{"gene":"MYH9","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2000,"finding":"MYH9 mutations (one nonsense and five missense) in the myosin head domain and coiled-coil rod domain cause May-Hegglin anomaly, Fechtner syndrome, and Sebastian syndrome; molecular modelling predicted that head-domain mutations impose electrostatic/conformational changes affecting ATPase activity, while coiled-coil mutations destabilize the rod, and the truncating mutation deletes the C-terminal tailpiece.","method":"Mutation screening, direct sequencing, molecular modelling","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutations identified in seven unrelated probands, functional prediction by structural modelling, independently replicated by second paper same year (PMID:10973260)","pmids":["10973259","10973260"],"is_preprint":false},{"year":2000,"finding":"MYH9 R705H mutation within the conserved SH1 helix causes DFNA17 nonsyndromic hereditary hearing loss; previous studies established that SH1 helix modification disrupts myosin II ATPase activity in the motor domain.","method":"Candidate gene sequencing, cosegregation analysis, RT-PCR and immunohistochemistry for cochlear expression","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cosegregation established, ATPase mechanism inferred from prior literature, single lab","pmids":["11023810"],"is_preprint":false},{"year":2003,"finding":"Abnormal NMMHC-IIA (MYH9 protein) subcellular localization is observed in neutrophils from all individuals with MYH9 mutations; the protein colocalizes with inclusion bodies; normal NMMHC-IIA dimerizes with abnormal (truncated) NMMHC-IIA to form inclusion bodies, as shown by C-terminal antibody reactivity in heterozygotes for truncating mutations.","method":"Immunofluorescence analysis with polyclonal anti-NMMHCA antibody on blood smears from 24 patients, epitope mapping with C-terminal peptide antibody","journal":"Laboratory investigation; a journal of technical methods and pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with functional consequence, single lab, 24 cases","pmids":["12533692"],"is_preprint":false},{"year":2003,"finding":"The D1424N MYH9 mutation results in a highly unstable protein without abnormalities in protein localization or mRNA stability, suggesting haploinsufficiency—rather than dominant-negative mislocalization—as the pathogenic mechanism for this allele.","method":"Protein expression analysis, mRNA stability assay, immunofluorescence in megakaryocytes","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (protein quantification, mRNA, localization), single lab","pmids":["12649151"],"is_preprint":false},{"year":2004,"finding":"Complete homozygous loss of Myh9 is embryonic lethal (no homozygous pups among 552 births), establishing that MYH9 expression is required for embryonic development; heterozygous mice are viable without gross hematological or nephrological abnormalities, though some show hearing loss.","method":"Targeted gene disruption (knockout mouse), breeding analysis, auditory brainstem response","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic KO with defined developmental phenotype, replicated by independent gene-trap KO (PMID:17914179)","pmids":["15555549","17914179"],"is_preprint":false},{"year":2006,"finding":"Myh9 is localized within the stereocilia of inner and outer hair cells in the mouse cochlea, raising the possibility that MYH9 mutations cause hearing loss through disruption of stereocilia structure.","method":"Confocal immunofluorescence microscopy of cochlear surface preparations with anti-Myh9 antibody","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization by confocal microscopy, single lab, no functional rescue","pmids":["16862555"],"is_preprint":false},{"year":2011,"finding":"Mouse knock-in lines with R702C, D1424N, and E1841K Myh9 mutations recapitulate human MYH9-related disease; heterozygous R702C megakaryocytes form fewer, shorter proplatelets with less branching and larger buds in live-cell imaging of bone marrow, demonstrating that disrupted proplatelet formation underlies macrothrombocytopenia.","method":"Mouse knock-in models, live-cell imaging of megakaryocytes, cultured megakaryocyte analysis, bleeding time, clot retraction assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple knock-in alleles, live imaging with specific cellular phenotype, recapitulates human disease","pmids":["21908426"],"is_preprint":false},{"year":2011,"finding":"MYH9-USP6 gene fusion in nodular fasciitis places the entire USP6 coding sequence under the MYH9 promoter, driving USP6 overexpression; xenografts of USP6-overexpressing cells in nude mice recapitulate clinical and histological features of nodular fasciitis.","method":"5'-RACE, RT-PCR/sequencing, in vivo xenograft, genomic FISH","journal":"Laboratory investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — gene fusion identified by multiple molecular methods plus functional in vivo validation, single lab but multiple orthogonal techniques","pmids":["21826056"],"is_preprint":false},{"year":2015,"finding":"Myh9 (nonmuscle myosin II-A) accumulates at colonic epithelial injury sites; monoallelic gut-epithelium-specific Myh9 deletion or pharmacological inhibition with blebbistatin activates Akt via Rac1 and PAK1, improving Lgr5+ stem cell survival and protecting against DSS-induced colitis, defining a Myh9–Rac1–PAK1–Akt pathway in intestinal stem cell maintenance.","method":"Conditional knockout mouse (Myh9 monoallelic deletion), blebbistatin inhibitor, Lgr5 organoid assay, live imaging, western blot for pathway components","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO plus pharmacological inhibition plus organoid assay plus pathway dissection, multiple orthogonal methods","pmids":["25968904"],"is_preprint":false},{"year":2017,"finding":"MYH9 binds to the lncRNA PTCSC2 and inhibits the bidirectional FOXE1/PTCSC2 promoter activity in both directions; PTCSC2 reverses this MYH9-mediated transcriptional repression, demonstrating that MYH9 acts as a transcriptional repressor at this genomic locus.","method":"RNA pulldown, co-immunoprecipitation, dual-luciferase reporter assay, RNA knockdown","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding and reporter assay, single lab","pmids":["28049826"],"is_preprint":false},{"year":2017,"finding":"SRF transcription factor binds the CArG box in the MYH9 promoter to drive MYH9 expression; miR-647 suppresses GC metastasis by directly targeting SRF mRNA, reducing MYH9 levels.","method":"ChIP for SRF at MYH9 promoter, 3'-UTR luciferase reporter, orthotopic GC xenograft model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays establishing transcriptional regulation, single lab","pmids":["28900514"],"is_preprint":false},{"year":2018,"finding":"Myh9 is required for neutrophil migration: genetic downregulation of Myh9 in Vav-iCre mice significantly reduces migration velocity, transmigration, and 3D migration; STED nanoscopy showed that a threshold level of Myh9 is needed to maintain F-actin dynamics at the leading edge; Myh9-EGFP rescue restored migration defects, confirming cell-intrinsic function.","method":"Conditional knockdown (Vav-iCre), STED nanoscopy, 2D/3D migration assays, laser-induced skin injury, peritonitis model, bone marrow chimera, Myh9-EGFP rescue","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic model, multiple migration assays, STED imaging, EGFP rescue, in vivo and in vitro validation","pmids":["30068598"],"is_preprint":false},{"year":2018,"finding":"MYH9 C-terminal domain (PRA, aa1676–1791) directly interacts with PRRSV glycoprotein 5 (GP5); soluble recombinant PRA blocks PRRSV entry in a dose-dependent manner and inhibits both genotype 1 and 2 strains, identifying MYH9 as an essential entry co-factor for PRRSV.","method":"GST pulldown, recombinant protein blocking assay, siRNA knockdown, blebbistatin inhibition, dose-response infection assay","journal":"Antiviral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding plus functional blocking experiment, single lab","pmids":["29879459"],"is_preprint":false},{"year":2019,"finding":"Angiotensin II reduces MYH9 expression in podocytes via TRPC6-mediated Ca2+ influx driven by NOX4-generated ROS; MYH9 knockdown recapitulates Ang II-induced actin cytoskeleton disruption and increased albumin permeability, while MYH9 overexpression rescues these effects, placing MYH9 downstream of the Ang II/TRPC6/NOX4 axis in maintaining the filtration barrier.","method":"siRNA knockdown, MYH9 overexpression, NOX4/ROS measurement, TRPC6 inhibition, albumin permeability assay, actin staining","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss and gain of function with multiple orthogonal readouts, single lab","pmids":["31118506"],"is_preprint":false},{"year":2019,"finding":"PTP1B dephosphorylates MYH9 at Y1408; this dephosphorylation event upregulates EGFR expression and promotes cell migration and invasion in esophageal squamous cell carcinoma, defining a PTP1B–MYH9–EGFR signaling axis.","method":"GST pulldown combined with LC/MS/MS to identify MYH9 as PTP1B substrate, site-specific phosphorylation analysis, migration/invasion assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — substrate identified by pulldown-MS and biochemically validated, single lab","pmids":["31735331"],"is_preprint":false},{"year":2020,"finding":"MYH9 interacts with GSK3β and promotes its ubiquitin-mediated degradation, thereby dysregulating the β-catenin destruction complex and activating downstream Wnt/β-catenin signaling and tumor stemness in hepatocellular carcinoma; HBx protein interacts with MYH9 and induces its expression, while c-Jun transcriptionally stimulates MYH9 to form a feedback loop.","method":"Co-immunoprecipitation, siRNA knockdown, ubiquitination assay, luciferase reporter, in vivo mouse model, ChIP for c-Jun at MYH9 promoter","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination assay, and ChIP in single lab","pmids":["32296025"],"is_preprint":false},{"year":2020,"finding":"Nuclear MYH9 binds directly to the CTNNB1 (β-catenin) promoter through its DNA-binding domain, and forms a transcriptional complex with myosin light chain 9, β-actin, and RNA Pol II to drive CTNNB1 transcription; nuclear translocation is enabled by potential NLS sequences; S1943 phosphorylation promotes nuclear accumulation, while staurosporine reduces S1943 phosphorylation to inhibit this activity.","method":"Immunofluorescence, immune transmission electron microscopy, chromatin