"pmids\": [\"41242206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Bacterial factor recruiting MYO1C to the inclusion not identified\", \"Whether actin cage assembly uses MYO1C motor activity or passive crosslinking not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: how MYO1C achieves cargo selectivity among its diverse vesicular cargoes; the precise mechanism by which nuclear MYO1C activates transcription; whether the three splice isoforms are differentially deployed to distinct organelles; and whether MYO1C mutations cause human Mendelian disease.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No human disease-causing MYO1C mutations established despite mouse hearing-loss and kidney phenotypes\", \"Cargo recognition code for tail domain not defined\", \"Nuclear vs. cytoplasmic isoform sorting mechanism unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 1, 3, 6, 15, 16, 19]},\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0, 1, 9, 10, 15, 28]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [9, 10, 20, 22, 30]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 7, 9, 11, 17]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 30]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [21, 29]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 8, 9]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [9, 10, 22, 30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 8, 9, 11]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 1, 6, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 11, 21]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12, 22]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [21, 29]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RALA\",\n      \"CALM1\",\n      \"RICTOR\",\n      \"IKBKG\",\n      \"KIRREL1\",\n      \"KDR\",\n      \"INPPL1\",\n      \"FLNA\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"MYO1C is an actin-based unconventional class-I myosin motor that functions as a force-sensitive molecular tether and cargo transporter across diverse membrane trafficking, transcriptional, and cytoskeletal processes. In the cytoplasm, MYO1C drives insulin-stimulated GLUT4 vesicle translocation and tethering to cortical actin at the plasma membrane through a PI3K-independent pathway regulated by CaMKIIδ phosphorylation at S701, with RalA serving as the vesicular cargo receptor and calmodulin as the regulatory light chain [PMID:12490950, PMID:19046570, PMID:17765682, PMID:22918957]; it additionally transports specific membrane cargoes—including Neph1, nephrin, rhodopsin, VEGFR2, Jagged1, and GPI-anchored proteins—to their surface destinations, stabilizes Golgi-associated actin for vesicle carrier arrival, delivers G-actin monomers to the leading edge of migrating cells, and promotes autophagosome–lysosome fusion through F-actin remodeling [PMID:21402783, PMID:34073294, PMID:23262137, PMID:22328521, PMID:22778278, PMID:30872458, PMID:25551774]. A nuclear isoform (NM1, bearing a 16-amino-acid N-terminal extension) associates with RNA polymerases I and II, activates rDNA transcription via TIF-IA, binds gene promoters such as GDF-15, and regulates ERα enhancer clustering, while single-molecule biophysics reveals that tension of ≥2 pN converts MYO1C from a low- to a high-duty-ratio motor by slowing actin detachment, and cryo-EM structures show a unique actin interface and skewed lever-arm trajectory that explain its leftward gliding path and force-sensing through ATP binding rather than ADP release [PMID:15558034, PMID:11030652, PMID:31097328, PMID:18599791, PMID:28893906].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"The discovery of a nuclear Myo1c isoform (NM1) bearing a unique 16-amino-acid N-terminal extension, co-immunoprecipitating RNA polymerase II and blocking in vitro RNA synthesis, established for the first time that an unconventional myosin operates in the nucleus during transcription.\",\n      \"evidence\": \"Isoform-specific antibody, confocal/EM colocalization, co-IP of Pol II, in vitro transcription inhibition in mammalian cells\",\n      \"pmids\": [\"11030652\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No direct evidence for NM1-specific gene targets at this stage\", \"Mechanism linking motor activity to transcription unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of MYO1C on purified GLUT4 vesicles and demonstration that dominant-negative cargo domain and siRNA knockdown block insulin-stimulated GLUT4 translocation and glucose uptake answered how insulin mobilizes GLUT4 independently of PI3K, establishing MYO1C as the motor for this trafficking step.\",\n      \"evidence\": \"Vesicle purification, dominant-negative overexpression, siRNA knockdown, glucose uptake assay in 3T3-L1 adipocytes\",\n      \"pmids\": [\"12490950\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo receptor linking MYO1C to GLUT4 vesicle unknown\", \"Upstream signaling events activating MYO1C unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"NM1 was shown to be essential for RNA polymerase I transcription at rDNA via direct binding to TIF-IA (requiring RSK-mediated S649 phosphorylation), extending the nuclear role of MYO1C from Pol II association to a defined mechanism in ribosomal RNA synthesis.\",\n      \"evidence\": \"Antibody microinjection, siRNA, overexpression, in vitro Pol I transcription on chromatin templates, co-IP of NMI–TIF-IA–Pol I\",\n      \"pmids\": [\"15558034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NM1 plays a catalytic versus structural role in Pol I complex assembly unknown\", \"No genome-wide assessment of NM1-dependent loci\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that RalA acts as the cargo receptor linking MYO1C to GLUT4 vesicles—modulated by calmodulin—and simultaneously connects the exocyst for vesicle tethering resolved the missing cargo-recognition step in insulin-stimulated GLUT4 trafficking.