{"gene":"MYO18A","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2003,"finding":"MYO18A (MysPDZ) has two isoforms: MysPDZα (containing PDZ domain) co-localizes with the ER-Golgi complex, while MysPDZβ (lacking PDZ domain) localizes diffusely in the cytoplasm. Expression of the PDZ-containing isoform is restricted to mature macrophages and absent from hematopoietic progenitors.","method":"Subcellular fractionation, immunofluorescence microscopy, isoform-specific expression analysis","journal":"Journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiments with functional inference, single lab, two orthogonal methods (imaging + expression profiling)","pmids":["12761286"],"is_preprint":false},{"year":2005,"finding":"MYO18A contains an ATP-insensitive actin-binding site located in the middle region of its N-terminal domain (outside the PDZ module), distinct from known actin-binding motifs. The protein forms stable dimers via its coiled-coil tail, suggesting it can cross-link actin filaments via two ATP-insensitive N-terminal actin-binding sites.","method":"Cosedimentation assay with truncated constructs, chemical cross-linking, GFP-tagged expression in HeLa cells","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro cosedimentation assay with multiple truncation mutants, chemical cross-linking, replicated with multiple constructs in single rigorous study","pmids":["15835906"],"is_preprint":false},{"year":2005,"finding":"MYO18A (MysPDZ) self-associates through its C-terminal coiled-coil domain. The KE-rich domain mediates interaction with actin filaments and controls co-distribution with actin fibers. The PDZ domain controls localization to the inner surface of the cell membrane. Movement in the cytoplasm is ATP-hydrolysis-independent.","method":"Co-immunoprecipitation, EYFP-tagged deletion mutants, time-lapse video microscopy","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mutants and live imaging, single lab, two orthogonal methods","pmids":["15582604"],"is_preprint":false},{"year":2004,"finding":"A novel 110 kDa isoform of MYO18A is tyrosine-phosphorylated following CSF-1 receptor (c-Fms) activation. This phosphorylation requires Tyr-559 in the cytoplasmic domain of CSF-1R and is therefore Src-family kinase-dependent.","method":"2D-SDS/PAGE, mass spectrometry identification, CSF-1R mutant receptor studies","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS identification combined with receptor mutation studies establishing kinase dependency, single lab","pmids":["14969583"],"is_preprint":false},{"year":2005,"finding":"MYO18A-FGFR1 fusion protein is generated by t(8;17)(p11;q23), joining exon 32 of MYO18A to exon 9 of FGFR1, creating a constitutively active tyrosine kinase fusion that is structurally similar to other oncogenic FGFR1 fusion kinases.","method":"RT-PCR fusion transcript identification, bubble-PCR genomic breakpoint mapping, FISH","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular characterization of fusion transcript and genomic breakpoints, single case but rigorous molecular methods","pmids":["15800673"],"is_preprint":false},{"year":2009,"finding":"MYO18A is a novel binding partner of the PAK2/βPIX/GIT1 complex. MYO18A binds PAK2 indirectly through the βPIX/GIT1 complex. Under normal conditions MYO18A and PAK2 co-localize in lamellipodia and membrane ruffles. Knockdown of MYO18A shifts PAK2/βPIX/GIT1 complex localization to focal adhesions, increases focal adhesion size and number, and decreases cell motility; re-expression of MYO18A restores migration.","method":"Proteomic approach (Co-IP/MS), siRNA knockdown, in vitro binding assay, fluorescence microscopy, migration assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, in vitro binding, siRNA rescue experiment, multiple orthogonal methods establishing both binding and functional consequence","pmids":["19923322"],"is_preprint":false},{"year":2009,"finding":"MYO18A-PDGFRB fusion gene is generated by t(5;17)(q33-34;q11.2), fusing MYO18A to PDGFRB to create a constitutively active kinase in myeloproliferative neoplasm; the resulting fusion is sensitive to imatinib.","method":"LDI-PCR genomic fusion identification, FISH, imatinib treatment response","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — molecular characterization of fusion with functional validation via imatinib response, single case","pmids":["19006078"],"is_preprint":false},{"year":2014,"finding":"MYO18Aα interacts directly with βPIX via binding of the MYO18Aα C-terminal globular domain to the extreme C-terminus of βPIX (residues 639-646, PAWDETNL motif). This interaction is required for proper localization of βPIX away from focal adhesions, maintenance of Rac1 activity, and epithelial cell migration.","method":"Deletion mutant analysis, Co-IP, fluorescence microscopy, Rac1 activity assay, migration assay","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Strong — precise domain mapping with multiple deletion mutants, reciprocal Co-IP, functional rescue experiments, multiple orthogonal readouts","pmids":["25014165"],"is_preprint":false},{"year":2015,"finding":"MYO18A (SP-R210) isoforms SP-R210L and SP-R210S differentially regulate macrophage inflammatory responses. SP-R210L dominant-negative disruption augments expression of SR-A, CD14, and CD36. SP-R210S physically associates with CD14 and SR-A, enhancing LPS response. SP-R210L and SP-R210S regulate internalization of CD14 via distinct macropinocytosis-like mechanisms.","method":"Dominant-negative disruption, flow cytometry, Co-immunoprecipitation, macrophage stimulation assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing physical association, dominant-negative functional studies, single lab with multiple methods","pmids":["25965346"],"is_preprint":false},{"year":2021,"finding":"MYO18A forms a ternary Smad4-MYO18A-PP1A complex. MYO18A interacts with PP1A via its RVFFR motif and with Smad4 via its CC (coiled-coil) domain. This complex acts as a PP1-interacting protein scaffold for substrate recognition, mediating dephosphorylation of PAK1 at T423, which in turn reduces β-catenin S675 phosphorylation and inhibits β-catenin nuclear translocation.","method":"LC-MS/MS, Co-IP, domain deletion/point mutation analysis, in vitro and in vivo functional assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1 / Strong — LC-MS/MS interactome with biochemical validation, precise domain mapping (RVFFR motif and CC domain), multiple orthogonal methods including in vivo","pmids":["34799729"],"is_preprint":false},{"year":2021,"finding":"MYO18A knockdown significantly reduces cell migration activity in HCT-116 colorectal cancer cells, establishing a direct role in cancer cell migration.","method":"siRNA knockdown, migration