fractionation, Co-IP, ChIP, dual luciferase reporter, agarose-oligonucleotide pulldown, nuclear localization signal mutation analysis, in vivo transgenic and xenograft models","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (ChIP, Co-IP, fractionation, reporter, EM, in vivo), single lab but comprehensive mechanistic dissection","pmids":["32685004"],"is_preprint":false},{"year":2020,"finding":"Conditional inactivation of Myh9 (and Myh10) in adult mouse renal tubular epithelia causes progressive kidney disease preceded by intracellular accumulation of uromodulin (UMOD), loss of NKCC2 from the apical membrane, expansion of ER tubules, and activation of ER stress/UPR pathways, demonstrating that NM2 proteins are required for UMOD transport and specialized renal epithelial trafficking.","method":"Inducible conditional knockout mouse (Myh9/Myh10 cKO), immunofluorescence, electron microscopy, ER stress marker analysis","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic cKO with multiple orthogonal readouts (protein localization, EM, ER stress markers), in vivo mechanistic link established","pmids":["33001861"],"is_preprint":false},{"year":2021,"finding":"NEK9 acts as a selective autophagy adaptor for MYH9: NEK9 interacts with MYH9 and its LC3-interacting region (LIR) directs autophagic degradation of MYH9, which otherwise stabilizes the actin network and inhibits primary cilia formation; MYH9 depletion restores ciliogenesis in NEK9 LIR-mutant cells.","method":"Co-IP, LIR mutation knock-in mice (in vivo cilia analysis in kidneys), MYH9 accumulation measurement, MYH9 siRNA rescue of ciliogenesis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, genetic LIR-mutant mice with kidney phenotype, mechanistic rescue by MYH9 depletion, multiple orthogonal approaches","pmids":["34078910"],"is_preprint":false},{"year":2021,"finding":"Myh9 is the major nonmuscle myosin II heavy chain during mouse preimplantation development: maternal-zygotic loss of Myh9 causes failed cytokinesis, prolonged cell cycle, weaker compaction, and reduced differentiation; double Myh9/Myh10 maternal-zygotic mutants show near-complete cytokinesis failure, while Myh10 single mutants are much less severely affected.","method":"Maternal-zygotic knockout mouse models, multiscale live imaging (light-sheet and confocal), morphometric analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic maternal-zygotic KO with multiscale imaging, single vs. double mutant comparison establishes isoform hierarchy","pmids":["33871354"],"is_preprint":false},{"year":2021,"finding":"MYH9 promotes lung cancer stem cell-like features by activating the mTOR signaling pathway; MYH9 knockdown or blebbistatin treatment reduces stemness markers (CD44, SOX2, Nanog, CD133, OCT4), sphere formation, and mTOR pathway activity.","method":"MYH9 overexpression/knockout, western blot for mTOR pathway, sphere formation assay, rapamycin inhibitor, in vivo blebbistatin treatment","journal":"Cell death discovery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway activation inferred from inhibitor studies without direct binding evidence","pmids":["34635641"],"is_preprint":false},{"year":2021,"finding":"MYH9 directly binds cytoplasmic segments aa368–411 of ATG9B via its head domain; ATG9B–MYH9 interaction decreases each protein's binding to E3 ubiquitin ligase STUB1, mutually stabilizing both proteins; during invasion, MYH9 transports ATG9B to the cell edge, where ATG9B promotes focal adhesion assembly by mediating interaction of endocytosed integrin β1 with Talin-1.","method":"Co-IP, peptide-domain mapping, STUB1 ubiquitination assay, live-cell imaging of ATG9B polarization, integrin β1-Talin-1 interaction assay","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-level binding defined, ubiquitination assay, live imaging, single lab","pmids":["34131310"],"is_preprint":false},{"year":2021,"finding":"TGF-β1 increases MYH9 expression via the ALK5/Smad2/3 pathway (but not p38 MAPK or Akt); siRNA-mediated knockdown or pharmacological inhibition of MYH9 ATPase activity suppresses TGF-β1-induced lung fibroblast-to-myofibroblast differentiation.","method":"siRNA knockdown, MYH9 ATPase inhibitor, pathway inhibitors (ALK5, p38, Akt), western blot for differentiation markers","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific phenotypic readout plus upstream pathway dissection, single lab","pmids":["33519439"],"is_preprint":false},{"year":2022,"finding":"Reduced myosin light chain phosphorylation after agonist stimulation in Myh9 mutant platelets (R702C, D1424N, E1841K) leads to altered biophysical properties and lower adhesion, interaction, and traction forces, directly underlying the increased bleeding tendency in MYH9-related disease; tranexamic acid restores clot retraction and reduces bleeding.","method":"Single-platelet force measurement, myosin light chain phosphorylation assay, clot retraction assay, patient platelet analysis, tranexamic acid treatment in mutant mice","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple mutant mouse lines, single-platelet biophysics, confirmed in patient platelets, pharmacological rescue","pmids":["35584211"],"is_preprint":false},{"year":2022,"finding":"TUBB4A interacts with MYH9 to protect the nucleus during constricted cell migration; TUBB4A knockout or MYH9 knockdown causes severe nuclear DNA damage (increased γH2AX, 53BP1) and reduces NF-κB signaling; TUBB4A/GSK3β binds the N-terminal domain of MYH9 and TUBB4A KO reduces MYH9-mediated GSK3β ubiquitination and degradation, decreasing β-catenin signaling.","method":"Co-IP, domain-mapping (N-terminal MYH9), MYH9 knockdown, TUBB4A KO, nuclear damage quantification (γH2AX/53BP1), ubiquitination assay, constricted migration assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping, ubiquitination assay, KD/KO with specific nuclear damage phenotype, single lab","pmids":["35589707"],"is_preprint":false},{"year":2022,"finding":"TPRG1-AS1 lncRNA directly interacts with MYH9 protein in HASMCs and promotes MYH9 protein degradation through the proteasome pathway, thereby hindering F-actin stress fiber formation and inhibiting smooth muscle cell migration; VSM-specific TPRG1-AS1 overexpression reduces neointima formation and atherosclerosis in vivo.","method":"RNA-protein interaction assay, Co-IP, proteasome inhibitor (MG132) rescue, F-actin staining, migration assay, transgenic/KO mouse vascular injury and atherosclerosis models","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA–protein interaction, proteasome degradation assay, in vivo vascular models, single lab","pmids":["36172865"],"is_preprint":false},{"year":2022,"finding":"OVGP1 interacts with MYH9 (shown by pulldown-MS and Co-IP); inhibition of MYH9 attenuates OVGP1-induced hypertension and vascular remodeling in transgenic mice, placing MYH9 downstream of OVGP1 in this pathway.","method":"Pulldown/mass spectrometry, Co-IP, MYH9 inhibitor in OVGP1 transgenic mice, blood pressure measurement","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal biochemical interaction plus in vivo inhibitor rescue, single lab","pmids":["36172862"],"is_preprint":false},{"year":2022,"finding":"Dlc1 (RhoGAP) interacts with MYH9 in multiprotein complexes; Dlc1 overexpression increases phosphorylation of MYH9 and activates Rac1 GTPase, linking MYH9 to Rac1-mediated cytoskeletal changes.","method":"Co-immunoprecipitation, mass spectrometry, western blot for MYH9 phosphorylation, Rac1 activation assay","journal":"Biology open","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/MS with phosphorylation endpoint, no mechanistic rescue experiment, single lab","pmids":["26977077"],"is_preprint":false},{"year":2022,"finding":"MYH9 promotes microglial homeostasis; YOD1 deubiquitinase binds MYH9 and removes K48-linked ubiquitin chains, stabilizing MYH9 protein; YOD1 knockout reduces MYH9 levels, impairs microglial migration, phagocytosis, and inflammatory response, and improves cognition in AD model mice.","method":"LC-MS/MS, Co-IP, ubiquitination assay (K48-chain specificity), YOD1 KO mouse, behavioral tests","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with ubiquitin chain-type specificity plus in vivo KO with phenotypic readout, single lab","pmids":["40041897"],"is_preprint":false},{"year":2023,"finding":"MYH9 is identified as a key secreted/extracellular regulator of rheumatoid arthritis fibroblast-like synoviocyte migration and invasion; IL-1β, TNF-α, TLR ligation, and ER stress induce MYH9 secretion; blebbistatin (MYH9 ATPase inhibitor) substantially inhibits RA-FLS migration/invasion in vitro and in a humanized synovitis mouse model.","method":"LC-MS/MS secretome analysis, western blot, ELISA, siRNA/blebbistatin functional assays, humanized synovitis mouse model","journal":"Annals of the rheumatic diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — secretome MS, loss-of-function with specific phenotype, in vivo model, single lab","pmids":["37188496"],"is_preprint":false},{"year":2023,"finding":"DNAJA4 facilitates MYH9 protein degradation via the ubiquitin-proteasome pathway by recruiting PSMD2; overexpression of MYH9 reverses the suppressive effects of DNAJA4 on NPC cell migration, invasion, and EMT, placing MYH9 downstream of the DNAJA4-PSMD2 complex.","method":"Co-IP, ubiquitination assay, MYH9 overexpression rescue, in vitro migration/invasion assay, in vivo metastasis model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, proteasome degradation, genetic rescue experiment, single lab","pmids":["37875476"],"is_preprint":false},{"year":2023,"finding":"SPC25 scaffolds a trimeric SPC25/RIOK1/MYH9 complex; RIOK1 phosphorylates MYH9 at Ser1943 within this complex, causing MYH9 to disengage from the cytoskeleton and accumulate in the nucleus, where it drives CTNNB1 transcription and Wnt/β-catenin signaling to promote cancer stemness and platinum resistance in ovarian cancer.","method":"Co-IP (trimeric complex), kinase assay (RIOK1-mediated MYH9 S1943 phosphorylation), subcellular fractionation, luciferase reporter for CTNNB1, competitive peptide (CBP1) disruption in vitro/in vivo/organoids","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical complex, phosphorylation-site assay, nuclear fractionation, functional rescue, single lab","pmids":["39488790"],"is_preprint":false},{"year":2023,"finding":"MYH9 binds NAP1L1 and recruits USP14 deubiquitinase to prevent NAP1L1 ubiquitination and degradation; stabilized NAP1L1 binds c-Myc and activates CCND1/CDK4 expression, promoting