\",\n      \"evidence\": \"Reciprocal co-IP, siRNA and dominant-negative RalA, glucose transport assay in adipocytes\",\n      \"pmids\": [\"17765682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of RalA–MYO1C interaction unresolved\", \"Whether calmodulin dissociation is the switch for RalA engagement unclear\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Reconstituted kinetic studies showed that calcium binding to IQ1-associated calmodulin regulates MYO1C motor activity—moderately stimulating ATPase but completely inhibiting actin gliding—establishing the primary regulatory site and mechanism for calcium-dependent control of the motor.\",\n      \"evidence\": \"In vitro ATPase, actin gliding, stopped-flow fluorescence with labeled calmodulin, peptide binding assays\",\n      \"pmids\": [\"17910470\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of calcium-induced calmodulin dissociation from IQ1 not directly tested\", \"Role of alternative light chains (CIB1, CaBP1) in modulating this regulation unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Single-molecule optical trapping revealed that MYO1C undergoes a dramatic load-dependent transition from low (<0.2) to high (>0.9) duty ratio at ≥2 pN tension, establishing it as a bona fide molecular force sensor—a property that explains its roles in membrane tethering and tension-dependent processes.\",\n      \"evidence\": \"Single-molecule optical trap measuring displacement and detachment kinetics under controlled loads\",\n      \"pmids\": [\"18599791\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for force-dependent detachment slowing unknown at this time\", \"How force sensing integrates with cargo-specific functions in cells not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identification of CaMKIIδ-mediated phosphorylation of MYO1C at S701 as the insulin-responsive switch—enhancing ATPase activity, promoting 14-3-3 binding, reducing calmodulin binding, and being required for GLUT4 translocation—connected upstream insulin signaling to motor activation.\",\n      \"evidence\": \"In vitro kinase assay, S701A/K111A mutagenesis, siRNA rescue, GLUT4 translocation assay in adipocytes\",\n      \"pmids\": [\"19046570\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How 14-3-3 binding alters MYO1C localization or interaction with RalA not defined\", \"Whether S701 phosphorylation regulates non-GLUT4 cargoes unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Hearing-loss-associated motor-domain mutations (R156W, V252A, T380M) were shown to differentially impair ATPase kinetics, actin affinity, and motility, linking specific mechanochemical defects to human disease and validating the kinetic cycle as a drug/mutation target.\",\n      \"evidence\": \"Transient kinetic analyses, steady-state ATPase, in vitro motility with purified mutant proteins\",\n      \"pmids\": [\"20640478\", \"21265502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No in vivo confirmation that these mutations cause hearing loss via MYO1C loss-of-function\", \"Structural explanation for switch-1 disruption by R156W not yet available\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"A series of studies expanded MYO1C's cargo repertoire beyond GLUT4: it was shown to tether GLUT4 vesicles to cortical actin via TIRF imaging, selectively recycle GPI-anchored/lipid-raft cargo from the perinuclear compartment, transport Neph1 to the podocyte membrane, deliver G-actin monomers to the leading edge, and traffic VEGFR2 to the endothelial surface—establishing MYO1C as a general membrane-cargo transporter with selectivity for specific membrane domains.\",\n      \"evidence\": \"TIRF single-vesicle tracking, siRNA and dominant-negative studies, raft fractionation, mass spectrometry cargo identification, photoactivatable actin tracking, VEGFR2 surface assays in multiple cell types\",\n      \"pmids\": [\"22918957\", \"22328521\", \"21402783\", \"22778278\", \"23262137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all cargoes use the same tail-domain binding surface unclear\", \"Mechanisms selecting which cargo is loaded at a given time unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Zebrafish morpholino knockdown of Myo1c causing pericardial edema, dilated tubules, and absent slit diaphragm—rescued by mouse Myo1c mRNA—demonstrated an essential in vivo requirement for MYO1C in glomerular development and podocyte integrity.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish, electron microscopy, mRNA rescue\",\n      \"pmids\": [\"23715127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MYO1C loss causes kidney disease in mammals not yet shown at this point\", \"Cargo(s) responsible for slit-diaphragm defect not identified in this model\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"MYO1C depletion was shown to block autophagosome–lysosome fusion selectively (without affecting endocytic degradation or lysosomal activity) by causing cholesterol-enriched membrane accumulation, revealing a lipid-homeostasis-dependent mechanism by which MYO1C supports autophagy.\",\n      \"evidence\": \"siRNA/dominant-negative knockdown, TEM, LC3/LAMP1 colocalization, EGFR degradation control, cholesterol quantification\",\n      \"pmids\": [\"25551774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MYO1C directly transports cholesterol or indirectly regulates its distribution unclear\", \"Actin remodeling contribution versus lipid redistribution not fully dissected\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Full-length kinetic characterization of the three MYO1C splice isoforms revealed that N-terminal extensions allosterically shift the actomyosin equilibrium between open and closed states—mediated by a specific Arg-21/Glu-469 salt bridge in the NTR35 isoform—explaining how a single gene produces motors with distinct force-generating properties.