assay","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (siRNA + migration assay), single cell line, no pathway mechanism identified beyond prior reports","pmids":["33194745"],"is_preprint":false},{"year":2024,"finding":"MYO18A γ isoform (striated muscle-specific) localizes to sarcomeric A-bands. Genetic deletion of Myo18a in mice is embryonic lethal and associated with cardiac sarcomere disorganization. The motor domain of Myo18Aγ has biochemically demonstrated negligible ATPase activity. Myo18Aγ is proposed to coassemble with thick filaments providing structural integrity through interactions with F-actin.","method":"Mouse genetic knockout (embryonic lethal phenotype), sarcomere localization (immunofluorescence), biochemical ATPase activity assay","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined phenotype, biochemical ATPase assay, localization studies; review paper synthesizing data from multiple studies","pmids":["38784114"],"is_preprint":false},{"year":2023,"finding":"MYO18A C-terminal coiled-coil domain and C-extension (CCex) interact with the TPR domains of synaptic scaffold proteins Tanc1 and Tanc2. This interaction is primarily driven by charge-charge interactions and can undergo liquid-liquid phase separation (LLPS) in both cultured cells and in vitro.","method":"Size exclusion chromatography, LLPS assay in cells and test tubes, sequence analysis, high-salt disruption experiments","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical binding assay with domain mapping and LLPS validation in cells and in vitro, single lab","pmids":["38092135"],"is_preprint":false},{"year":2025,"finding":"MYO18A physically interacts with GOLPH3 at the trans-Golgi network. Golgicide A (GCA) enhances GOLPH3-MYO18A binding, causing TGN dispersion (dTGN), which recruits NLRP3 and induces pyroptosis in lung cancer stem cells.","method":"Co-immunoprecipitation, confocal co-localization, western blotting, caspase-1 activity assay, xenograft model","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing physical interaction, functional consequence measured by multiple biochemical assays and in vivo model, single lab","pmids":["40055842"],"is_preprint":false},{"year":2026,"finding":"The GOLPH3-MYO18A complex at the Golgi apparatus is required and rate-limiting for delivery of receptor tyrosine kinases (RTKs) to the plasma membrane, thereby enhancing RTK signaling. The oncogenic activity of GOLPH3 depends on its interaction with MYO18A.","method":"RTK signaling assays, plasma membrane delivery assays, GOLPH3-MYO18A interaction disruption experiments across multiple cell types and RTK receptors","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell types and receptor types tested, interaction-dependent mechanism established with multiple orthogonal methods, peer-reviewed","pmids":["42154838"],"is_preprint":false},{"year":2024,"finding":"MYO18A physically interacts with MTSS1 (I-bar protein) as demonstrated by co-immunoprecipitation in iPSC-derived cardiomyocytes, placing MYO18A in a complex relevant to early sarcomere formation.","method":"Co-immunoprecipitation in iPSC-cardiomyocytes","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP in preprint, no mechanistic follow-up on MYO18A's specific role","pmids":["bio_10.1101_2024.08.14.24311020"],"is_preprint":true}],"current_model":"MYO18A is a dimeric, unconventional class XVIII myosin with negligible ATPase/motor activity that functions primarily as a scaffolding and actin cross-linking protein: its N-terminal domain contains an ATP-insensitive actin-binding site, its KE-rich domain mediates actin fiber association, its PDZ domain controls membrane localization, and its C-terminal coiled-coil mediates dimerization and interactions with partners including βPIX (directing the PAK2/βPIX/GIT1 complex away from focal adhesions to promote cell migration), PP1A (as part of a Smad4-MYO18A-PP1A complex that dephosphorylates PAK1-T423 to suppress β-catenin nuclear signaling), GOLPH3 (at the trans-Golgi network where the complex is rate-limiting for RTK delivery to the plasma membrane and oncogenic signaling), Tanc1/2 (via LLPS-capable charge interactions), and MTSS1 (in sarcomere formation); a muscle-specific γ-isoform localizes to sarcomeric A-bands and is essential for cardiac sarcomere integrity in mice."},"narrative":{"mechanistic_narrative":"MYO18A is an unconventional class XVIII myosin that operates not as a force-generating motor but as a dimeric actin cross-linking and scaffolding protein, coordinating actin organization, membrane trafficking, and signaling complex localization [PMID:15835906, PMID:15582604]. It binds actin filaments through an ATP-insensitive actin-binding site in its N-terminal domain and through a separate KE-rich domain, while self-associating into dimers via its C-terminal coiled-coil, allowing it to cross-link actin via two ATP-independent binding sites; its movement in the cytoplasm is ATP-hydrolysis-independent and its motor domain has negligible ATPase activity [PMID:15835906, PMID:15582604, PMID:38784114]. The PDZ-containing isoform localizes to membranes and the ER-Golgi region, and its expression and isoform composition are cell-type specific [PMID:12761286, PMID:25965346]. Through its C-terminal coiled-coil/globular region MYO18A serves as a hub for multiple complexes: it binds βPIX directly via a PAWDETNL motif to direct the PAK2/βPIX/GIT1 complex away from focal adhesions, sustaining Rac1 activity and promoting cell migration [PMID:19923322, PMID:25014165]; it assembles a Smad4-MYO18A-PP1A complex that uses an RVFFR motif to recruit PP1A and dephosphorylate PAK1-T423, suppressing β-catenin nuclear signaling [PMID:34799729]; and it partners with GOLPH3 at the trans-Golgi network, where the complex is rate-limiting for receptor tyrosine kinase delivery to the plasma membrane and underlies GOLPH3 oncogenic signaling [PMID:40055842, PMID:42154838]. A striated-muscle-specific γ isoform localizes to sarcomeric A-bands, and genetic deletion of Myo18a in mice is embryonic lethal with cardiac sarcomere disorganization, establishing an essential structural role in sarcomere integrity [PMID:38784114]. MYO18A is recurrently involved in oncogenic gene fusions: MYO18A-FGFR1 from t(8;17) and MYO18A-PDGFRB from t(5;17) generate constitutively active tyrosine kinases in myeloid neoplasms [PMID:15800673, PMID:19006078].","teleology":[{"year":2003,"claim":"Established that MYO18A exists as distinct isoforms with different subcellular destinations, framing the PDZ domain as a localization determinant and linking the gene to macrophage biology.","evidence":"Subcellular fractionation, immunofluorescence, and isoform-specific expression