Affinage

MYO18A

Unconventional myosin-XVIIIa · UniProt Q92614

Length
2054 aa
Mass
233.1 kDa
Annotated
2026-06-10
28 papers in source corpus 16 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2003 Medium

    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

    PMID:12761286

    Open questions at the time
    • Molecular basis of PDZ-mediated membrane targeting not defined
    • No functional consequence of isoform switching established
  2. 2004 Medium

    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

    PMID:14969583

    Open questions at the time
    • Functional consequence of MYO18A tyrosine phosphorylation unknown
    • Phosphorylation sites on MYO18A not mapped
  3. 2005 High

    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

    PMID:15582604 PMID:15835906

    Open questions at the time
    • Whether residual motor activity exists in any context not resolved
    • Structural model of the actin-binding interface absent
  4. 2005 Medium

    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

    PMID:15800673 PMID:19006078

    Open questions at the time
    • Contribution of MYO18A sequence beyond providing oligomerization not dissected
    • Single cases each
  5. 2014 High

    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

    PMID:19923322 PMID:25014165

    Open questions at the time
    • How MYO18A physically relocates the complex mechanistically unclear
    • Upstream signals controlling MYO18A-βPIX binding unknown
  6. 2015 Medium

    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

    PMID:25965346

    Open questions at the time
    • Direct vs indirect nature of CD14/SR-A association not fully resolved
    • Mechanism of isoform-specific macropinocytosis unclear
  7. 2021 High

    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

    PMID:34799729

    Open questions at the time
    • How this scaffold is integrated with the migration-promoting βPIX role not reconciled
    • Stoichiometry of the ternary complex undefined
  8. 2023 Medium

    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

    PMID:38092135

    Open questions at the time
    • Physiological role of MYO18A-Tanc condensates in neurons not tested
    • Whether actin cross-linking and LLPS co-occur unknown
  9. 2024 Medium

    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)

    PMID:38784114

    Open questions at the time
    • Direct thick-filament interaction partners not mapped in vivo
    • Mechanism by which sarcomere integrity is lost not defined
  10. 2025 Medium

    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

    PMID:40055842

    Open questions at the time
    • How GOLPH3-MYO18A binding state is normally regulated unclear
    • Connection between TGN dispersion and NLRP3 recruitment mechanistically incomplete
  11. 2026 High

    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

    PMID:42154838

    Open questions at the time
    • How the complex selects RTK cargo not defined
    • Role of MYO18A actin cross-linking in this transport step not isolated

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3 GO:0060090 molecular adaptor activity 3 GO:0005198 structural molecule activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005794 Golgi apparatus 3 GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2 R-HSA-9609507 Protein localization 2 R-HSA-397014 Muscle contraction 1
Partners
ARHGEF7GIT1GOLPH3MTSS1PAK2PPP1CASMAD4TANC1
Complex memberships
GOLPH3-MYO18A complexPAK2/βPIX/GIT1 complexSmad4-MYO18A-PP1A complexsarcomeric A-band (thick filament)

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 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. Subcellular fractionation, immunofluorescence microscopy, isoform-specific expression analysis Journal of biochemistry Medium 12761286
2005 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. Cosedimentation assay with truncated constructs, chemical cross-linking, GFP-tagged expression in HeLa cells Biochemistry High 15835906
2005 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. Co-immunoprecipitation, EYFP-tagged deletion mutants, time-lapse video microscopy Biochemical and biophysical research communications Medium 15582604
2004 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. 2D-SDS/PAGE, mass spectrometry identification, CSF-1R mutant receptor studies The Biochemical journal Medium 14969583
2005 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. RT-PCR fusion transcript identification, bubble-PCR genomic breakpoint mapping, FISH Leukemia Medium 15800673
2009 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. Proteomic approach (Co-IP/MS), siRNA knockdown, in vitro binding assay, fluorescence microscopy, migration assay Molecular biology of the cell High 19923322
2009 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. LDI-PCR genomic fusion identification, FISH, imatinib treatment response Genes, chromosomes & cancer Medium 19006078
2014 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. Deletion mutant analysis, Co-IP, fluorescence microscopy, Rac1 activity assay, migration assay Biochimica et biophysica acta High 25014165
2015 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. Dominant-negative disruption, flow cytometry, Co-immunoprecipitation, macrophage stimulation assays PloS one Medium 25965346
2021 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. LC-MS/MS, Co-IP, domain deletion/point mutation analysis, in vitro and in vivo functional assays Cell death and differentiation High 34799729
2021 MYO18A knockdown significantly reduces cell migration activity in HCT-116 colorectal cancer cells, establishing a direct role in cancer cell migration. siRNA knockdown, migration assay Frontiers in oncology Low 33194745
2024 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. Mouse genetic knockout (embryonic lethal phenotype), sarcomere localization (immunofluorescence), biochemical ATPase activity assay Frontiers in physiology Medium 38784114
2023 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. Size exclusion chromatography, LLPS assay in cells and test tubes, sequence analysis, high-salt disruption experiments Biochimica et biophysica acta. Molecular cell research Medium 38092135
2025 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. Co-immunoprecipitation, confocal co-localization, western blotting, caspase-1 activity assay, xenograft model Stem cell research & therapy Medium 40055842
2026 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. RTK signaling assays, plasma membrane delivery assays, GOLPH3-MYO18A interaction disruption experiments across multiple cell types and RTK receptors Science signaling High 42154838
2024 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. Co-immunoprecipitation in iPSC-cardiomyocytes bioRxivpreprint Low bio_10.1101_2024.08.14.24311020