\",\n      \"evidence\": \"Purified full-length isoform kinetics from HEK cells, global numerical simulation, R21G mutagenesis, NTR peptide addition\",\n      \"pmids\": [\"28893906\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Isoform-specific cargo assignments not established\", \"Tissue-specific expression ratios of isoforms not systematically mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Two studies revealed MYO1C's roles beyond vesicle transport: it stabilizes Golgi-associated actin required for both anterograde and retrograde carrier arrival (phenocopying Arp2/3 loss), and podocyte-specific knockout in mice conferred resistance to fibrotic kidney injury by blunting TGF-β signaling, with nuclear MYO1C directly binding the GDF-15 promoter.\",\n      \"evidence\": \"siRNA with Golgi transport assays and F-actin quantification; conditional KO mice with multiple injury models, ChIP at GDF-15 promoter\",\n      \"pmids\": [\"30872458\", \"31097328\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Golgi actin stabilization requires MYO1C motor activity or passive tethering not tested\", \"Genome-wide map of nuclear MYO1C promoter occupancy incomplete\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Systemic Myo1c knockout mice exhibited progressive photoreceptor degeneration with rhodopsin mislocalization to inner segments, and direct MYO1C–rhodopsin binding was demonstrated, extending MYO1C's cargo transport function to sensory neurons.\",\n      \"evidence\": \"Myo1c KO mice, electroretinography, immunohistochemistry, direct binding assay\",\n      \"pmids\": [\"34073294\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether MYO1C transports rhodopsin via the connecting cilium or an alternative route unknown\", \"Other visual-cycle cargoes of MYO1C not explored\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Non-canonical K27/K63-linked polyubiquitination of MYO1C by RNF41 was found to stabilize (rather than degrade) MYO1C, promoting actin remodeling and prostate cancer bone metastasis, identifying a post-translational mechanism controlling MYO1C protein levels.\",\n      \"evidence\": \"Ubiquitination assay defining linkage type, RNF41 knockdown, in vivo bone-metastasis xenograft, MYO1C rescue\",\n      \"pmids\": [\"39112516\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Deubiquitinase counteracting RNF41 not identified\", \"Whether K27/K63-Ub stabilization operates in non-cancer contexts unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Cryo-EM structures of actin-bound MYO1C ± ADP revealed a unique actin interface that reorients the motor domain relative to other myosin-I family members, skewing the lever-arm swing to explain leftward actin gliding; the N-terminal extension was shown to participate in force sensing through regulation of ATP binding rather than ADP release.\",\n      \"evidence\": \"Cryo-EM structure determination of actomyosin-MYO1C ± ADP, integration with crystallography for full-length modeling (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.01.10.632429\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures not yet peer-reviewed\", \"No structure with cargo bound to the tail domain\", \"How NTR isoform differences alter the actin interface is not resolved structurally\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"MYO1C was shown to interact with the Notch ligand Jagged1 and to be required for its polarized trafficking under static conditions, with shear stress reducing the MYO1C–Jagged1 interaction, and separately, purified MYO1C was demonstrated sufficient to assemble an actin cage around giant membranes in vitro, explaining how Chlamydia exploits MYO1C for inclusion integrity.\",\n      \"evidence\": \"Proximity labeling + co-IP + KO with shear-stress platform for Jagged1; in vitro reconstitution of actin cage assembly with purified MYO1C for Chlamydia inclusion\",\n      \"pmids\": [\"41321631\", \"41242206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Jagged1 transport uses the same tail-domain surface as Neph1/rhodopsin not tested\", \"In vitro actin cage assembly conditions may not recapitulate physiological membrane composition\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: how isoform-specific cargoes are assigned in vivo; the full structural basis of tail-domain cargo recognition; whether nuclear MYO1C transcriptional functions require motor activity or tension; and how force sensing integrates with specific trafficking decisions at the single-molecule level inside cells.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No atomic-resolution structure of MYO1C tail bound to any cargo\", \"Isoform-specific knockout models not yet reported\", \"Single-molecule force measurements inside living cells not achieved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0, 1, 8, 10, 12, 20, 22, 32]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [4, 10, 20, 22]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [12, 13, 23, 34]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [11, 16]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [18, 19, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 9, 11, 12, 14, 29]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 1, 2, 12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [18, 19, 24, 33, 35]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [5, 13, 23, 34]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13, 27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 1, 2, 4, 8, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 14, 28]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [18, 19, 24]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [16, 25]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [8, 29]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [9, 11, 14, 26]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"RALA\",\n      \"CALM1\",\n      \"IKBKG\",\n      \"RPTOR\",\n      \"KIRREL1\",\n      \"RHO\",\n      \"FLNA\",\n      \"EMD\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}