profiling","pmids":["12761286"],"confidence":"Medium","gaps":["Molecular basis of PDZ-mediated membrane targeting not defined","No functional consequence of isoform switching established"]},{"year":2004,"claim":"Connected MYO18A to receptor tyrosine kinase signaling by showing a 110 kDa isoform is tyrosine-phosphorylated downstream of CSF-1R via Src-family kinases.","evidence":"2D-SDS/PAGE, mass spectrometry, and CSF-1R mutant receptor studies","pmids":["14969583"],"confidence":"Medium","gaps":["Functional consequence of MYO18A tyrosine phosphorylation unknown","Phosphorylation sites on MYO18A not mapped"]},{"year":2005,"claim":"Defined the core biochemical architecture: MYO18A binds actin through an ATP-insensitive N-terminal site and a KE-rich domain, dimerizes via its coiled-coil, and localizes to membrane via its PDZ domain, recasting it as an ATP-independent actin cross-linker rather than a conventional motor.","evidence":"Cosedimentation with truncation mutants, chemical cross-linking, Co-IP with domain deletions, and live-cell imaging in HeLa cells","pmids":["15835906","15582604"],"confidence":"High","gaps":["Whether residual motor activity exists in any context not resolved","Structural model of the actin-binding interface absent"]},{"year":2005,"claim":"Showed MYO18A is recurrently captured in oncogenic kinase fusions, identifying it as a fusion partner that contributes a dimerization-competent coiled-coil to constitutively activate FGFR1 and PDGFRB.","evidence":"Fusion transcript and genomic breakpoint mapping (RT-PCR, bubble-PCR, LDI-PCR), FISH, and imatinib response","pmids":["15800673","19006078"],"confidence":"Medium","gaps":["Contribution of MYO18A sequence beyond providing oligomerization not dissected","Single cases each"]},{"year":2014,"claim":"Mapped a direct βPIX-MYO18A interaction and established its role in steering the PAK2/βPIX/GIT1 complex away from focal adhesions to sustain Rac1 activity and migration, converting a correlative association into a defined regulatory mechanism.","evidence":"Co-IP/MS, in vitro binding, deletion-mutant mapping of the PAWDETNL motif, siRNA rescue, Rac1 activity and migration assays","pmids":["19923322","25014165"],"confidence":"High","gaps":["How MYO18A physically relocates the complex mechanistically unclear","Upstream signals controlling MYO18A-βPIX binding unknown"]},{"year":2015,"claim":"Extended MYO18A's scaffolding role to innate immunity, showing isoforms differentially associate with surface receptors and tune macrophage inflammatory and endocytic responses.","evidence":"Dominant-negative disruption, Co-IP, flow cytometry, and macrophage stimulation assays","pmids":["25965346"],"confidence":"Medium","gaps":["Direct vs indirect nature of CD14/SR-A association not fully resolved","Mechanism of isoform-specific macropinocytosis unclear"]},{"year":2021,"claim":"Defined MYO18A as a PP1-targeting scaffold within a Smad4-MYO18A-PP1A complex that dephosphorylates PAK1-T423 to restrain β-catenin nuclear signaling, providing a substrate-recognition mechanism linking MYO18A to a tumor-suppressive phosphatase axis.","evidence":"LC-MS/MS interactome, Co-IP, RVFFR/CC domain mutation analysis, and in vitro and in vivo functional assays","pmids":["34799729"],"confidence":"High","gaps":["How this scaffold is integrated with the migration-promoting βPIX role not reconciled","Stoichiometry of the ternary complex undefined"]},{"year":2023,"claim":"Demonstrated that the MYO18A C-terminal coiled-coil and C-extension engage Tanc1/2 TPR domains via charge-charge interactions capable of liquid-liquid phase separation, revealing a biophysical mode by which MYO18A can organize synaptic scaffold condensates.","evidence":"Size-exclusion chromatography, LLPS assays in cells and in vitro, and high-salt disruption","pmids":["38092135"],"confidence":"Medium","gaps":["Physiological role of MYO18A-Tanc condensates in neurons not tested","Whether actin cross-linking and LLPS co-occur unknown"]},{"year":2024,"claim":"Established an essential structural role for the muscle-specific γ isoform at sarcomeric A-bands, with genetic deletion causing embryonic lethality and cardiac sarcomere disorganization, while confirming negligible ATPase activity.","evidence":"Mouse knockout phenotyping, A-band immunolocalization, and biochemical ATPase assay (review synthesizing primary data)","pmids":["38784114"],"confidence":"Medium","gaps":["Direct thick-filament interaction partners not mapped in vivo","Mechanism by which sarcomere integrity is lost not defined"]},{"year":2025,"claim":"Linked MYO18A-GOLPH3 binding at the TGN to organelle morphology and inflammatory cell death, showing that enhanced binding disperses the TGN to recruit NLRP3 and drive pyroptosis.","evidence":"Co-IP, confocal co-localization, caspase-1 activity assay, and xenograft model","pmids":["40055842"],"confidence":"Medium","gaps":["How GOLPH3-MYO18A binding state is normally regulated unclear","Connection between TGN dispersion and NLRP3 recruitment mechanistically incomplete"]},{"year":2026,"claim":"Defined the GOLPH3-MYO18A complex as the rate-limiting machinery for RTK delivery to the plasma membrane, establishing that GOLPH3 oncogenic signaling depends on MYO18A and tying MYO18A's actin-coupled trafficking role to cancer signaling.","evidence":"RTK signaling and plasma-membrane delivery assays with interaction-disruption across multiple cell types and receptors","pmids":["42154838"],"confidence":"High","gaps":["How the complex selects RTK cargo not defined","Role of MYO18A actin cross-linking in this transport step not isolated"]},{"year":null,"claim":"How MYO18A's distinct scaffolding modules — actin cross-linking, PP1A-substrate recognition, βPIX/migration control, GOLPH3 trafficking, sarcomeric assembly, and LLPS-driven condensation — are integrated, isoform-partitioned, and regulated within a single cell remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model unifying the actin-binding and partner-binding regions","Isoform-specific assignment of each function incomplete","Regulatory inputs switching MYO18A between complexes unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,2,11]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,7,9]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,13,14]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,5]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,7,9,14]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[13,14]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[11]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,6]}],"complexes":["PAK2/βPIX/GIT1 complex","Smad4-MYO18A-PP1A complex","GOLPH3-MYO18A complex","sarcomeric A-band (thick