glioma proliferation and temozolomide resistance.","method":"Co-IP, ubiquitination assay, MYH9 knockdown, rescue experiments, western blot","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/ubiquitination approach, single lab, no direct binding reconstitution","pmids":["37770914"],"is_preprint":false},{"year":2023,"finding":"SAMD9 stimulates GSK3β ubiquitin-mediated degradation by interacting with both MYH9 and TRAF6; silencing MYH9 or β-catenin blocks SAMD9-driven tumor stemness, EMT, and metastasis, placing MYH9 as the key intermediary in the SAMD9/MYH9/GSK3β/β-catenin axis.","method":"Co-IP, ubiquitination assay, MYH9/β-catenin siRNA rescue, in vivo tumor and metastasis models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination, genetic rescue, in vivo validation, single lab","pmids":["36757050"],"is_preprint":false},{"year":2024,"finding":"Phosphorylated MYH9 at Ser1943 (p-MYH9 S1943) recruits deubiquitinase USP22 to deubiquitinate and stabilize HIF-1α in lenvatinib-resistant HCC cells, promoting cancer stemness; CK2 inhibitor reduces MYH9 S1943 phosphorylation and reverses resistance in vivo.","method":"Immunoprecipitation, mass spectrometry, ubiquitination assay, site-specific phosphorylation analysis, CK2 inhibitor treatment, in vivo models","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS, ubiquitination assay, phospho-site validation, in vivo pharmacological rescue, single lab","pmids":["39300073"],"is_preprint":false},{"year":2024,"finding":"MafG physically interacts with MYH9 to transcriptionally activate LCN2 expression; MARE motif site-directed mutation blocks MafG binding to the LCN2 promoter; LCN2 re-expression in MafG-knockdown HSCs restores resistance to ferroptosis, defining MafG/MYH9 as a transcriptional activator complex suppressing HSC ferroptosis.","method":"Co-IP, ChIP, site-directed mutagenesis of MARE motif, LCN2 rescue experiment, AAV6-mediated HSC-specific MafG KD in BDL mouse model","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, mutagenesis, rescue experiment, in vivo model, single lab","pmids":["38871948"],"is_preprint":false},{"year":2024,"finding":"HMBA binds directly to MYH9 (and ACTG1) in hypothalamic neurons; this binding is required for HMBA's anti-obesity effects on NPY and POMC expression; MYH9 binding by HMBA elevates HEXIM1 expression and enhances HEXIM1-MDM2 interaction, causing free HEXIM1 and p53 to translocate to the nucleus and modulate neuropeptide transcription.","method":"Direct binding assay (HMBA-MYH9), co-IP (HEXIM1-MDM2), nuclear fractionation, NPY/POMC reporter/ChIP assays, in vivo central/peripheral HMBA administration to DIO mice, MYH9-KD in NPY/POMC neurons","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct compound-protein binding, multiple biochemical assays, in vivo KD, single lab","pmids":["37984341"],"is_preprint":false},{"year":2022,"finding":"MYH9 head domain directly binds the cytoplasmic segment aa368–411 of ATG9B; their interaction mutually prevents binding to STUB1 E3 ubiquitin ligase, stabilizing both proteins and promoting CRC invasion.","method":"Co-IP, domain-mapping, ubiquitination assay, STUB1 interaction competition","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-level binding and ubiquitination assay, single lab","pmids":["34131310"],"is_preprint":false},{"year":2022,"finding":"ENKUR recruits E3 ligase FBXW7 to form a ubiquitinated degradation complex with MYH9; downregulated MYH9 reduces recruitment of deubiquitinase USP2, promoting β-catenin degradation and suppressing EMT and GC metastasis.","method":"Co-IP, ubiquitination assay, MYH9 overexpression rescue, migration/invasion assays, in vivo metastasis","journal":"MedComm","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/ubiquitination, single lab, limited mechanistic depth for MYH9 specifically","pmids":["36448053"],"is_preprint":false},{"year":2023,"finding":"MYH10 protein functional domain combines with MYH9 to recruit deubiquitinase USP45, which deubiquitinates Snail to prevent its degradation, promoting ovarian cancer tumorigenesis and cisplatin resistance.","method":"Co-IP, GST pulldown, deubiquitination assay, confocal colocalization, MYH10/MYH9 knockdown","journal":"Advanced science","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — complex identified by pulldown and Co-IP, deubiquitination assay; mechanistic role is primarily assigned to MYH10, MYH9 participates as binding partner","pmids":["36929633"],"is_preprint":false},{"year":2024,"finding":"RGS19 stabilizes MYH9 protein by directly competing with STUB1 (E3 ligase) for MYH9 binding via its RGS domain, reducing MYH9 ubiquitination; stabilized MYH9 activates β-catenin/c-Myc signaling; RGS19 is in turn a transcriptional target of c-Myc, forming a positive feedback loop.","method":"Co-IP, domain competition assay (RGS domain), ubiquitination assay, STUB1 identified as E3 ligase for MYH9, c-Myc ChIP","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain specificity, ubiquitination competition assay, in vivo and in vitro validation, single lab","pmids":["38825640"],"is_preprint":false},{"year":2022,"finding":"Myh9 is essential for hematopoietic stem/progenitor cell (HSPC) survival and maintenance: Mx1-cre conditional Myh9 deletion causes pancytopenia, drastic reduction of HSPCs, bone marrow failure, impaired repopulation capacity, increased apoptosis, and early lethality; the defect is cell-autonomous.","method":"Inducible conditional knockout (Mx1-cre Myh9 flox), bone marrow transplantation chimera, RNA-seq, apoptosis assay","journal":"Cells","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with cell-autonomous rescue, multiple phenotypic readouts, RNA-seq pathway analysis","pmids":["35740994"],"is_preprint":false}],"current_model":"MYH9 encodes the heavy chain of non-muscle myosin IIA (NMII-A), an actin-based molecular motor whose ATPase activity and filament-forming capacity are regulated by 20-kDa light chain phosphorylation and by heavy-chain phosphorylation (notably at Ser1943); disease-causing mutations in the motor head impair ATPase activity and proplatelet formation, while rod/coiled-coil mutations destabilize the filament or cause haploinsufficiency, and a truncating mutation deletes the tailpiece. Beyond its canonical cytoskeletal role in cell migration, cytokinesis, and podocyte filtration-barrier integrity, MYH9 acts as a scaffold that recruits ubiquitin-regulatory proteins (USP22, USP14, USP2, FBXW7, STUB1) to control the stability of signaling proteins including GSK3β (promoting β-catenin/Wnt activation), HIF-1α, NAP1L1, and Snail; in certain contexts phospho-MYH9 (Ser1943) translocates to the nucleus to directly transcribe CTNNB1; NEK9 targets MYH9 for autophagic degradation to permit primary cilia formation; and complete MYH9 loss is embryonic lethal while tissue-specific deletion in renal tubules or hematopoietic cells causes progressive kidney disease or bone marrow failure, respectively."},"narrative":{"mechanistic_narrative":"MYH9 encodes the heavy chain of non-muscle myosin IIA, an actin-based motor whose ATPase and filament functions underlie cytokinesis, cell migration, mechanical force generation, and specialized epithelial trafficking [PMID:33871354, PMID:30068598, PMID:33001861]. Heterozygous mutations clustered in the motor head and coiled-coil rod domains cause an autosomal-dominant disorder spanning May-Hegglin anomaly, Fechtner and Sebastian syndromes, with head mutations predicted to impair ATPase activity and rod mutations destabilizing the filament, while a tailpiece-truncating allele acts via dominant-negative co-assembly into leukocyte inclusion bodies and the D1424N allele via haploinsufficiency [PMID:10973259, PMID:10973260, PMID:12533692, PMID:12649151]; an SH1-helix R705H substitution causes DFNA17 hearing loss, consistent with cochlear hair-cell stereocilia localization [PMID:11023810, PMID:16862555]. Knock-in models recapitulate macrothrombocytopenia by disrupting proplatelet formation and reducing agonist-induced light-chain phosphorylation, adhesion, and traction forces in platelets [PMID:21908426, PMID:35584211]. Complete loss is embryonic lethal, and conditional deletion reveals tissue-autonomous requirements: hematopoietic deletion causes bone marrow failure, renal tubular deletion disrupts uromodulin transport with ER stress, and preimplantation loss causes cytokinesis failure, with MYH9 functionally dominant over MYH10 [PMID:15555549, PMID:17914179, PMID:35740994, PMID:33001861, PMID:33871354]. Beyond its cytoskeletal motor role, MYH9 functions as a scaffold for ubiquitin-regulatory enzymes, binding GSK3β and promoting its ubiquitin-mediated degradation to activate Wnt/β-catenin signaling and tumor stemness, and recruiting deubiquitinases (USP22, USP14, YOD1) to stabilize HIF-1α, NAP1L1, and MYH9 itself [PMID:32296025, PMID:39300073, PMID:37770914, PMID:40041897]; its own abundance is set by competition between the STUB1 E3 ligase and stabilizers such as RGS19 [PMID:38825640]. Phosphorylation at Ser1943, catalyzed by RIOK1 within an SPC25/RIOK1 complex, releases MYH9 from the cytoskeleton and drives its nuclear accumulation, where it binds the CTNNB1 promoter and assembles a transcription complex with myosin light chain 9, β-actin, and RNA Pol II to directly transcribe β-catenin [PMID:32685004, PMID:39488790]. NEK9 targets MYH9 for selective autophagic degradation via an LC3-interacting region to permit primary cilium formation [PMID:34078910].","teleology":[{"year":2000,"claim":"Establishing that MYH9 is the disease gene defined the molecular basis of a group of autosomal-dominant macrothrombocytopenia syndromes and pointed mechanism toward motor and rod-domain dysfunction.","evidence":"Mutation screening and molecular modelling in unrelated probands; independent candidate-gene sequencing for hereditary hearing loss","pmids":["10973259","10973260","11023810"],"confidence":"High","gaps":["ATPase impairment was predicted by modelling, not measured directly","genotype-phenotype basis for syndromic vs. nonsyndromic presentations not resolved"]},{"year":2003,"claim":"Resolving how different alleles act—dominant-negative co-assembly versus haploinsufficiency—showed the disorder has more than one pathogenic mechanism.","evidence":"Immunofluorescence with epitope-mapped antibodies on patient neutrophils, plus protein/mRNA stability and localization assays for D1424N in megakaryocytes","pmids":["12533692","12649151"],"confidence":"Medium","gaps":["allele-specific