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 The t(8;17)(p11;q23) in the 8p11 myeloproliferative syndrome fuses MYO18A to FGFR1. Leukemia 73 15800673
2009 Identification of MYO18A as a novel interacting partner of the PAK2/betaPIX/GIT1 complex and its potential function in modulating epithelial cell migration. Molecular biology of the cell 66 19923322
2010 TGF-β induces TIAF1 self-aggregation via type II receptor-independent signaling that leads to generation of amyloid β plaques in Alzheimer's disease. Cell death & disease 52 21368882
2003 Genome structure and differential expression of two isoforms of a novel PDZ-containing myosin (MysPDZ) (Myo18A). Journal of biochemistry 43 12761286
2021 The Smad4-MYO18A-PP1A complex regulates β-catenin phosphorylation and pemigatinib resistance by inhibiting PAK1 in cholangiocarcinoma. Cell death and differentiation 41 34799729
2005 The N-terminal domain of MYO18A has an ATP-insensitive actin-binding site. Biochemistry 38 15835906
2017 MYO18A: An unusual myosin. Advances in biological regulation 34 28942352
2012 TIAF1 self-aggregation in peritumor capsule formation, spontaneous activation of SMAD-responsive promoter in p53-deficient environment, and cell death. Cell death & disease 31 22534828
2015 WWOX dysfunction induces sequential aggregation of TRAPPC6AΔ, TIAF1, tau and amyloid β, and causes apoptosis. Cell death discovery 30 27551439
1998 Cloning and characterization of a novel transforming growth factor-beta1-induced TIAF1 protein that inhibits tumor necrosis factor cytotoxicity. Biochemical and biophysical research communications 30 9918798
2009 Identification of a MYO18A-PDGFRB fusion gene in an eosinophilia-associated atypical myeloproliferative neoplasm with a t(5;17)(q33-34;q11.2). Genes, chromosomes & cancer 29 19006078
2019 A p53/TIAF1/WWOX triad exerts cancer suppression but may cause brain protein aggregation due to p53/WWOX functional antagonism. Cell communication and signaling : CCS 26 31315632
2005 Subcellular localization and dynamics of MysPDZ (Myo18A) in live mammalian cells. Biochemical and biophysical research communications 26 15582604
2015 SP-R210 (Myo18A) Isoforms as Intrinsic Modulators of Macrophage Priming and Activation. PloS one 24 25965346
2014 Binding of the extreme carboxyl-terminus of PAK-interacting exchange factor β (βPIX) to myosin 18A (MYO18A) is required for epithelial cell migration. Biochimica et biophysica acta 19 25014165
2004 A novel 110 kDa form of myosin XVIIIA (MysPDZ) is tyrosine-phosphorylated after colony-stimulating factor-1 receptor signalling. The Biochemical journal 17 14969583
2004 TIAF1 and p53 functionally interact in mediating apoptosis and silencing of TIAF1 abolishes nuclear translocation of serine 15-phosphorylated p53. DNA and cell biology 16 14965474
2013 Self-aggregating TIAF1 in lung cancer progression. Translational respiratory medicine 15 27234387
2012 A three-way translocation of MLL, MLLT11, and the novel reciprocal partner gene MYO18A in a child with acute myeloid leukemia. Cancer genetics 15 22682626
2003 High expression of TIAF-1 in chronic kidney and liver allograft rejection and in activated T-helper cells. Transplantation 15 12829915
2020 Intratumor Heterogeneity of MYO18A and FBXW7 Variants Impact the Clinical Outcome of Stage III Colorectal Cancer. Frontiers in oncology 14 33194745
2003 TIAF1 participates in the transforming growth factor beta1--mediated growth regulation. Annals of the New York Academy of Sciences 11 12814935
2017 Multiple MYO18A-PDGFRB fusion transcripts in a myeloproliferative neoplasm patient with t(5;17)(q32;q11). Molecular cytogenetics 10 28261327
2021 Genomic and epigenomic adaptation in SP-R210 (Myo18A) isoform-deficient macrophages. Immunobiology 6 34735924
2025 Golgicide A induces pyroptosis of lung cancer stem cells by regulating dTGN formation via GOLPH3/MYO18A complex. Stem cell research & therapy 4 40055842
2024 Are the class 18 myosins Myo18A and Myo18B specialist sarcomeric proteins? Frontiers in physiology 4 38784114
2023 Tanc1/2 TPR domain interacts with Myo18a C-terminus and undergoes liquid-liquid phase separation. Biochimica et biophysica acta. Molecular cell research 3 38092135
2026 Oncogenic receptor tyrosine kinase signaling is driven by the Golgi protein GOLPH3 and its interaction with MYO18A. Science signaling 0 42154838

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