filament)"],"partners":["ARHGEF7","PAK2","GIT1","PPP1CA","SMAD4","GOLPH3","TANC1","MTSS1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92614","full_name":"Unconventional myosin-XVIIIa","aliases":["Molecule associated with JAK3 N-terminus","MAJN","Myosin containing a PDZ domain","Surfactant protein receptor SP-R210","SP-R210"],"length_aa":2054,"mass_kda":233.1,"function":"May link Golgi membranes to the cytoskeleton and participate in the tensile force required for vesicle budding from the Golgi. Thereby, may play a role in Golgi membrane trafficking and could indirectly give its flattened shape to the Golgi apparatus (PubMed:19837035, PubMed:23345592). Alternatively, in concert with LURAP1 and CDC42BPA/CDC42BPB, has been involved in modulating lamellar actomyosin retrograde flow that is crucial to cell protrusion and migration (PubMed:18854160). May be involved in the maintenance of the stromal cell architectures required for cell to cell contact (By similarity). Regulates trafficking, expression, and activation of innate immune receptors on macrophages. Plays a role to suppress inflammatory responsiveness of macrophages via a mechanism that modulates CD14 trafficking (PubMed:25965346). Acts as a receptor of surfactant-associated protein A (SFTPA1/SP-A) and plays an important role in internalization and clearance of SFTPA1-opsonized S.aureus by alveolar macrophages (PubMed:16087679, PubMed:21123169). Strongly enhances natural killer cell cytotoxicity (PubMed:27467939)","subcellular_location":"Cell surface","url":"https://www.uniprot.org/uniprotkb/Q92614/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYO18A","classification":"Not Classified","n_dependent_lines":126,"n_total_lines":1208,"dependency_fraction":0.10430463576158941},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALD1","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"MYL12A","stoichiometry":0.2},{"gene":"MYL12B","stoichiometry":0.2},{"gene":"MYL6","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MYO18A","total_profiled":1310},"omim":[{"mim_id":"616129","title":"LEUCINE-RICH ADAPTOR PROTEIN 1; LURAP1","url":"https://www.omim.org/entry/616129"},{"mim_id":"614062","title":"CDC42-BINDING PROTEIN KINASE, BETA; CDC42BPB","url":"https://www.omim.org/entry/614062"},{"mim_id":"613523","title":"CHROMOSOME 8p11 MYELOPROLIFERATIVE SYNDROME","url":"https://www.omim.org/entry/613523"},{"mim_id":"612208","title":"GOLGI PHOSPHOPROTEIN 3-LIKE; GOLPH3L","url":"https://www.omim.org/entry/612208"},{"mim_id":"612207","title":"GOLGI PHOSPHOPROTEIN 3; GOLPH3","url":"https://www.omim.org/entry/612207"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":381.4},{"tissue":"tongue","ntpm":115.5}],"url":"https://www.proteinatlas.org/search/MYO18A"},"hgnc":{"alias_symbol":["KIAA0216","MysPDZ"],"prev_symbol":["TIAF1"]},"alphafold":{"accession":"Q92614","domains":[{"cath_id":"2.30.42.10","chopping":"192-326","consensus_level":"medium","plddt":74.9211,"start":192,"end":326},{"cath_id":"2.30.30.360","chopping":"339-400","consensus_level":"medium","plddt":82.9697,"start":339,"end":400},{"cath_id":"1.20.120.720","chopping":"493-717_746-802_952-1038","consensus_level":"medium","plddt":84.6219,"start":493,"end":1038},{"cath_id":"-","chopping":"1115-1168","consensus_level":"medium","plddt":82.1091,"start":1115,"end":1168},{"cath_id":"1.20.5","chopping":"1205-1247","consensus_level":"medium","plddt":87.406,"start":1205,"end":1247}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92614","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92614-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92614-F1-predicted_aligned_error_v6.png","plddt_mean":70.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYO18A","jax_strain_url":"https://www.jax.org/strain/search?query=MYO18A"},"sequence":{"accession":"Q92614","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92614.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92614/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92614"}},"corpus_meta":[{"pmid":"15800673","id":"PMC_15800673","title":"The t(8;17)(p11;q23) in the 8p11 myeloproliferative syndrome fuses MYO18A to FGFR1.","date":"2005","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/15800673","citation_count":73,"is_preprint":false},{"pmid":"19923322","id":"PMC_19923322","title":"Identification of MYO18A as a novel interacting partner of the PAK2/betaPIX/GIT1 complex and its potential function in modulating epithelial cell migration.","date":"2009","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/19923322","citation_count":66,"is_preprint":false},{"pmid":"21368882","id":"PMC_21368882","title":"TGF-β induces TIAF1 self-aggregation via type II receptor-independent signaling that leads to generation of amyloid β plaques in Alzheimer's disease.","date":"2010","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/21368882","citation_count":52,"is_preprint":false},{"pmid":"12761286","id":"PMC_12761286","title":"Genome structure and differential expression of two isoforms of a novel PDZ-containing myosin (MysPDZ) (Myo18A).","date":"2003","source":"Journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12761286","citation_count":43,"is_preprint":false},{"pmid":"34799729","id":"PMC_34799729","title":"The Smad4-MYO18A-PP1A complex regulates β-catenin phosphorylation and pemigatinib resistance by inhibiting PAK1 in cholangiocarcinoma.","date":"2021","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/34799729","citation_count":41,"is_preprint":false},{"pmid":"15835906","id":"PMC_15835906","title":"The N-terminal domain of MYO18A has an ATP-insensitive actin-binding site.","date":"2005","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15835906","citation_count":38,"is_preprint":false},{"pmid":"28942352","id":"PMC_28942352","title":"MYO18A: An unusual myosin.","date":"2017","source":"Advances in biological regulation","url":"https://pubmed.ncbi.nlm.nih.gov/28942352","citation_count":34,"is_preprint":false},{"pmid":"22534828","id":"PMC_22534828","title":"TIAF1 self-aggregation in peritumor capsule formation, spontaneous activation of SMAD-responsive promoter in p53-deficient environment, and cell death.","date":"2012","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/22534828","citation_count":31,"is_preprint":false},{"pmid":"9918798","id":"PMC_9918798","title":"Cloning and characterization of a novel transforming growth factor-beta1-induced TIAF1 protein that inhibits tumor necrosis factor cytotoxicity.","date":"1998","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9918798","citation_count":30,"is_preprint":false},{"pmid":"27551439","id":"PMC_27551439","title":"WWOX dysfunction induces sequential aggregation of TRAPPC6AΔ, TIAF1, tau and amyloid β, and causes