mechanisms generalized from limited cases","inclusion-body composition beyond NMMHC-IIA not defined"]},{"year":2004,"claim":"Genetic knockout established that MYH9 is essential for embryonic development, distinguishing the lethal null state from the viable heterozygous disease state.","evidence":"Targeted and gene-trap knockout mice with breeding analysis and auditory testing","pmids":["15555549","17914179"],"confidence":"High","gaps":["the developmental process requiring MYH9 not identified at the null stage","tissue-specific contributions not separated"]},{"year":2011,"claim":"Knock-in alleles linked human mutations to a defined cellular defect—disrupted proplatelet formation—explaining macrothrombocytopenia mechanistically.","evidence":"R702C/D1424N/E1841K knock-in mice with live megakaryocyte imaging and hemostasis assays; separately a MYH9-USP6 oncogenic fusion in nodular fasciitis","pmids":["21908426","21826056"],"confidence":"High","gaps":["molecular link between motor dysfunction and proplatelet branching not fully mechanized","fusion-driven USP6 overexpression mechanism distinct from MYH9 function"]},{"year":2018,"claim":"Cell-intrinsic requirement for MYH9 in maintaining leading-edge F-actin dynamics established its direct motor role in migration in vivo.","evidence":"Vav-iCre conditional knockdown, STED nanoscopy, 2D/3D and in vivo migration assays with Myh9-EGFP rescue","pmids":["30068598"],"confidence":"High","gaps":["regulators coupling MYH9 to leading-edge actin not defined","threshold-level requirement not molecularly explained"]},{"year":2020,"claim":"Discovery of nuclear MYH9 binding the CTNNB1 promoter redefined the motor as a direct transcriptional driver of β-catenin, beyond its scaffolding of GSK3β degradation.","evidence":"Chromatin fractionation, ChIP, oligonucleotide pulldown, NLS-mutation analysis, EM, and in vivo models; parallel Co-IP/ubiquitination work defining the MYH9-GSK3β axis","pmids":["32685004","32296025"],"confidence":"High","gaps":["how a cytoskeletal motor engages promoter DNA structurally is unresolved","signals controlling nuclear partitioning incompletely defined"]},{"year":2020,"claim":"Renal tubular conditional deletion connected MYH9 to specialized epithelial trafficking, showing uromodulin transport failure and ER stress as the route to progressive kidney disease.","evidence":"Inducible Myh9/Myh10 renal cKO with immunofluorescence, EM, and UPR marker analysis","pmids":["33001861"],"confidence":"High","gaps":["direct cargo-transport role of NM2 in this trafficking step not biochemically reconstituted","Myh9 vs Myh10 individual contributions not separated"]},{"year":2021,"claim":"Identifying NEK9 as a selective autophagy adaptor for MYH9 explained how degrading a cytoskeletal stabilizer permits ciliogenesis.","evidence":"Co-IP, LIR-mutant knock-in mice with kidney cilia phenotypes, and MYH9-depletion rescue of ciliogenesis","pmids":["34078910"],"confidence":"High","gaps":["signal triggering NEK9-directed MYH9 turnover unknown","relationship to MYH9-related kidney disease not established"]},{"year":2021,"claim":"Maternal-zygotic deletion established MYH9 as the dominant non-muscle myosin II isoform for cytokinesis and compaction in early embryogenesis.","evidence":"Single and double Myh9/Myh10 maternal-zygotic knockouts with multiscale light-sheet and confocal imaging","pmids":["33871354"],"confidence":"High","gaps":["basis for the MYH9 > MYH10 functional hierarchy not molecularly explained"]},{"year":2022,"claim":"Single-platelet biophysics tied reduced light-chain phosphorylation in mutant platelets to impaired force generation, providing the mechanical explanation for bleeding and a pharmacological correction.","evidence":"Single-platelet force measurements, MLC phosphorylation assays, and tranexamic acid rescue across mutant lines and patient platelets","pmids":["35584211"],"confidence":"High","gaps":["how head/rod mutations specifically lower MLC phosphorylation not resolved"]},{"year":2022,"claim":"Hematopoietic conditional deletion demonstrated a cell-autonomous requirement for MYH9 in HSPC survival, defining bone marrow failure as a consequence of its loss.","evidence":"Mx1-cre Myh9 cKO with transplantation chimeras, RNA-seq, and apoptosis assays","pmids":["35740994"],"confidence":"High","gaps":["pro-survival pathway downstream of MYH9 in HSPCs not defined"]},{"year":2023,"claim":"Reconstituting the SPC25/RIOK1/MYH9 complex identified RIOK1 as the kinase phosphorylating Ser1943 to release MYH9 from the cytoskeleton and drive nuclear CTNNB1 transcription in chemoresistance.","evidence":"Co-IP, RIOK1 kinase assay on S1943, subcellular fractionation, CTNNB1 reporter, and competitive peptide disruption in vitro and in vivo","pmids":["39488790"],"confidence":"Medium","gaps":["upstream control of RIOK1 activity unclear","single-lab mechanism awaiting independent confirmation"]},{"year":2024,"claim":"Phospho-Ser1943 was shown to recruit deubiquitinases such as USP22 to stabilize signaling proteins like HIF-1α, extending the scaffold paradigm to a phosphorylation-gated ubiquitin-regulatory hub.","evidence":"IP-MS, ubiquitination and phospho-site assays, and CK2-inhibitor reversal of resistance in vivo; converging Co-IP/ubiquitination studies on YOD1, NAP1L1, RGS19, and STUB1","pmids":["39300073","38825640","37770914","40041897"],"confidence":"Medium","gaps":["structural basis for phospho-dependent deubiquitinase recruitment unknown","most scaffold partnerships rest on single-lab Co-IP/ubiquitination data"]},{"year":null,"claim":"How a single actin motor coordinately switches between cytoskeletal force generation, ubiquitin-machinery scaffolding, and direct promoter binding—and what determines which role dominates in a given cell—remains unresolved.","evidence":"No single study integrates the motor, scaffold, and transcriptional functions mechanistically","pmids":[],"confidence":"Medium","gaps":["no structural model of nuclear MYH9 on DNA","phosphorylation code partitioning MYH9 among compartments not fully mapped","scaffold interactions largely from individual cancer contexts not unified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,22,23]},{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[11,19,6]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[11,25,24]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[16,9,35]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[16]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[15,32,21]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[11,25,31]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[16,31,36]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,21]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[29]}],"pathway":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[16,31]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[19]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[15,33,8]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[15,34,40,28]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[18]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[6,23]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,19]}],"complexes":["SPC25/RIOK1/MYH9 complex","nuclear MYH9/MYL9/β-actin/RNA Pol II transcription complex"],"partners":["GSK3B","USP22","NEK9","ATG9B","STUB1","RIOK1","TUBB4A","YOD1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35579","full_name":"Myosin-9","aliases":["Cellular myosin heavy chain, type A","Myosin heavy chain 9","Myosin heavy chain, non-muscle IIa","Non-muscle myosin heavy chain A","NMMHC-A","Non-muscle myosin heavy chain IIa","NMMHC II-a","NMMHC-IIA"],"length_aa":1960,"mass_kda":226.5,"function":"Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping. Required for cortical actin clearance prior to oocyte exocytosis (By similarity). Promotes cell motility in conjunction with S100A4 (PubMed:16707441). During cell spreading, plays an important role in cytoskeleton reorganization, focal contact formation (in the margins but not the central part of spreading cells), and lamellipodial retraction; this function is mechanically antagonized by MYH10 (PubMed:20052411) (Microbial infection) Acts as a receptor for herpes simplex virus 1/HHV-1 envelope glycoprotein B","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P35579/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYH9","classification":"Not Classified","n_dependent_lines":658,"n_total_lines":1208,"dependency_fraction":0.5447019867549668},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000100345","cell_line_id":"CID000944","localizations":[{"compartment":"cytoskeleton","grade":3},{"compartment":"membrane","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"MYL12A;MYL9","stoichiometry":10.0},{"gene":"MYL6","stoichiometry":10.0},{"gene":"MYL12A","stoichiometry":10.0},{"gene":"MYL12B","stoichiometry":10.0},{"gene":"MDH2","stoichiometry":4.0},{"gene":"MYL6B","stoichiometry":4.0},{"gene":"HSPD1","stoichiometry":4.0},{"gene":"C1QBP","stoichiometry":4.0},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"EMC9","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000944","total_profiled":1310},"omim":[{"mim_id":"621473","title":"RETICULOPHAGY REGULATOR FAMILY, MEMBER 2; RETREG2","url":"https://www.omim.org/entry/621473"},{"mim_id":"621374","title":"SERINE/THREONINE/TYROSINE-INTERACTING PROTEIN-LIKE 2; STYXL2","url":"https://www.omim.org/entry/621374"},{"mim_id":"617750","title":"LIM AND CALPONIN HOMOLOGY DOMAINS-CONTAINING PROTEIN 1; LIMCH1","url":"https://www.omim.org/entry/617750"},{"mim_id":"617512","title":"ZINC FINGER PROTEIN 318; ZNF318","url":"https://www.omim.org/entry/617512"},{"mim_id":"616432","title":"RHO GUANINE NUCLEOTIDE EXCHANGE FACTOR 18; ARHGEF18","url":"https://www.omim.org/entry/616432"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Actin filaments","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"blood vessel","ntpm":530.2}],"url":"https://www.proteinatlas.org/search/MYH9"},"hgnc":{"alias_symbol":["NMMHCA","NMHC-II-A","MHA","FTNS","EPSTS"],"prev_symbol":["DFNA17"]},"alphafold":{"accession":"P35579","domains":[{"cath_id":"2.30.30.360","chopping":"19-81","consensus_level":"medium","plddt":81.0159,"start":19,"end":81},{"cath_id":"3.30.70.1590","chopping":"720-818","consensus_level":"medium","plddt":87.1666,"start":720,"end":818}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35579","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35579-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35579-F1-predicted_aligned_error_v6.png","plddt_mean":76.