apoptosis.","date":"2015","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/27551439","citation_count":30,"is_preprint":false},{"pmid":"19006078","id":"PMC_19006078","title":"Identification of a MYO18A-PDGFRB fusion gene in an eosinophilia-associated atypical myeloproliferative neoplasm with a t(5;17)(q33-34;q11.2).","date":"2009","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19006078","citation_count":29,"is_preprint":false},{"pmid":"15582604","id":"PMC_15582604","title":"Subcellular localization and dynamics of MysPDZ (Myo18A) in live mammalian cells.","date":"2005","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/15582604","citation_count":26,"is_preprint":false},{"pmid":"31315632","id":"PMC_31315632","title":"A p53/TIAF1/WWOX triad exerts cancer suppression but may cause brain protein aggregation due to p53/WWOX functional antagonism.","date":"2019","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/31315632","citation_count":26,"is_preprint":false},{"pmid":"25965346","id":"PMC_25965346","title":"SP-R210 (Myo18A) Isoforms as Intrinsic Modulators of Macrophage Priming and Activation.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25965346","citation_count":24,"is_preprint":false},{"pmid":"25014165","id":"PMC_25014165","title":"Binding of the extreme carboxyl-terminus of PAK-interacting exchange factor β (βPIX) to myosin 18A (MYO18A) is required for epithelial cell migration.","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25014165","citation_count":19,"is_preprint":false},{"pmid":"14969583","id":"PMC_14969583","title":"A novel 110 kDa form of myosin XVIIIA (MysPDZ) is tyrosine-phosphorylated after colony-stimulating factor-1 receptor signalling.","date":"2004","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/14969583","citation_count":17,"is_preprint":false},{"pmid":"14965474","id":"PMC_14965474","title":"TIAF1 and p53 functionally interact in mediating apoptosis and silencing of TIAF1 abolishes nuclear translocation of serine 15-phosphorylated p53.","date":"2004","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14965474","citation_count":16,"is_preprint":false},{"pmid":"27234387","id":"PMC_27234387","title":"Self-aggregating TIAF1 in lung cancer progression.","date":"2013","source":"Translational respiratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27234387","citation_count":15,"is_preprint":false},{"pmid":"22682626","id":"PMC_22682626","title":"A three-way translocation of MLL, MLLT11, and the novel reciprocal partner gene MYO18A in a child with acute myeloid leukemia.","date":"2012","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22682626","citation_count":15,"is_preprint":false},{"pmid":"12829915","id":"PMC_12829915","title":"High expression of TIAF-1 in chronic kidney and liver allograft rejection and in activated T-helper cells.","date":"2003","source":"Transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/12829915","citation_count":15,"is_preprint":false},{"pmid":"33194745","id":"PMC_33194745","title":"Intratumor Heterogeneity of MYO18A and FBXW7 Variants Impact the Clinical Outcome of Stage III Colorectal Cancer.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33194745","citation_count":14,"is_preprint":false},{"pmid":"12814935","id":"PMC_12814935","title":"TIAF1 participates in the transforming growth factor beta1--mediated growth regulation.","date":"2003","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/12814935","citation_count":11,"is_preprint":false},{"pmid":"28261327","id":"PMC_28261327","title":"Multiple MYO18A-PDGFRB fusion transcripts in a myeloproliferative neoplasm patient with t(5;17)(q32;q11).","date":"2017","source":"Molecular cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/28261327","citation_count":10,"is_preprint":false},{"pmid":"34735924","id":"PMC_34735924","title":"Genomic and epigenomic adaptation in SP-R210 (Myo18A) isoform-deficient macrophages.","date":"2021","source":"Immunobiology","url":"https://pubmed.ncbi.nlm.nih.gov/34735924","citation_count":6,"is_preprint":false},{"pmid":"38784114","id":"PMC_38784114","title":"Are the class 18 myosins Myo18A and Myo18B specialist sarcomeric proteins?","date":"2024","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/38784114","citation_count":4,"is_preprint":false},{"pmid":"40055842","id":"PMC_40055842","title":"Golgicide A induces pyroptosis of lung cancer stem cells by regulating dTGN formation via GOLPH3/MYO18A complex.","date":"2025","source":"Stem cell research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/40055842","citation_count":4,"is_preprint":false},{"pmid":"38092135","id":"PMC_38092135","title":"Tanc1/2 TPR domain interacts with Myo18a C-terminus and undergoes liquid-liquid phase separation.","date":"2023","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/38092135","citation_count":3,"is_preprint":false},{"pmid":"42154838","id":"PMC_42154838","title":"Oncogenic receptor tyrosine kinase signaling is driven by the Golgi protein GOLPH3 and its interaction with MYO18A.","date":"2026","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/42154838","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.08.14.24311020","title":"Reduced Expression of MTSS1 Increases Sarcomere Number and Improves Contractility in Select Forms of Monogenic DCM","date":"2024-08-20","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.14.24311020","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16895,"output_tokens":3916,"usd":0.054712,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11740,"output_tokens":4417,"usd":0.084562,"stage2_stop_reason":"end_turn"},"total_usd":0.139274,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"MYO18A (MysPDZ) has two isoforms: MysPDZα (containing PDZ domain) co-localizes with the ER-Golgi complex, while MysPDZβ (lacking PDZ domain) localizes diffusely in the cytoplasm. Expression of the PDZ-containing isoform is restricted to mature macrophages and absent from hematopoietic progenitors.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence microscopy, isoform-specific expression analysis\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiments with functional inference, single lab, two orthogonal methods (imaging + expression profiling)\",\n      \"pmids\": [\"12761286\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MYO18A contains an ATP-insensitive actin-binding site located in the middle region of its N-terminal domain (outside the PDZ module), distinct from known actin-binding motifs. The protein forms stable dimers via its coiled-coil tail, suggesting it can cross-link actin filaments via two ATP-insensitive N-terminal actin-binding sites.\",\n      \"method\": \"Cosedimentation assay with truncated constructs, chemical cross-linking, GFP-tagged expression in HeLa cells\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro cosedimentation assay with multiple truncation mutants, chemical cross-linking, replicated with multiple constructs in single rigorous study\",\n      \"pmids\": [\"15835906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MYO18A (MysPDZ) self-associates through its C-terminal coiled-coil domain. The KE-rich domain mediates interaction with actin filaments and controls co-distribution with actin fibers. The PDZ domain controls localization to the inner surface of the cell membrane. Movement in the cytoplasm is ATP-hydrolysis-independent.\",\n      \"method\": \"Co-immunoprecipitation, EYFP-tagged deletion mutants, time-lapse video microscopy\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mutants and live imaging, single lab, two orthogonal methods\",\n      \"pmids\": [\"15582604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A novel 110 kDa isoform of MYO18A is tyrosine-phosphorylated following CSF-1 receptor (c-Fms) activation. This phosphorylation requires Tyr-559 in the cytoplasmic domain of CSF-1R and is therefore Src-family kinase-dependent.\",\n      \"method\": \"2D-SDS/PAGE, mass spectrometry identification, CSF-1R mutant receptor studies\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS identification combined with receptor mutation studies establishing kinase dependency, single lab\",\n      \"pmids\": [\"14969583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MYO18A-FGFR1 fusion protein is generated by t(8;17)(p11;q23), joining exon 32 of MYO18A to exon 9 of FGFR1, creating a constitutively active tyrosine kinase fusion that is structurally similar to other oncogenic FGFR1 fusion kinases.\",\n      \"method\": \"RT-PCR fusion transcript identification, bubble-PCR genomic breakpoint mapping, FISH\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular characterization of fusion transcript and genomic breakpoints, single case but rigorous molecular methods\",\n      \"pmids\": [\"15800673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MYO18A is a novel binding partner of the PAK2/βPIX/GIT1 complex. MYO18A binds PAK2 indirectly through the βPIX/GIT1 complex. Under normal conditions MYO18A and PAK2 co-localize in lamellipodia and membrane ruffles. Knockdown of MYO18A shifts PAK2/βPIX/GIT1 complex localization to focal adhesions, increases focal adhesion size and number, and decreases cell motility; re-expression of MYO18A restores migration.\",\n      \"method\": \"Proteomic approach (Co-IP/MS), siRNA knockdown, in vitro binding assay, fluorescence microscopy, migration assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, in vitro binding, siRNA rescue experiment, multiple orthogonal methods establishing both binding and functional consequence\",\n      \"pmids\": [\"19923322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MYO18A-PDGFRB fusion gene is generated by t(5;17)(q33-34;q11.2), fusing MYO18A to PDGFRB to create a constitutively active kinase in myeloproliferative neoplasm; the resulting fusion is sensitive to imatinib.\",\n      \"method\": \"LDI-PCR genomic fusion identification, FISH, imatinib treatment response\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — molecular characterization of fusion with functional validation via imatinib response, single case\",\n      \"pmids\": [\"19006078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MYO18Aα interacts directly with βPIX via binding of the MYO18Aα C-terminal globular domain to the extreme C-terminus of βPIX (residues 639-646, PAWDETNL motif). This interaction is required for proper localization of βPIX away from focal adhesions, maintenance of Rac1 activity, and epithelial cell migration.\",\n      \"method\": \"Deletion mutant analysis, Co-IP, fluorescence microscopy, Rac1 activity assay, migration assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — precise domain mapping with multiple deletion mutants, reciprocal Co-IP, functional rescue experiments, multiple orthogonal readouts\",\n      \"pmids\": [\"25014165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MYO18A (SP-R210) isoforms SP-R210L and SP-R210S differentially regulate macrophage inflammatory responses. SP-R210L dominant-negative disruption augments expression of SR-A, CD14, and CD36. SP-R210S physically associates with CD14 and SR-A, enhancing LPS response. SP-R210L and SP-R210S regulate internalization of CD14 via distinct macropinocytosis-like mechanisms.\",\n      \"method\": \"Dominant-negative disruption, flow cytometry, Co-immunoprecipitation, macrophage stimulation assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing physical association, dominant-negative functional studies, single lab with multiple methods\",\n      \"pmids\": [\"25965346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYO18A forms a ternary Smad4-MYO18A-PP1A complex. MYO18A interacts with PP1A via its RVFFR motif and with Smad4 via its CC (coiled-coil) domain. This complex acts as a PP1-interacting protein scaffold for substrate recognition, mediating dephosphorylation of PAK1 at T423, which in turn reduces β-catenin S675 phosphorylation and inhibits β-catenin nuclear translocation.\",\n      \"method\": \"LC-MS/MS, Co-IP, domain deletion/point mutation analysis, in vitro and in vivo functional assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — LC-MS/MS interactome with biochemical validation, precise domain mapping (RVFFR motif and CC domain), multiple orthogonal methods including in vivo\",\n      \"pmids\": [\"34799729\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYO18A knockdown significantly reduces cell migration activity in HCT-116 colorectal cancer cells, establishing a direct role in cancer cell migration.\",\n      \"method\": \"siRNA knockdown, migration assay\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (siRNA + migration assay), single cell line, no pathway mechanism identified beyond prior reports\",\n      \"pmids\": [\"33194745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYO18A γ isoform (striated muscle-specific) localizes to sarcomeric A-bands. Genetic deletion of Myo18a in mice is embryonic lethal and associated with cardiac sarcomere disorganization. The motor domain of Myo18Aγ has biochemically demonstrated negligible ATPase activity. Myo18Aγ is proposed to coassemble with thick filaments providing structural integrity through interactions with F-actin.