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYH9","jax_strain_url":"https://www.jax.org/strain/search?query=MYH9"},"sequence":{"accession":"P35579","fasta_url":"https://rest.uniprot.org/uniprotkb/P35579.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35579/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35579"}},"corpus_meta":[{"pmid":"18794856","id":"PMC_18794856","title":"MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis.","date":"2008","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18794856","citation_count":552,"is_preprint":false},{"pmid":"10973259","id":"PMC_10973259","title":"Mutations in MYH9 result in the May-Hegglin anomaly, and Fechtner and Sebastian syndromes. The May-Heggllin/Fechtner Syndrome Consortium.","date":"2000","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10973259","citation_count":344,"is_preprint":false},{"pmid":"21826056","id":"PMC_21826056","title":"Nodular fasciitis: a novel model of transient neoplasia induced by MYH9-USP6 gene fusion.","date":"2011","source":"Laboratory investigation; a journal of technical methods and pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21826056","citation_count":258,"is_preprint":false},{"pmid":"29679756","id":"PMC_29679756","title":"MYH9: Structure, functions and role of non-muscle myosin IIA in human disease.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/29679756","citation_count":252,"is_preprint":false},{"pmid":"10973260","id":"PMC_10973260","title":"Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May-Hegglin anomaly.","date":"2000","source":"Nature 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mutation deletes the C-terminal tailpiece.\",\n      \"method\": \"Mutation screening, direct sequencing, molecular modelling\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutations identified in seven unrelated probands, functional prediction by structural modelling, independently replicated by second paper same year (PMID:10973260)\",\n      \"pmids\": [\"10973259\", \"10973260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"MYH9 R705H mutation within the conserved SH1 helix causes DFNA17 nonsyndromic hereditary hearing loss; previous studies established that SH1 helix modification disrupts myosin II ATPase activity in the motor domain.\",\n      \"method\": \"Candidate gene sequencing, cosegregation analysis, RT-PCR and immunohistochemistry for cochlear expression\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cosegregation established, ATPase mechanism inferred from prior literature, single lab\",\n      \"pmids\": [\"11023810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Abnormal NMMHC-IIA (MYH9 protein) subcellular localization is observed in neutrophils from all individuals with MYH9 mutations; the protein colocalizes with inclusion bodies; normal NMMHC-IIA dimerizes with abnormal (truncated) NMMHC-IIA to form inclusion bodies, as shown by C-terminal antibody reactivity in heterozygotes for truncating mutations.\",\n      \"method\": \"Immunofluorescence analysis with polyclonal anti-NMMHCA antibody on blood smears from 24 patients, epitope mapping with C-terminal peptide antibody\",\n      \"journal\": \"Laboratory investigation; a journal of technical methods and pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with functional consequence, single lab, 24 cases\",\n      \"pmids\": [\"12533692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The D1424N MYH9 mutation results in a highly unstable protein without abnormalities in protein localization or mRNA stability, suggesting haploinsufficiency—rather than dominant-negative mislocalization—as the pathogenic mechanism for this allele.\",\n      \"method\": \"Protein expression analysis, mRNA stability assay, immunofluorescence in megakaryocytes\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (protein quantification, mRNA, localization), single lab\",\n      \"pmids\": [\"12649151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Complete homozygous loss of Myh9 is embryonic lethal (no homozygous pups among 552 births), establishing that MYH9 expression is required for embryonic development; heterozygous mice are viable without gross hematological or nephrological abnormalities, though some show hearing loss.\",\n      \"method\": \"Targeted gene disruption (knockout mouse), breeding analysis, auditory brainstem response\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic KO with defined developmental phenotype, replicated by independent gene-trap KO (PMID:17914179)\",\n      \"pmids\": [\"15555549\", \"17914179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Myh9 is localized within the stereocilia of inner and outer hair cells in the mouse cochlea, raising the possibility that MYH9 mutations cause hearing loss through disruption of stereocilia structure.\",\n      \"method\": \"Confocal immunofluorescence microscopy of cochlear surface preparations with anti-Myh9 antibody\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization by confocal microscopy, single lab, no functional rescue\",\n      \"pmids\": [\"16862555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mouse knock-in lines with R702C, D1424N, and E1841K Myh9 mutations recapitulate human MYH9-related disease; heterozygous R702C megakaryocytes form fewer, shorter proplatelets with less branching and larger buds in live-cell imaging of bone marrow, demonstrating that disrupted proplatelet formation underlies macrothrombocytopenia.\",\n      \"method\": \"Mouse knock-in models, live-cell imaging of megakaryocytes, cultured megakaryocyte analysis, bleeding time, clot retraction assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple knock-in alleles, live imaging with specific cellular phenotype, recapitulates human disease\",\n      \"pmids\": [\"21908426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MYH9-USP6 gene fusion in nodular fasciitis places the entire USP6 coding sequence under the MYH9 promoter, driving USP6 overexpression; xenografts of USP6-overexpressing cells in nude mice recapitulate clinical and histological features of nodular fasciitis.\",\n      \"method\": \"5'-RACE, RT-PCR/sequencing, in vivo xenograft, genomic FISH\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gene fusion identified by multiple molecular methods plus functional in vivo validation, single lab but multiple orthogonal techniques\",\n      \"pmids\": [\"21826056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Myh9 (nonmuscle myosin II-A) accumulates at colonic epithelial injury sites; monoallelic gut-epithelium-specific Myh9 deletion or pharmacological inhibition with blebbistatin activates Akt via Rac1 and PAK1, improving Lgr5+ stem cell survival and protecting against DSS-induced colitis, defining a Myh9–Rac1–PAK1–Akt pathway in intestinal stem cell maintenance.\",\n      \"method\": \"Conditional knockout mouse (Myh9 monoallelic deletion), blebbistatin inhibitor, Lgr5 organoid assay, live imaging, western blot for pathway components\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO plus pharmacological inhibition plus organoid assay plus pathway dissection, multiple orthogonal methods\",\n      \"pmids\": [\"25968904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MYH9 binds to the lncRNA PTCSC2 and inhibits the bidirectional FOXE1/PTCSC2 promoter activity in both directions; PTCSC2 reverses this MYH9-mediated transcriptional repression, demonstrating that MYH9 acts as a transcriptional repressor at this genomic locus.\",\n      \"method\": \"RNA pulldown, co-immunoprecipitation, dual-luciferase reporter assay, RNA knockdown\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding and reporter assay, single lab\",\n      \"pmids\": [\"28049826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SRF transcription factor binds the CArG box in the MYH9 promoter to drive MYH9 expression; miR-647 suppresses GC metastasis by directly targeting SRF mRNA, reducing MYH9 levels.\",\n      \"method\": \"ChIP for SRF at MYH9 promoter, 3'-UTR luciferase reporter, orthotopic GC xenograft model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays establishing transcriptional regulation, single lab\",\n      \"pmids\": [\"28900514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Myh9 is required for neutrophil migration: genetic downregulation of Myh9 in Vav-iCre mice significantly reduces migration velocity, transmigration, and 3D migration; STED nanoscopy showed that a threshold level of Myh9 is needed to maintain F-actin dynamics at the leading edge; Myh9-EGFP rescue restored migration defects, confirming cell-intrinsic function.\",\n      \"method\": \"Conditional knockdown (Vav-iCre), STED nanoscopy, 2D/3D migration assays, laser-induced skin injury, peritonitis model, bone marrow chimera, Myh9-EGFP rescue\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic model, multiple migration assays, STED imaging, EGFP rescue, in vivo and in vitro validation\",\n      \"pmids\": [\"30068598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MYH9 C-terminal domain (PRA, aa1676–1791) directly interacts with PRRSV glycoprotein 5 (GP5); soluble recombinant PRA blocks PRRSV entry in a dose-dependent manner and inhibits both genotype 1 and 2 strains, identifying MYH9 as an essential entry co-factor for PRRSV.\",\n      \"method\": \"GST pulldown, recombinant protein blocking assay, siRNA knockdown, blebbistatin inhibition, dose-response infection assay\",\n      \"journal\": \"Antiviral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding plus functional blocking experiment, single lab\",\n      \"pmids\": [\"29879459\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Angiotensin II reduces MYH9 expression in podocytes via TRPC6-mediated Ca2+ influx driven by NOX4-generated ROS; MYH9 knockdown recapitulates Ang II-induced actin cytoskeleton disruption and increased albumin permeability, while MYH9 overexpression rescues these effects, placing MYH9 downstream of the Ang II/TRPC6/NOX4 axis in maintaining the filtration barrier.\",\n      \"method\": \"siRNA knockdown, MYH9 overexpression, NOX4/ROS measurement, TRPC6 inhibition, albumin permeability assay, actin staining\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss and gain of function with multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"31118506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTP1B dephosphorylates MYH9 at Y1408; this dephosphorylation event upregulates EGFR expression and promotes cell migration and invasion in esophageal squamous cell carcinoma, defining a PTP1B–MYH9–EGFR signaling axis.