\",\n      \"method\": \"Mouse genetic knockout (embryonic lethal phenotype), sarcomere localization (immunofluorescence), biochemical ATPase activity assay\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined phenotype, biochemical ATPase assay, localization studies; review paper synthesizing data from multiple studies\",\n      \"pmids\": [\"38784114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MYO18A C-terminal coiled-coil domain and C-extension (CCex) interact with the TPR domains of synaptic scaffold proteins Tanc1 and Tanc2. This interaction is primarily driven by charge-charge interactions and can undergo liquid-liquid phase separation (LLPS) in both cultured cells and in vitro.\",\n      \"method\": \"Size exclusion chromatography, LLPS assay in cells and test tubes, sequence analysis, high-salt disruption experiments\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical binding assay with domain mapping and LLPS validation in cells and in vitro, single lab\",\n      \"pmids\": [\"38092135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MYO18A physically interacts with GOLPH3 at the trans-Golgi network. Golgicide A (GCA) enhances GOLPH3-MYO18A binding, causing TGN dispersion (dTGN), which recruits NLRP3 and induces pyroptosis in lung cancer stem cells.\",\n      \"method\": \"Co-immunoprecipitation, confocal co-localization, western blotting, caspase-1 activity assay, xenograft model\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing physical interaction, functional consequence measured by multiple biochemical assays and in vivo model, single lab\",\n      \"pmids\": [\"40055842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The GOLPH3-MYO18A complex at the Golgi apparatus is required and rate-limiting for delivery of receptor tyrosine kinases (RTKs) to the plasma membrane, thereby enhancing RTK signaling. The oncogenic activity of GOLPH3 depends on its interaction with MYO18A.\",\n      \"method\": \"RTK signaling assays, plasma membrane delivery assays, GOLPH3-MYO18A interaction disruption experiments across multiple cell types and RTK receptors\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell types and receptor types tested, interaction-dependent mechanism established with multiple orthogonal methods, peer-reviewed\",\n      \"pmids\": [\"42154838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYO18A physically interacts with MTSS1 (I-bar protein) as demonstrated by co-immunoprecipitation in iPSC-derived cardiomyocytes, placing MYO18A in a complex relevant to early sarcomere formation.\",\n      \"method\": \"Co-immunoprecipitation in iPSC-cardiomyocytes\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP in preprint, no mechanistic follow-up on MYO18A's specific role\",\n      \"pmids\": [\"bio_10.1101_2024.08.14.24311020\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MYO18A is a dimeric, unconventional class XVIII myosin with negligible ATPase/motor activity that functions primarily as a scaffolding and actin cross-linking protein: its N-terminal domain contains an ATP-insensitive actin-binding site, its KE-rich domain mediates actin fiber association, its PDZ domain controls membrane localization, and its C-terminal coiled-coil mediates dimerization and interactions with partners including βPIX (directing the PAK2/βPIX/GIT1 complex away from focal adhesions to promote cell migration), PP1A (as part of a Smad4-MYO18A-PP1A complex that dephosphorylates PAK1-T423 to suppress β-catenin nuclear signaling), GOLPH3 (at the trans-Golgi network where the complex is rate-limiting for RTK delivery to the plasma membrane and oncogenic signaling), Tanc1/2 (via LLPS-capable charge interactions), and MTSS1 (in sarcomere formation); a muscle-specific γ-isoform localizes to sarcomeric A-bands and is essential for cardiac sarcomere integrity in mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYO18A is an unconventional class XVIII myosin that operates not as a force-generating motor but as a dimeric actin cross-linking and scaffolding protein, coordinating actin organization, membrane trafficking, and signaling complex localization [#1, #2]. It binds actin filaments through an ATP-insensitive actin-binding site in its N-terminal domain and through a separate KE-rich domain, while self-associating into dimers via its C-terminal coiled-coil, allowing it to cross-link actin via two ATP-independent binding sites; its movement in the cytoplasm is ATP-hydrolysis-independent and its motor domain has negligible ATPase activity [#1, #2, #11]. The PDZ-containing isoform localizes to membranes and the ER-Golgi region, and its expression and isoform composition are cell-type specific [#0, #8]. Through its C-terminal coiled-coil/globular region MYO18A serves as a hub for multiple complexes: it binds \\u03b2PIX directly via a PAWDETNL motif to direct the PAK2/\\u03b2PIX/GIT1 complex away from focal adhesions, sustaining Rac1 activity and promoting cell migration [#5, #7]; it assembles a Smad4-MYO18A-PP1A complex that uses an RVFFR motif to recruit PP1A and dephosphorylate PAK1-T423, suppressing \\u03b2-catenin nuclear signaling [#9]; and it partners with GOLPH3 at the trans-Golgi network, where the complex is rate-limiting for receptor tyrosine kinase delivery to the plasma membrane and underlies GOLPH3 oncogenic signaling [#13, #14]. A striated-muscle-specific \\u03b3 isoform localizes to sarcomeric A-bands, and genetic deletion of Myo18a in mice is embryonic lethal with cardiac sarcomere disorganization, establishing an essential structural role in sarcomere integrity [#11]. MYO18A is recurrently involved in oncogenic gene fusions: MYO18A-FGFR1 from t(8;17) and MYO18A-PDGFRB from t(5;17) generate constitutively active tyrosine kinases in myeloid neoplasms [#4, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that MYO18A exists as distinct isoforms with different subcellular destinations, framing the PDZ domain as a localization determinant and linking the gene to macrophage biology.\",\n      \"evidence\": \"Subcellular fractionation, immunofluorescence, and isoform-specific expression profiling\",\n      \"pmids\": [\"12761286\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of PDZ-mediated membrane targeting not defined\", \"No functional consequence of isoform switching established\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected MYO18A to receptor tyrosine kinase signaling by showing a 110 kDa isoform is tyrosine-phosphorylated downstream of CSF-1R via Src-family kinases.\",\n      \"evidence\": \"2D-SDS/PAGE, mass spectrometry, and CSF-1R mutant receptor studies\",\n      \"pmids\": [\"14969583\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of MYO18A tyrosine phosphorylation unknown\", \"Phosphorylation sites on MYO18A not mapped\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined the core biochemical architecture: MYO18A binds actin through an ATP-insensitive N-terminal site and a KE-rich domain, dimerizes via its coiled-coil, and localizes to membrane via its PDZ domain, recasting it as an ATP-independent actin cross-linker rather than a conventional motor.\",\n      \"evidence\": \"Cosedimentation with truncation mutants, chemical cross-linking, Co-IP with domain deletions, and live-cell imaging in HeLa cells\",\n      \"pmids\": [\"15835906\", \"15582604\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether residual motor activity exists in any context not resolved\", \"Structural model of the actin-binding interface absent\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed MYO18A is recurrently captured in oncogenic kinase fusions, identifying it as a fusion partner that contributes a dimerization-competent coiled-coil to constitutively activate FGFR1 and PDGFRB.\",\n      \"evidence\": \"Fusion transcript and genomic breakpoint mapping (RT-PCR, bubble-PCR, LDI-PCR), FISH, and imatinib response\",\n      \"pmids\": [\"15800673\", \"19006078\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contribution of MYO18A sequence beyond providing oligomerization not dissected\", \"Single cases each\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped a direct \\u03b2PIX-MYO18A interaction and established its role in steering the PAK2/\\u03b2PIX/GIT1 complex away from focal adhesions to sustain Rac1 activity and migration, converting a correlative association into a defined regulatory mechanism.\",\n      \"evidence\": \"Co-IP/MS, in vitro binding, deletion-mutant mapping of the PAWDETNL motif, siRNA rescue, Rac1 activity and migration assays\",\n      \"pmids\": [\"19923322\", \"25014165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How MYO18A physically relocates the complex mechanistically unclear\", \"Upstream signals controlling MYO18A-\\u03b2PIX binding unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended MYO18A's scaffolding role to innate immunity, showing isoforms differentially associate with surface receptors and tune macrophage inflammatory and endocytic responses.\",\n      \"evidence\": \"Dominant-negative disruption, Co-IP, flow cytometry, and macrophage stimulation assays\",\n      \"pmids\": [\"25965346\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect nature of CD14/SR-A association not fully resolved\", \"Mechanism of isoform-specific macropinocytosis unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined MYO18A as a PP1-targeting scaffold within a Smad4-MYO18A-PP1A complex that dephosphorylates PAK1-T423 to restrain \\u03b2-catenin nuclear signaling, providing a substrate-recognition mechanism linking MYO18A to a tumor-suppressive phosphatase axis.\",\n      \"evidence\": \"LC-MS/MS interactome, Co-IP, RVFFR/CC domain mutation analysis, and in vitro and in vivo functional assays\",\n      \"pmids\": [\"34799729\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How this scaffold is integrated with the migration-promoting \\u03b2PIX role not reconciled\", \"Stoichiometry of the ternary complex undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that the MYO18A C-terminal coiled-coil and C-extension engage Tanc1/2 TPR domains via charge-charge interactions capable of liquid-liquid phase separation, revealing a biophysical mode by which MYO18A can organize synaptic scaffold condensates.\",\n      \"evidence\": \"Size-exclusion chromatography, LLPS assays in cells and in vitro, and high-salt disruption\",\n      \"pmids\": [\"38092135\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological role of MYO18A-Tanc condensates in neurons not tested\", \"Whether actin cross-linking and LLPS co-occur unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established an essential structural role for the muscle-specific \\u03b3 isoform at sarcomeric A-bands, with genetic deletion causing embryonic lethality and cardiac sarcomere disorganization, while confirming negligible ATPase activity.\",\n      \"evidence\": \"Mouse knockout phenotyping, A-band immunolocalization, and biochemical ATPase assay (review synthesizing primary data)\",\n      \"pmids\": [\"38784114\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct thick-filament interaction partners not mapped in vivo\", \"Mechanism by which sarcomere integrity is lost not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked MYO18A-GOLPH3 binding at the TGN to organelle morphology and inflammatory cell death, showing that enhanced binding disperses the TGN to recruit NLRP3 and drive pyroptosis.\",\n      \"evidence\": \"Co-IP, confocal co-localization, caspase-1 activity assay, and xenograft model\",\n      \"pmids\": [\"40055842\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How GOLPH3-MYO18A binding state is normally regulated unclear\", \"Connection between TGN dispersion and NLRP3 recruitment mechanistically incomplete\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined the GOLPH3-MYO18A complex as the rate-limiting machinery for RTK delivery to the plasma membrane, establishing that GOLPH3 oncogenic signaling depends on MYO18A and tying MYO18A's actin-coupled trafficking role to cancer signaling.\",\n      \"evidence\": \"RTK signaling and plasma-membrane delivery assays with interaction-disruption across multiple cell types and receptors\",\n      \"pmids\": [\"42154838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the complex selects RTK cargo not defined\", \"Role of MYO18A actin cross-linking in this transport step not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MYO18A's distinct scaffolding modules — actin cross-linking, PP1A-substrate recognition, \\u03b2PIX/migration control, GOLPH3 trafficking, sarcomeric assembly, and LLPS-driven condensation — are integrated, isoform-partitioned, and regulated within a single cell remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model unifying the actin-binding and partner-binding regions\", \"Isoform-specific assignment of each function incomplete\", \"Regulatory inputs switching MYO18A between complexes unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 2, 11]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 7, 9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 13, 14]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 7, 9, 14]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [13, 14]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 6]}\n    ],\n    \"complexes\": [\n      \"PAK2/\\u03b2PIX/GIT1 complex\",\n      \"Smad4-MYO18A-PP1A complex\",\n      \"GOLPH3-MYO18A complex\",\n      \"sarcomeric A-band (thick filament)\"\n    ],\n    \"partners\": [\n      \"ARHGEF7\",\n      \"PAK2\",\n      \"GIT1\",\n      \"PPP1CA\",\n      \"SMAD4\",\n      \"GOLPH3\",\n      \"TANC1\",\n      \"MTSS1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}