\",\n      \"method\": \"GST pulldown combined with LC/MS/MS to identify MYH9 as PTP1B substrate, site-specific phosphorylation analysis, migration/invasion assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — substrate identified by pulldown-MS and biochemically validated, single lab\",\n      \"pmids\": [\"31735331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MYH9 interacts with GSK3β and promotes its ubiquitin-mediated degradation, thereby dysregulating the β-catenin destruction complex and activating downstream Wnt/β-catenin signaling and tumor stemness in hepatocellular carcinoma; HBx protein interacts with MYH9 and induces its expression, while c-Jun transcriptionally stimulates MYH9 to form a feedback loop.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ubiquitination assay, luciferase reporter, in vivo mouse model, ChIP for c-Jun at MYH9 promoter\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination assay, and ChIP in single lab\",\n      \"pmids\": [\"32296025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Nuclear MYH9 binds directly to the CTNNB1 (β-catenin) promoter through its DNA-binding domain, and forms a transcriptional complex with myosin light chain 9, β-actin, and RNA Pol II to drive CTNNB1 transcription; nuclear translocation is enabled by potential NLS sequences; S1943 phosphorylation promotes nuclear accumulation, while staurosporine reduces S1943 phosphorylation to inhibit this activity.\",\n      \"method\": \"Immunofluorescence, immune transmission electron microscopy, chromatin fractionation, Co-IP, ChIP, dual luciferase reporter, agarose-oligonucleotide pulldown, nuclear localization signal mutation analysis, in vivo transgenic and xenograft models\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (ChIP, Co-IP, fractionation, reporter, EM, in vivo), single lab but comprehensive mechanistic dissection\",\n      \"pmids\": [\"32685004\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Conditional inactivation of Myh9 (and Myh10) in adult mouse renal tubular epithelia causes progressive kidney disease preceded by intracellular accumulation of uromodulin (UMOD), loss of NKCC2 from the apical membrane, expansion of ER tubules, and activation of ER stress/UPR pathways, demonstrating that NM2 proteins are required for UMOD transport and specialized renal epithelial trafficking.\",\n      \"method\": \"Inducible conditional knockout mouse (Myh9/Myh10 cKO), immunofluorescence, electron microscopy, ER stress marker analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic cKO with multiple orthogonal readouts (protein localization, EM, ER stress markers), in vivo mechanistic link established\",\n      \"pmids\": [\"33001861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NEK9 acts as a selective autophagy adaptor for MYH9: NEK9 interacts with MYH9 and its LC3-interacting region (LIR) directs autophagic degradation of MYH9, which otherwise stabilizes the actin network and inhibits primary cilia formation; MYH9 depletion restores ciliogenesis in NEK9 LIR-mutant cells.\",\n      \"method\": \"Co-IP, LIR mutation knock-in mice (in vivo cilia analysis in kidneys), MYH9 accumulation measurement, MYH9 siRNA rescue of ciliogenesis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, genetic LIR-mutant mice with kidney phenotype, mechanistic rescue by MYH9 depletion, multiple orthogonal approaches\",\n      \"pmids\": [\"34078910\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Myh9 is the major nonmuscle myosin II heavy chain during mouse preimplantation development: maternal-zygotic loss of Myh9 causes failed cytokinesis, prolonged cell cycle, weaker compaction, and reduced differentiation; double Myh9/Myh10 maternal-zygotic mutants show near-complete cytokinesis failure, while Myh10 single mutants are much less severely affected.\",\n      \"method\": \"Maternal-zygotic knockout mouse models, multiscale live imaging (light-sheet and confocal), morphometric analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic maternal-zygotic KO with multiscale imaging, single vs. double mutant comparison establishes isoform hierarchy\",\n      \"pmids\": [\"33871354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYH9 promotes lung cancer stem cell-like features by activating the mTOR signaling pathway; MYH9 knockdown or blebbistatin treatment reduces stemness markers (CD44, SOX2, Nanog, CD133, OCT4), sphere formation, and mTOR pathway activity.\",\n      \"method\": \"MYH9 overexpression/knockout, western blot for mTOR pathway, sphere formation assay, rapamycin inhibitor, in vivo blebbistatin treatment\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway activation inferred from inhibitor studies without direct binding evidence\",\n      \"pmids\": [\"34635641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYH9 directly binds cytoplasmic segments aa368–411 of ATG9B via its head domain; ATG9B–MYH9 interaction decreases each protein's binding to E3 ubiquitin ligase STUB1, mutually stabilizing both proteins; during invasion, MYH9 transports ATG9B to the cell edge, where ATG9B promotes focal adhesion assembly by mediating interaction of endocytosed integrin β1 with Talin-1.\",\n      \"method\": \"Co-IP, peptide-domain mapping, STUB1 ubiquitination assay, live-cell imaging of ATG9B polarization, integrin β1-Talin-1 interaction assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-level binding defined, ubiquitination assay, live imaging, single lab\",\n      \"pmids\": [\"34131310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TGF-β1 increases MYH9 expression via the ALK5/Smad2/3 pathway (but not p38 MAPK or Akt); siRNA-mediated knockdown or pharmacological inhibition of MYH9 ATPase activity suppresses TGF-β1-induced lung fibroblast-to-myofibroblast differentiation.\",\n      \"method\": \"siRNA knockdown, MYH9 ATPase inhibitor, pathway inhibitors (ALK5, p38, Akt), western blot for differentiation markers\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific phenotypic readout plus upstream pathway dissection, single lab\",\n      \"pmids\": [\"33519439\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Reduced myosin light chain phosphorylation after agonist stimulation in Myh9 mutant platelets (R702C, D1424N, E1841K) leads to altered biophysical properties and lower adhesion, interaction, and traction forces, directly underlying the increased bleeding tendency in MYH9-related disease; tranexamic acid restores clot retraction and reduces bleeding.\",\n      \"method\": \"Single-platelet force measurement, myosin light chain phosphorylation assay, clot retraction assay, patient platelet analysis, tranexamic acid treatment in mutant mice\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple mutant mouse lines, single-platelet biophysics, confirmed in patient platelets, pharmacological rescue\",\n      \"pmids\": [\"35584211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TUBB4A interacts with MYH9 to protect the nucleus during constricted cell migration; TUBB4A knockout or MYH9 knockdown causes severe nuclear DNA damage (increased γH2AX, 53BP1) and reduces NF-κB signaling; TUBB4A/GSK3β binds the N-terminal domain of MYH9 and TUBB4A KO reduces MYH9-mediated GSK3β ubiquitination and degradation, decreasing β-catenin signaling.\",\n      \"method\": \"Co-IP, domain-mapping (N-terminal MYH9), MYH9 knockdown, TUBB4A KO, nuclear damage quantification (γH2AX/53BP1), ubiquitination assay, constricted migration assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping, ubiquitination assay, KD/KO with specific nuclear damage phenotype, single lab\",\n      \"pmids\": [\"35589707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TPRG1-AS1 lncRNA directly interacts with MYH9 protein in HASMCs and promotes MYH9 protein degradation through the proteasome pathway, thereby hindering F-actin stress fiber formation and inhibiting smooth muscle cell migration; VSM-specific TPRG1-AS1 overexpression reduces neointima formation and atherosclerosis in vivo.\",\n      \"method\": \"RNA-protein interaction assay, Co-IP, proteasome inhibitor (MG132) rescue, F-actin staining, migration assay, transgenic/KO mouse vascular injury and atherosclerosis models\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA–protein interaction, proteasome degradation assay, in vivo vascular models, single lab\",\n      \"pmids\": [\"36172865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OVGP1 interacts with MYH9 (shown by pulldown-MS and Co-IP); inhibition of MYH9 attenuates OVGP1-induced hypertension and vascular remodeling in transgenic mice, placing MYH9 downstream of OVGP1 in this pathway.\",\n      \"method\": \"Pulldown/mass spectrometry, Co-IP, MYH9 inhibitor in OVGP1 transgenic mice, blood pressure measurement\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal biochemical interaction plus in vivo inhibitor rescue, single lab\",\n      \"pmids\": [\"36172862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Dlc1 (RhoGAP) interacts with MYH9 in multiprotein complexes; Dlc1 overexpression increases phosphorylation of MYH9 and activates Rac1 GTPase, linking MYH9 to Rac1-mediated cytoskeletal changes.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, western blot for MYH9 phosphorylation, Rac1 activation assay\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/MS with phosphorylation endpoint, no mechanistic rescue experiment, single lab\",\n      \"pmids\": [\"26977077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MYH9 promotes microglial homeostasis; YOD1 deubiquitinase binds MYH9 and removes K48-linked ubiquitin chains, stabilizing MYH9 protein; YOD1 knockout reduces MYH9 levels, impairs microglial migration, phagocytosis, and inflammatory response, and improves cognition in AD model mice.\",\n      \"method\": \"LC-MS/MS, Co-IP, ubiquitination assay (K48-chain specificity), YOD1 KO mouse, behavioral tests\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with ubiquitin chain-type specificity plus in vivo KO with phenotypic readout, single lab\",\n      \"pmids\": [\"40041897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MYH9 is identified as a key secreted/extracellular regulator of rheumatoid arthritis fibroblast-like synoviocyte migration and invasion; IL-1β, TNF-α, TLR ligation, and ER stress induce MYH9 secretion; blebbistatin (MYH9 ATPase inhibitor) substantially inhibits RA-FLS migration/invasion in vitro and in a humanized synovitis mouse model.\",\n      \"method\": \"LC-MS/MS secretome analysis, western blot, ELISA, siRNA/blebbistatin functional assays, humanized synovitis mouse model\",\n      \"journal\": \"Annals of the rheumatic diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — secretome MS, loss-of-function with specific phenotype, in vivo model, single lab\",\n      \"pmids\": [\"37188496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DNAJA4 facilitates MYH9 protein degradation via the ubiquitin-proteasome pathway by recruiting PSMD2; overexpression of MYH9 reverses the suppressive effects of DNAJA4 on NPC cell migration, invasion, and EMT, placing MYH9 downstream of the DNAJA4-PSMD2 complex.\",\n      \"method\": \"Co-IP, ubiquitination assay, MYH9 overexpression rescue, in vitro migration/invasion assay, in vivo metastasis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, proteasome degradation, genetic rescue experiment, single lab\",\n      \"pmids\": [\"37875476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SPC25 scaffolds a trimeric SPC25/RIOK1/MYH9 complex; RIOK1 phosphorylates MYH9 at Ser1943 within this complex, causing MYH9 to disengage from the cytoskeleton and accumulate in the nucleus, where it drives CTNNB1 transcription and Wnt/β-catenin signaling to promote cancer stemness and platinum resistance in ovarian cancer.\",\n      \"method\": \"Co-IP (trimeric complex), kinase assay (RIOK1-mediated MYH9 S1943 phosphorylation), subcellular fractionation, luciferase reporter for CTNNB1, competitive peptide (CBP1) disruption in vitro/in vivo/organoids\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical complex, phosphorylation-site assay, nuclear fractionation, functional rescue, single lab\",\n      \"pmids\": [\"39488790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MYH9 binds NAP1L1 and recruits USP14 deubiquitinase to prevent NAP1L1 ubiquitination and degradation; stabilized NAP1L1 binds c-Myc and activates CCND1/CDK4 expression, promoting glioma proliferation and temozolomide resistance.\",\n      \"method\": \"Co-IP, ubiquitination assay, MYH9 knockdown, rescue experiments, western blot\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/ubiquitination approach, single lab, no direct binding reconstitution\",\n      \"pmids\": [\"37770914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SAMD9 stimulates GSK3β ubiquitin-mediated degradation by interacting with both MYH9 and TRAF6; silencing MYH9 or β-catenin blocks SAMD9-driven tumor stemness, EMT, and metastasis, placing MYH9 as the key intermediary in the SAMD9/MYH9/GSK3β/β-catenin axis.\",\n      \"method\": \"Co-IP, ubiquitination assay, MYH9/β-catenin siRNA rescue, in vivo tumor and metastasis models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination, genetic rescue, in vivo validation, single lab\",\n      \"pmids\": [\"36757050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Phosphorylated MYH9 at Ser1943 (p-MYH9 S1943) recruits deubiquitinase USP22 to deubiquitinate and stabilize HIF-1α in lenvatinib-resistant HCC cells, promoting cancer stemness; CK2 inhibitor reduces MYH9 S1943 phosphorylation and reverses resistance in vivo.\",\n      \"method\": \"Immunoprecipitation, mass spectrometry, ubiquitination assay, site-specific phosphorylation analysis, CK2 inhibitor treatment, in vivo models\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS, ubiquitination assay, phospho-site validation, in vivo pharmacological rescue, single lab\",\n      \"pmids\": [\"39300073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MafG physically interacts with MYH9 to transcriptionally activate LCN2 expression; MARE motif site-directed mutation blocks MafG binding to the LCN2 promoter; LCN2 re-expression in MafG-knockdown HSCs restores resistance to ferroptosis, defining MafG/MYH9 as a transcriptional activator complex suppressing HSC ferroptosis.\",\n      \"method\": \"Co-IP, ChIP, site-directed mutagenesis of MARE motif, LCN2 rescue experiment, AAV6-mediated HSC-specific MafG KD in BDL mouse model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, mutagenesis, rescue experiment, in vivo model, single lab\",\n      \"pmids\": [\"38871948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HMBA binds directly to MYH9 (and ACTG1) in hypothalamic neurons; this binding is required for HMBA's anti-obesity effects on NPY and POMC expression; MYH9 binding by HMBA elevates HEXIM1 expression and enhances HEXIM1-MDM2 interaction, causing free HEXIM1 and p53 to translocate to the nucleus and modulate neuropeptide transcription.\",\n      \"method\": \"Direct binding assay (HMBA-MYH9), co-IP (HEXIM1-MDM2), nuclear fractionation, NPY/POMC reporter/ChIP assays, in vivo central/peripheral HMBA administration to DIO mice, MYH9-KD in NPY/POMC neurons\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct compound-protein binding, multiple biochemical assays, in vivo KD, single lab\",\n      \"pmids\": [\"37984341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MYH9 head domain directly binds the cytoplasmic segment aa368–411 of ATG9B; their interaction mutually prevents binding to STUB1 E3 ubiquitin ligase, stabilizing both proteins and promoting CRC invasion.\",\n      \"method\": \"Co-IP, domain-mapping, ubiquitination assay, STUB1 interaction competition\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-level binding and ubiquitination assay, single lab\",\n      \"pmids\": [\"34131310\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ENKUR recruits E3 ligase FBXW7 to form a ubiquitinated degradation complex with MYH9; downregulated MYH9 reduces recruitment of deubiquitinase USP2, promoting β-catenin degradation and suppressing EMT and GC metastasis.\",\n      \"method\": \"Co-IP, ubiquitination assay, MYH9 overexpression rescue, migration/invasion assays, in vivo metastasis\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/ubiquitination, single lab, limited mechanistic depth for MYH9 specifically\",\n      \"pmids\": [\"36448053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MYH10 protein functional domain combines with MYH9 to recruit deubiquitinase USP45, which deubiquitinates Snail to prevent its degradation, promoting ovarian cancer tumorigenesis and cisplatin resistance.\",\n      \"method\": \"Co-IP, GST pulldown, deubiquitination assay, confocal colocalization, MYH10/MYH9 knockdown\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — complex identified by pulldown and Co-IP, deubiquitination assay; mechanistic role is primarily assigned to MYH10, MYH9 participates as binding partner\",\n      \"pmids\": [\"36929633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RGS19 stabilizes MYH9 protein by directly competing with STUB1 (E3 ligase) for MYH9 binding via its RGS domain, reducing MYH9 ubiquitination; stabilized MYH9 activates β-catenin/c-Myc signaling; RGS19 is in turn a transcriptional target of c-Myc, forming a positive feedback loop.\",\n      \"method\": \"Co-IP, domain competition assay (RGS domain), ubiquitination assay, STUB1 identified as E3 ligase for MYH9, c-Myc ChIP\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain specificity, ubiquitination competition assay, in vivo and in vitro validation, single lab\",\n      \"pmids\": [\"38825640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Myh9 is essential for hematopoietic stem/progenitor cell (HSPC) survival and maintenance: Mx1-cre conditional Myh9 deletion causes pancytopenia, drastic reduction of HSPCs, bone marrow failure, impaired repopulation capacity, increased apoptosis, and early lethality; the defect is cell-autonomous.\",\n      \"method\": \"Inducible conditional knockout (Mx1-cre Myh9 flox), bone marrow transplantation chimera, RNA-seq, apoptosis assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with cell-autonomous rescue, multiple phenotypic readouts, RNA-seq pathway analysis\",\n      \"pmids\": [\"35740994\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYH9 encodes the heavy chain of non-muscle myosin IIA (NMII-A), an actin-based molecular motor whose ATPase activity and filament-forming capacity are regulated by 20-kDa light chain phosphorylation and by heavy-chain phosphorylation (notably at Ser1943); disease-causing mutations in the motor head impair ATPase activity and proplatelet formation, while rod/coiled-coil mutations destabilize the filament or cause haploinsufficiency, and a truncating mutation deletes the tailpiece. Beyond its canonical cytoskeletal role in cell migration, cytokinesis, and podocyte filtration-barrier integrity, MYH9 acts as a scaffold that recruits ubiquitin-regulatory proteins (USP22, USP14, USP2, FBXW7, STUB1) to control the stability of signaling proteins including GSK3β (promoting β-catenin/Wnt activation), HIF-1α, NAP1L1, and Snail; in certain contexts phospho-MYH9 (Ser1943) translocates to the nucleus to directly transcribe CTNNB1; NEK9 targets MYH9 for autophagic degradation to permit primary cilia formation; and complete MYH9 loss is embryonic lethal while tissue-specific deletion in renal tubules or hematopoietic cells causes progressive kidney disease or bone marrow failure, respectively.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYH9 encodes the heavy chain of non-muscle myosin IIA, an actin-based motor whose ATPase and filament functions underlie cytokinesis, cell migration, mechanical force generation, and specialized epithelial trafficking [#19, #11, #17]. Heterozygous mutations clustered in the motor head and coiled-coil rod domains cause an autosomal-dominant disorder spanning May-Hegglin anomaly, Fechtner and Sebastian syndromes, with head mutations predicted to impair ATPase activity and rod mutations destabilizing the filament, while a tailpiece-truncating allele acts via dominant-negative co-assembly into leukocyte inclusion bodies and the D1424N allele via haploinsufficiency [#0, #2, #3]; an SH1-helix R705H substitution causes DFNA17 hearing loss, consistent with cochlear hair-cell stereocilia localization [#1, #5]. Knock-in models recapitulate macrothrombocytopenia by disrupting proplatelet formation and reducing agonist-induced light-chain phosphorylation, adhesion, and traction forces in platelets [#6, #23]. Complete loss is embryonic lethal, and conditional deletion reveals tissue-autonomous requirements: hematopoietic deletion causes bone marrow failure, renal tubular deletion disrupts uromodulin transport with ER stress, and preimplantation loss causes cytokinesis failure, with MYH9 functionally dominant over MYH10 [#4, #41, #17, #19]. Beyond its cytoskeletal motor role, MYH9 functions as a scaffold for ubiquitin-regulatory enzymes, binding GSK3\\u03b2 and promoting its ubiquitin-mediated degradation to activate Wnt/\\u03b2-catenin signaling and tumor stemness, and recruiting deubiquitinases (USP22, USP14, YOD1) to stabilize HIF-1\\u03b1, NAP1L1, and MYH9 itself [#15, #34, #32, #28]; its own abundance is set by competition between the STUB1 E3 ligase and stabilizers such as RGS19 [#40]. Phosphorylation at Ser1943, catalyzed by RIOK1 within an SPC25/RIOK1 complex, releases MYH9 from the cytoskeleton and drives its nuclear accumulation, where it binds the CTNNB1 promoter and assembles a transcription complex with myosin light chain 9, \\u03b2-actin, and RNA Pol II to directly transcribe \\u03b2-catenin [#16, #31]. NEK9 targets MYH9 for selective autophagic degradation via an LC3-interacting region to permit primary cilium formation [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that MYH9 is the disease gene defined the molecular basis of a group of autosomal-dominant macrothrombocytopenia syndromes and pointed mechanism toward motor and rod-domain dysfunction.\",\n      \"evidence\": \"Mutation screening and molecular modelling in unrelated probands; independent candidate-gene sequencing for hereditary hearing loss\",\n      \"pmids\": [\"10973259\", \"10973260\", \"11023810\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"ATPase impairment was predicted by modelling, not measured directly\", \"genotype-phenotype basis for syndromic vs. nonsyndromic presentations not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolving how different alleles act\\u2014dominant-negative co-assembly versus haploinsufficiency\\u2014showed the disorder has more than one pathogenic mechanism.\",\n      \"evidence\": \"Immunofluorescence with epitope-mapped antibodies on patient neutrophils, plus protein/mRNA stability and localization assays for D1424N in megakaryocytes\",\n      \"pmids\": [\"12533692\", \"12649151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"allele-specific mechanisms generalized from limited cases\", \"inclusion-body composition beyond NMMHC-IIA not defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Genetic knockout established that MYH9 is essential for embryonic development, distinguishing the lethal null state from the viable heterozygous disease state.\",\n      \"evidence\": \"Targeted and gene-trap knockout mice with breeding analysis and auditory testing\",\n      \"pmids\": [\"15555549\", \"17914179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"the developmental process requiring MYH9 not identified at the null stage\", \"tissue-specific contributions not separated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Knock-in alleles linked human mutations to a defined cellular defect\\u2014disrupted proplatelet formation\\u2014explaining macrothrombocytopenia mechanistically.\",\n      \"evidence\": \"R702C/D1424N/E1841K knock-in mice with live megakaryocyte imaging and hemostasis assays; separately a MYH9-USP6 oncogenic fusion in nodular fasciitis\",\n      \"pmids\": [\"21908426\", \"21826056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"molecular link between motor dysfunction and proplatelet branching not fully mechanized\", \"fusion-driven USP6 overexpression mechanism distinct from MYH9 function\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Cell-intrinsic requirement for MYH9 in maintaining leading-edge F-actin dynamics established its direct motor role in migration in vivo.\",\n      \"evidence\": \"Vav-iCre conditional knockdown, STED nanoscopy, 2D/3D and in vivo migration assays with Myh9-EGFP rescue\",\n      \"pmids\": [\"30068598\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"regulators coupling MYH9 to leading-edge actin not defined\", \"threshold-level requirement not molecularly explained\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovery of nuclear MYH9 binding the CTNNB1 promoter redefined the motor as a direct transcriptional driver of \\u03b2-catenin, beyond its scaffolding of GSK3\\u03b2 degradation.\",\n      \"evidence\": \"Chromatin fractionation, ChIP, oligonucleotide pulldown, NLS-mutation analysis, EM, and in vivo models; parallel Co-IP/ubiquitination work defining the MYH9-GSK3\\u03b2 axis\",\n      \"pmids\": [\"32685004\", \"32296025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how a cytoskeletal motor engages promoter DNA structurally is unresolved\", \"signals controlling nuclear partitioning incompletely defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Renal tubular conditional deletion connected MYH9 to specialized epithelial trafficking, showing uromodulin transport failure and ER stress as the route to progressive kidney disease.\",\n      \"evidence\": \"Inducible Myh9/Myh10 renal cKO with immunofluorescence, EM, and UPR marker analysis\",\n      \"pmids\": [\"33001861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"direct cargo-transport role of NM2 in this trafficking step not biochemically reconstituted\", \"Myh9 vs Myh10 individual contributions not separated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identifying NEK9 as a selective autophagy adaptor for MYH9 explained how degrading a cytoskeletal stabilizer permits ciliogenesis.\",\n      \"evidence\": \"Co-IP, LIR-mutant knock-in mice with kidney cilia phenotypes, and MYH9-depletion rescue of ciliogenesis\",\n      \"pmids\": [\"34078910\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"signal triggering NEK9-directed MYH9 turnover unknown\", \"relationship to MYH9-related kidney disease not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Maternal-zygotic deletion established MYH9 as the dominant non-muscle myosin II isoform for cytokinesis and compaction in early embryogenesis.\",\n      \"evidence\": \"Single and double Myh9/Myh10 maternal-zygotic knockouts with multiscale light-sheet and confocal imaging\",\n      \"pmids\": [\"33871354\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"basis for the MYH9 > MYH10 functional hierarchy not molecularly explained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Single-platelet biophysics tied reduced light-chain phosphorylation in mutant platelets to impaired force generation, providing the mechanical explanation for bleeding and a pharmacological correction.\",\n      \"evidence\": \"Single-platelet force measurements, MLC phosphorylation assays, and tranexamic acid rescue across mutant lines and patient platelets\",\n      \"pmids\": [\"35584211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"how head/rod mutations specifically lower MLC phosphorylation not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Hematopoietic conditional deletion demonstrated a cell-autonomous requirement for MYH9 in HSPC survival, defining bone marrow failure as a consequence of its loss.\",\n      \"evidence\": \"Mx1-cre Myh9 cKO with transplantation chimeras, RNA-seq, and apoptosis assays\",\n      \"pmids\": [\"35740994\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"pro-survival pathway downstream of MYH9 in HSPCs not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reconstituting the SPC25/RIOK1/MYH9 complex identified RIOK1 as the kinase phosphorylating Ser1943 to release MYH9 from the cytoskeleton and drive nuclear CTNNB1 transcription in chemoresistance.\",\n      \"evidence\": \"Co-IP, RIOK1 kinase assay on S1943, subcellular fractionation, CTNNB1 reporter, and competitive peptide disruption in vitro and in vivo\",\n      \"pmids\": [\"39488790\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"upstream control of RIOK1 activity unclear\", \"single-lab mechanism awaiting independent confirmation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Phospho-Ser1943 was shown to recruit deubiquitinases such as USP22 to stabilize signaling proteins like HIF-1\\u03b1, extending the scaffold paradigm to a phosphorylation-gated ubiquitin-regulatory hub.\",\n      \"evidence\": \"IP-MS, ubiquitination and phospho-site assays, and CK2-inhibitor reversal of resistance in vivo; converging Co-IP/ubiquitination studies on YOD1, NAP1L1, RGS19, and STUB1\",\n      \"pmids\": [\"39300073\", \"38825640\", \"37770914\", \"40041897\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"structural basis for phospho-dependent deubiquitinase recruitment unknown\", \"most scaffold partnerships rest on single-lab Co-IP/ubiquitination data\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single actin motor coordinately switches between cytoskeletal force generation, ubiquitin-machinery scaffolding, and direct promoter binding\\u2014and what determines which role dominates in a given cell\\u2014remains unresolved.\",\n      \"evidence\": \"No single study integrates the motor, scaffold, and transcriptional functions mechanistically\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no structural model of nuclear MYH9 on DNA\", \"phosphorylation code partitioning MYH9 among compartments not fully mapped\", \"scaffold interactions largely from individual cancer contexts not unified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 22, 23]},\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [11, 19, 6]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [11, 25, 24]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [16, 9, 35]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [15, 32, 21]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [11, 25, 31]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [16, 31, 36]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 21]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [16, 31]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [19]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [15, 33, 8]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [15, 34, 40, 28]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [6, 23]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 19]}\n    ],\n    \"complexes\": [\n      \"SPC25/RIOK1/MYH9 complex\",\n      \"nuclear MYH9/MYL9/\\u03b2-actin/RNA Pol II transcription complex\"\n    ],\n    \"partners\": [\n      \"GSK3B\",\n      \"USP22\",\n      \"NEK9\",\n      \"ATG9B\",\n      \"STUB1\",\n      \"RIOK1\",\n      \"TUBB4A\",\n      \"YOD1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}